Loss to follow-up and mortality among HIV-infected adolescents receiving antiretroviral therapy in Pune, India.

OBJECTIVES: India has the highest number of HIV-infected adolescents in Asia, but little is known about their treatment outcomes. We assessed rates and factors associated with loss to follow-up (LTFU) and mortality among Indian adolescents. METHODS: The analysis included adolescents (10-19 years old) starting antiretroviral therapy (ART) between 2005 and 2014 at BJ Government Medical College, Pune, India. LTFU was defined as missing more than three consecutive monthly visits. The competing-risks method was used to calculate subdistribution hazard ratios (SHRs) of predictors for LTFU, with death as the competing risk. Cox proportional hazard models were used to identify predictors of mortality. RESULTS: Of 717 adolescents starting ART, 402 with complete data were included in the analysis. Of these, 61% were male and 80% were perinatally infected, and the median baseline CD4 count was 174 cells/µL. LTFU and mortality rates were 4.4 and 4.9/100-person years, respectively. Cumulative LTFU incidence increased from 6% to 15% over 6 years. Age ≥ 15 years [adjusted SHR (aSHR) 2.44; 95% confidence interval (CI) 1.18-5.02] was a risk factor for LTFU. Cumulative mortality increased from 9.5% to 17.9% over 6 years. World Health Organization (WHO) stages III and IV [adjusted hazard ratio (aHR) 2.26; 95% CI: 1.14-4.48] and an increase in CD4 count by 100 cells/µL (aHR: 0.59; 95% CI: 0.43-0.83) were associated with mortality. CONCLUSIONS: A third of adolescents had been lost to follow-up or died by follow-up year 6. Older age was a risk factor for LTFU and advanced clinical disease for death. Strategies to improve retention counselling for older adolescents and closer clinical monitoring of all adolescents must be considered.

Impact of maternal hepatitis B virus coinfection on mother-to-child transmission of HIV.

OBJECTIVES: Despite high hepatitis B virus (HBV) endemicity in various resource-limited settings (RLSs), the impact of maternal HIV/HBV coinfection on infant health outcomes has not been defined. We aimed to assess the prevalence of HBV coinfection among HIV-infected pregnant women and its impact on HIV transmission and infant mortality. METHODS: In this study, the seroprevalence of HBV coinfection was determined among HIV-infected pregnant women enrolled in the Six-Week Extended-Dose Nevirapine (SWEN) India trial. The impact of maternal HIV/HBV coinfection on mother-to-child transmission (MTCT) of HIV and infant mortality was assessed using univariate and multivariate logistic regression analysis. RESULTS: Among 689 HIV-infected pregnant Indian women, 32 (4.6%) had HBV coinfection [95% confidence interval (CI) 3.4%, 5.3%]. HBV DNA was detectable in 18 (64%) of 28 HIV/HBV-coinfected women; the median HBV viral load was 155 copies/mL [interquartile range (IQR) < 51-6741 copies/mL]. Maternal HIV/HBV coinfection did not increase HIV transmission risk [adjusted odds ratio (aOR) 1.06; 95% CI 0.30, 3.66; P = 0.93]. Increased odds of all-cause infant mortality was noted (aOR 3.12; 95% CI 0.67, 14.57; P = 0.15), but was not statistically significant. CONCLUSIONS: The prevalence of active maternal HBV coinfection in HIV-infected pregnant women in India was 4.6%. HIV/HBV coinfection was not independently associated with HIV transmission.

Bloodstream infections in neonates with central venous catheters in three tertiary neonatal intensive care units in Pune, India.

BACKGROUND: Neonates admitted to the neonatal intensive care unit (NICU) are at risk for healthcare-associated infections, including central line-associated bloodstream infections. We aimed to characterize the epidemiology of bloodstream infections among neonates with central venous catheters admitted to three Indian NICUs. METHODS: We conducted a prospective cohort study in three tertiary NICUs, from May 1, 2017 until July 31, 2019. All neonates admitted to the NICU were enrolled and followed until discharge, transfer, or death. Cases were defined as positive blood cultures in neonates with a central venous catheter in place for greater than 2 days or within 2 days of catheter removal. RESULTS: During the study period, 140 bloodstream infections were identified in 131 neonates with a central venous catheter. The bloodstream infection rate was 11.9 per 1000 central line-days. Gram-negative organisms predominated, with 38.6% of cases caused by Klebsiella spp. and 14.9% by Acinetobacter spp. Antimicrobial resistance was prevalent among Gram-negative isolates, with 86.9% resistant to third- or fourth-generation cephalosporins, 63.1% to aminoglycosides, 61.9% to fluoroquinolones, and 42.0% to carbapenems. Mortality and length of stay were greater in neonates with bloodstream infection than in neonates without bloodstream infection (unadjusted analysis, p < 0.001). CONCLUSIONS: We report a high bloodstream infection rate among neonates with central venous catheters admitted to three tertiary care NICUs in India. Action to improve infection prevention and control practices in the NICU is needed to reduce the morbidity and mortality associated with BSI in this high-risk population.

Performance of Xpert® MTB/RIF and Xpert® Ultra for the diagnosis of tuberculous meningitis in children.

OBJECTIVE: To assess Xpert® MTB/RIF (Xpert) and Xpert® MTB/RIF Ultra (Ultra) performance in diagnosing pediatric tuberculous meningitis (TBM).METHODS: We conducted a study among children with suspected meningoencephalitis in Pune, India. Clinical, radiological, laboratory, and treatment data were analyzed to classify disease as definite, probable, possible or no TBM, using microbiologic or composite reference standards. We tested cerebrospinal fluid (CSF) either using Xpert or Ultra and estimated test performance characteristics.RESULTS: Of 341 participants, 149 (43.7%) were tested using Ultra and 192 (56.3%) with Xpert. Ultra had higher sensitivity (50% vs. 18%), lower specificity (91% vs. 99%), poor positive predictive value (PPV) (13% vs. 75%), and higher negative predictive value (NPV) (99% vs. 93%) than Xpert using the composite reference standard, with similar results by the microbiologic reference standard. Of 10 participants with trace positivity on Ultra, none met clinical TBM definitions.CONCLUSION: This is the first study to report on diagnostic performance of Ultra in pediatric TBM, which showed higher sensitivity and NPV than Xpert. For children presenting with nonspecific clinical features, Ultra is a promising diagnostic test. Further studies are required to define its optimal clinical use, including interpretation of trace positive results.

Concomitant pulmonary disease is common among patients with extrapulmonary TB.

BACKGROUND: Microbiologic screening of extrapulmonary TB (EPTB) patients could inform recommendations for aerosol precautions and close contact prophylaxis. However, this is currently not routinely recommended in India. Therefore, we estimated the proportion of Indian patients with EPTB with microbiologic evidence of pulmonary TB (PTB).METHODS: We characterized baseline clinical, radiological and sputum microbiologic data of 885 adult and pediatric TB patients in Chennai and Pune, India, between March 2014 and November 2018.RESULTS: Of 277 patients with EPTB, enhanced screening led to the identification of 124 (45%) with concomitant PTB, including 53 (19%) who reported a cough >2 weeks; 158 (63%) had an abnormal CXR and 51 (19%) had a positive sputum for TB. Of 70 participants with a normal CXR and without any cough, 14 (20%) had a positive sputum for TB. Overall, the incremental yield of enhanced screening of patients with EPTB to identify concomitant PTB disease was 14% (95% CI 12-16).CONCLUSIONS: A high proportion of patients classified as EPTB in India have concomitant PTB. Our results support the need for improved symptom and CXR screening, and recommends routine sputum TB microbiology screening of all Indian patients with EPTB.

Incidence of malaria--three years prospective study.

Malaria continues to be one of the major health problems in India. The India has witnessed a spectacular achievement in 1960's (1964) but a comeback lateron. A continued rise of Plasmodium falciparum was observed in many areas. The study was undertaken to analyze the incidence of malaria and compare the rapid diagnostic test--Immunochromatographic technique (ICT-Malaria) with conventional Giemsa staining. A total of 14,092 peripheral blood smears were screened for malaria. Plasmodium falciparum (57.82%) was major species followed by Plasmodium vivax (42.18%). More cases were found in males (54.56%) and in younger age group (1-12 yrs) and (21-30 yrs). We found the ICT Malaria test sensitivity (99.03%) and specificity (99.9%) as compared to blood smear positivity. The ICT Malaria test found to be easy, less time consuming and with diagnostic accuracy as equivalent to gold standard that is conventional Giemsa staining.

Measuring TB drug levels in the hair in adults and children to monitor drug exposure and outcomes.

INTRODUCTION: Testing for anti-TB drugs in small hair samples may serve as a non-invasive tool to measure cumulative drug exposure and/or adherence, as these determine treatment success. We aimed to assess how well hair assays of TB drugs predict TB treatment outcomes.METHODS: A small thatch of hair, ~30 strands, was cut from the occipital region in adults and children from a prospective TB cohort in India. Isoniazid (INH), acetyl-INH and pyrazinamide (PZA) were extracted from the hair samples and quantified using liquid-chromatography-tandem mass spectrometry. The relationship between drug concentrations in hair and time to unfavourable outcomes was assessed using Cox-proportional hazards regression models.RESULTS: A two-fold increase in hair acetyl-INH concentrations in the 264 participants in our cohort with hair assays for TB drugs indicated a lower hazard of unfavourable TB treatment outcomes (aHR 0.67, 95%CI 0.44-1.02) and TB treatment failure (aHR 0.65, 95%CI 0.42-1.01). Higher summed concentrations (a summed measure of INH and acetyl-INH) indicated a lower hazard of treatment failure (aHR 0.69, 95%CI 0.45-1.05)CONCLUSION: Hair levels of INH and its metabolite may predict TB treatment outcomes, indicating the potential utility of this measure to assess and optimise TB treatment outcomes.

Shewanelia putrefaciens: a rare microbial agent associated with a non-healing ulcer in a leprosy patient.

Female aged 55 years presented with signs and symptoms of borderline lepromatous leprosy and presence of a non-healing ulcer and multiple haemorrhagic blisters over dorsum of both feet. Discharge from the various lesions was subjected to microbiological examination and an unusual organism Shewanella purtefaciens was isolated which was sensitive to most routine antibiotics. Patient responded well to cephadroxil therapy with uneventful and complete healing of ulcer and blisters.

Challenges in conducting trials for pediatric tuberculous meningitis: lessons from the field.

SETTING: TBM-KIDS is a phase I/II trial enrolling children with tuberculous meningitis (TBM) in three tertiary referral centers in India and Malawi.OBJECTIVE: To describe the challenges encountered in conducting the first randomized clinical trial of antimicrobial agents in pediatric TBM.DESIGN: The sources of the data were primarily monthly trial reports, non-enrollment case report forms, study diaries and registers maintained for recruitment, experiences shared by key team members during regular study calls and comments from site review visits. We reviewed, broadly categorized, and describe in detail the challenges encountered by study teams in trial implementation.RESULTS: Over 17 months, 3371 children with clinical presentations consistent with meningoencephalitis or undergoing lumbar puncture were assessed for eligibility; 21 (<1%) met enrollment criteria. We encountered challenges related to diagnosis, management of sick children, large catchment areas, adverse event attribution, concomitant medications, infrastructure requirements, expensive pediatric formulations with short expiry, and detection of treatment response in a highly variable disease across the age continuum. Training and adaptation of tools for neurocognitive and neurologic function assessment were necessary. Special care was undertaken to explain study participation to distraught caregivers and manage children longitudinally.CONCLUSION: Interventional trials in pediatric TBM are challenging but are critically important for improving the treatment of a disease that disables children physically, cognitively and emotionally. Sharing these challenges may help to address them more effectively as a TB research community and to advance treatments for this at-risk population.

Delays and barriers to early treatment initiation for childhood tuberculosis in India.

BACKGROUND: India accounts for 27% of global childhood tuberculosis (TB) burden. Understanding barriers to early diagnosis and treatment in children may improve care and outcomes.METHODS: A cross-sectional study was performed among 89 children initiated on anti-TB treatment from a public hospital in Pune during 2016, using a structured questionnaire and hospital records. Health care providers (HCPs) were defined as medical personnel consulted about the child's TB symptoms. Time-to-treatment initiation (TTI) was defined as the number of days between onset of TB symptoms and anti-TB treatment initiation. Based on Revised National TB Control Programme recommendations, delayed TTI was defined as >28 days.RESULTS: Sixty-seven (75%) of 89 enrolled children had significant TTI delays (median 51 days, interquartile range [IQR] 27-86). Sixty-six (74%) children visited 1-8 HCPs in the private sector before approaching the public sector. The median HCP delay was 28 days (IQR 10-75). Bacille Calmette-Guérin vaccination (aOR 10.96, P = 0.04) and loss of appetite (aOR 4.44, P = 0.04) were associated with delayed TTI.CONCLUSION: The majority of the children had TTI delays due to delays by HCPs in the private sector. Strengthening HCP competency in TB symptom screening and encouraging early referrals are crucial for rapid scaling up of early treatment initiation in childhood TB.

Barriers to screening and isoniazid preventive therapy for child contacts of tuberculosis patients.

BACKGROUND: India's guidelines recommend tuberculosis (TB) screening of household contacts aged <6 years and isoniazid preventive therapy (IPT) for children without active disease. We evaluated the current status and barriers to screening and IPT provision among the child contacts of TB patients. METHODS: Questionnaire and health record data were collected from index cases and health care providers (HCPs) at Sassoon General Hospital, Pune, India. RESULTS: Of 80 adult TB cases, 24 (30%) reported that an HCP recommended TB screening of their child contacts; 49/178 (28%) child contacts were screened. Sixteen (33%) children had active TB, and 28 (85%) of those who screened negative were prescribed IPT. Nineteen (76%) HCPs reported recommending child contact screening. Only 8 (32%) reported ever prescribing IPT. Lack of TB screening and IPT provision for child contacts was associated with inadequate HCP counseling (aOR 19.5, P < 0.001), a non-parent index case (aOR 3.72, P = 0.008) and lack of postgraduate HCP qualification (aOR 19.12, P = 0.04). CONCLUSIONS: TB screening and IPT provision for child contacts of adults with TB were infrequent. Many screened children had active TB. Universal, timely TB screening and IPT for exposed children are urgently needed to reduce pediatric TB in India.

Novel interferon-gamma assays for diagnosing tuberculosis in young children in India.

SETTING: The tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are used as supportive evidence to diagnose active tuberculosis (TB). Novel IGRAs could improve diagnosis, but data are lacking in young children. DESIGN: Children (age 5 years) with suspected TB were prospectively screened at a tertiary hospital in Pune, India; the children underwent TST, and standard (early secretory antigenic target 6 and culture filtrate protein 10) and enhanced (five additional novel antigens) enzyme-linked immunospot (ELISpot) assays. RESULTS: Of 313 children (median age 30 months) enrolled, 92% had received bacille Calmette-Guérin vaccination, 53% were malnourished and 9% were coinfected with the human immunodeficiency virus (HIV); 48 (15%) had TB, 128 (41%) did not, and TB could not be ruled out in 137 (44%). The sensitivity of enhanced (45%) and standard (42%) ELISpot assays for diagnosing TB was better than that of TST (20%) (P  0.03); however, enhanced ELISpot was not more sensitive than the standard ELISpot assay (P = 0.50). The specificity of enhanced ELISpot, standard ELISpot and TST was respectively 82% (95%CI 74-89), 88% (95%CI 81-94) and 98% (95%CI 93-100). Rv3879c and Rv3615c, previously reported to be promising antigens, failed to improve the diagnostic performance of the ELISpot assay. CONCLUSION: The TST and the standard and novel ELISpot assays performed poorly in diagnosing active TB among young children in India.

Isoniazid hair concentrations in children with tuberculosis: a proof of concept study.

Assessing treatment adherence and quantifying exposure to anti-tuberculosis drugs among children is challenging. We undertook a 'proof of concept' study to assess the drug concentrations of isoniazid (INH) in hair as a therapeutic drug monitoring tool. Children aged <12 years initiated on a thrice-weekly treatment regimen including INH (10 mg/kg) for newly diagnosed tuberculosis were enrolled. INH concentrations in hair were measured using liquid chromatography-tandem mass spectrometry at 1, 2, 4 and 6 months after initiating anti-tuberculosis treatment. We found that INH hair concentrations in all children on thrice-weekly INH were detectable and displayed variability across a dynamic range.

Epidemiology of streptococcal infection with reference to rheumatic fever.

Antistreptolysin antibodies were estimated in 787 normal children and young adults by latex test. This test detects titres of 200 IU/ml and above, which is the western cut off point, for diagnosis. Children below one year showed no antibodies. Unlike western studies where no antibodies are detected below the age of 3 years, our study revealed that 7.9% children between 1-3 years had significantly elevated antibodies. This epidemiological pattern is well reflected in the different clinical profile of younger children developing rheumatic heart disease in our country. Antibodies progressively increased with age--11.8% in 4-8 years group to 15.8% in 9-12 years age group. All these were from the lower socio-economic group. ASO was positive in 16.7% of young adults from lower socio-economic status while it was positive only in 9.2% in the upper socio-economic status. A total of 522 patients of rheumatic carditis were studied. Only 23.4% had no antibodies or less than 200 IU/ml, and 77% were positive (26.9% had greater than 400 IU/ml and 49.7% had 200 IU/ml). Throat swab culture and ASO antibodies were done simultaneously in 76 outdoor patients, clinically diagnosed as acute bacterial pharyngitis. Group A beta hemolytic streptococci were isolated in 64% and significant antistreptolysin antibodies were seen in 62%. School health records were scanned in more than 50,000 school children. Point prevalence of rheumatic heart disease was estimated to be 0.17% in lower and 0.05% in upper socio-economic groups. Age and socio-economic factors are important variables in epidemiology of streptococcal infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Modifiable risk factors associated with tuberculosis disease in children in Pune, India.

SETTING: India accounts for the largest burden of tuberculosis (TB) worldwide, with 26% of the world's cases. OBJECTIVE: To assess the association between novel modifiable risk factors and TB in Indian children. DESIGN: Cases were children aged ≤ 5 years with confirmed/probable TB based on World Health Organization definitions (definition 1). Controls were healthy children aged ≤ 5 years. Logistic regression was performed to estimate the adjusted odds ratio (aOR) of being a TB case given exposure, including indoor air pollution (IAP; exposure to tobacco smoke and/or biomass fuels) and vitamin D deficiency. Cases were re-analyzed according to a new consensus research definition of pediatric TB (definition 2). RESULTS: Sixty cases and 118 controls were enrolled. Both groups had high levels of vitamin D deficiency (55% vs. 50%, P = 0.53). In multivariable analysis, TB was associated with household TB exposure (aOR 25.41, 95%CI 7.03-91.81), household food insecurity (aOR 11.55, 95%CI 3.33-40.15) and IAP exposure (aOR 2.67, 95%CI 1.02-6.97), but not vitamin D deficiency (aOR 1.00, 95%CI 0.38-2.66). Use of definition 2 reduced the number of cases to 25. In multivariate analysis, TB exposure, household food insecurity and IAP remained associated with TB. CONCLUSIONS: Household TB exposure, exposure to IAP and household food insecurity were independently associated with pediatric TB.

Oral fluid, a substitute for serum to monitor measles IgG antibody?

We have analyzed the suitability and potential of Oral Fluid (OF) to substitute serum in estimating measles IgG antibodies, during community surveys, by comparing the Optical Density (OD) of measles IgG antibodies in OF and serum of 100 apparently asymptomatic children. IgG antibody status was determined using commercially available - Measles IgG Capture ELISA. Sensitivity 89.5%, specificity 90.6% Concordance of 89%, coefficient of correlation r is equal to 0.97 (Karl Pearson's) and rho is equal to 0.86 (Spearman's), was found between OD value of OF and serum. The study emphasizes the potential of OF to surrogate serum in estimating Measles IgG antibody among children. The OF collection is advantageous over blood as it is painless. It is suitable for non-technical staff, easy to transport and less bio-hazardous.

Hepatitis B Prevalence during pregnancy.

In order to determine the efficacy of a new hepatitis B immune globulin (HBIG), a phase 3, vertical transmission (mother to child) clinical interventional trial of hepatitis B virus (HBV) post exposure prophylaxis (PEP) was conducted at selected sites (n=15) throughout India. This required a large screening program for HBsAg positivity at prenatal clinics located in tertiary care hospitals. 36,379 pregnant women consented to be tested for Hepatitis B surface antigen (HBsAg) by Rapid Test and if positive-confirmed by ELISA. The weighted mean prevalence was 0.82% (95% CI, 0.72, 0.91). In conclusion, the prevalence of HBV carrier state during pregnancy in India in this study was low compared to previous reports.