Incident TB Research Articles

P-779. Macronutrient Status and Risk of Tuberculosis vs. Other Lower Respiratory Tract Infections

Abstract Background Nutritional status is a major risk factor for incident tuberculosis disease (TB), but the underlying biological mechanisms remain unknown. If this effect is mediated immunologically, then other lower respiratory tract infections (LRTI) that elicit different immune responses would differ in this regard. If it is due to “body habitus,” then a similar association might be seen in anatomically similar infections. We compared the effect of nutritional status on TB, pneumococcal pneumonia (pneumonia), and influenza pneumonia (flu). Methods The first National Health and Nutrition Examination Survey (NHANES-I) provided data on baseline nutritional status of a probability sample of the US population, 1971-1975. Nutrition indicators included body mass index (BMI), skinfold thickness (SFT), cross-sectional upper arm muscle area (AMA), serum albumin, serum vitamin A, and iron status. The NHANES-I Epidemiological Follow-up Study provided follow-up data through 1992. Incident TB, pneumonia, and flu were ascertained through ICD9 codes in medical records and death certificates. For each nutrition indicator, we compared population-estimated percentages of those who later develop TB, pneumonia, and flu. Results An estimated 1.2% of the population developed TB: 9.6% (95% CI: 4.3, 15.0) of those with BMI < 18.5 kg/m2) developed TB compared with 1% (0.5, 1.4) of those with normal BMI, 18.5-25 kg/m2, and 0.4% (0.1, 0.6) of those with BMI 25-30 kg/m2 (Table 1). In contrast, BMI was not associated with developing pneumonia or flu. Like BMI, SFT and AMA were also inversely associated with incident TB but not with flu or pneumonia. In fact, pneumonia had an “U”-shaped association with AMA (Table 1). Among those with hypoalbuminemia (≤3.5 g/dL), 12.8% (0, 32.5) developed TB versus 0.8% (0.4, 1.2) of those with normal albumin >3.5 g/dL. Serum albumin was not associated with incident pneumonia or flu. Serum Vitamin A and iron deficiency were not associated with any of these three LRTI. Conclusion These differences suggest host defenses against TB, mainly adaptive cell-mediated immune responses, are sensitive to macronutrient status while the acute granulocytic and innate humoral defenses against other LRTI pathogens are not affected in the same way. Disclosures All Authors: No reported disclosures

Identifying local foci of tuberculosis transmission in Moldova using a spatial multinomial logistic regression model

BackgroundMultidrug resistant tuberculosis (MDR-TB) represents a major public health concern in the Republic of Moldova, with an estimated 31% of new and 56% of previously treated TB cases having MDR disease in 2022. A recent genomic epidemiology study of incident TB occurring in 2018 and 2019 found that 92% of MDR-TB was the result of transmission. The MDR phenotype was concentrated among two M. tuberculosis (Mtb) lineages: L2.2.1 (Beijing) and L4.2.1 (Ural). MethodsWe developed and applied a hierarchical Bayesian multinominal logistic regression model to Mtb genomic, spatial, and epidemiological data collected from all individuals with diagnosed TB in Moldova in 2018 and 2019 to identify locations in which specific Mtb strains are being transmitted. We then used a logistic regression model to estimate locality-level factors associated with local transmission. FindingsWe found differences in the spatial distribution and degree of local concentration of disease due to specific strains of Beijing and Ural lineage Mtb. Foci of transmission for four strains of Beijing lineage Mtb, predominantly of the MDR-TB phenotype, were located in several regions, but largely concentrated in Transnistria. In contrast, transmission of Ural lineage Mtb had less marked patterns of spatial aggregation, with a single strain (also of the MDR phenotype) spatially clustered in southern Transnistria. We found a 30% (95% credible interval 2%-80%) increase in odds of a locality being a transmission cluster for each increase of 100 persons per square kilometer, while higher local tuberculosis incidence and poverty were not associated with a locality being a transmission focus. InterpretationOur results identified localities where specific Mtb transmission networks were concentrated and quantified the association between locality-level factors and focal transmission. This analysis revealed Transnistria as the primary area where specific Mtb strains (predominantly of the MDR-TB phenotype) were locally transmitted and suggests that targeted intensified case finding in this region may be an attractive policy option.

Who Transmits Tuberculosis to Whom: A Cross-Sectional Analysis of a Cohort Study in Lima, Peru.

Rationale: The persistent burden of tuberculosis (TB) disease emphasizes the need to identify individuals with TB for treatment and those at a high risk of incident TB for prevention. Targeting interventions toward those at high risk of developing and transmitting TB is a public health priority. Objectives: We aimed to identify characteristics of individuals involved in TB transmission in a community setting, which may guide the prioritization of targeted interventions. Methods: We collected clinical and sociodemographic data from a cohort of patients with TB in Lima, Peru. We used whole-genome sequencing data to assess the genetic distance between all possible pairs of patients; we considered pairs to be the result of a direct transmission event if they differed by three or fewer SNPs, and we assumed that the first diagnosed patient in a pair was the transmitter and the second was the recipient. We used logistic regression to examine the association between host factors and the likelihood of direct TB transmission. Measurements and Main Results: Analyzing data from 2,518 index patients with TB, we identified 1,447 direct transmission pairs. Regardless of recipient attributes, individuals less than 34 years old, males, and those with a history of incarceration had a higher likelihood of being transmitters in direct transmission pairs. Direct transmission was more likely when both patients were drinkers or smokers. Conclusions: This study identifies men, young adults, former prisoners, alcohol consumers, and smokers as priority groups for targeted interventions. Innovative strategies are needed to extend TB screening to social groups such as young adults and prisoners with limited access to routine preventive care.

Management of drug-resistant tuberculosis in Indonesia: a four-year cascade of care analysis

In Indonesia, drug resistance testing for TB largely relies on Xpert MTB/RIF, and it is unknown what proportion of drug-resistant (DR) TB is adequately diagnosed and treated. We conducted a cascade of care analysis on a cohort of presumptive rifampicin-resistant (RR) TB patients registered in 2015-2018 in a tertiary hospital in Indonesia. Estimated incidences of (presumptive) DR-TB cases were assumption-based using global reports. Data on diagnosis and consecutive cascades steps, including their timing were collected from national electronic registers, and medical records. We described a secondary cascade for patients receiving treatment not supported by phenotypic drug susceptibility testing (pDST). Factors associated with delay and loss between diagnosis and treatment were identified using logistic regression. Less than a third of estimated incident TB cases at risk of DR-TB were identified as presumptive DR-TB case and tested, and 9.8% (982/10,065) of estimated true DR-TB cases was diagnosed. Of those diagnosed, only 45.1% (443/982) had treatment regimens supported by pDST results, but this did not significantly influence treatment outcomes. Only 25.5% (250/982) of diagnosed patients completed all steps of the cascade including successful treatment. Delays between diagnosis and treatment were substantial, and more common among those referred from a primary healthcare facility, and among those who were employed, living outside of Bandung, and reporting engagement with the private sector. The DR-TB care cascade in this urban setting in Indonesia is characterized by substantial attrition and delays. Strategies to increase access to DR-TB diagnosis accompanied by optimisation of clinical care could substantially improve outcomes and reduce onward transmission. Radboud university medical center and University of Otago.

Blurring cluster randomized trials and observational studies: Two-Stage TMLE for subsampling, missingness, and few independent units.

Cluster randomized trials (CRTs) often enroll large numbers of participants; yet due to resource constraints, only a subset of participants may be selected for outcome assessment, and those sampled may not be representative of all cluster members. Missing data also present a challenge: if sampled individuals with measured outcomes are dissimilar from those with missing outcomes, unadjusted estimates of arm-specific endpoints and the intervention effect may be biased. Further, CRTs often enroll and randomize few clusters, limiting statistical power and raising concerns about finite sample performance. Motivated by SEARCH-TB, a CRT aimed at reducing incident tuberculosis infection, we demonstrate interlocking methods to handle these challenges. First, we extend Two-Stage targeted minimum loss-based estimation to account for three sources of missingness: (i) subsampling; (ii) measurement of baseline status among those sampled; and (iii) measurement of final status among those in the incidence cohort (persons known to be at risk at baseline). Second, we critically evaluate the assumptions under which subunits of the cluster can be considered the conditionally independent unit, improving precision and statistical power but also causing the CRT to behave like an observational study. Our application to SEARCH-TB highlights the real-world impact of different assumptions on measurement and dependence; estimates relying on unrealistic assumptions suggested the intervention increased the incidence of TB infection by 18% (risk ratio [RR]=1.18, 95% confidence interval [CI]: 0.85-1.63), while estimates accounting for the sampling scheme, missingness, and within community dependence found the intervention decreased the incident TB by 27% (RR=0.73, 95% CI: 0.57-0.92).

The impact of a combined TB/HIV intervention on the incidence of TB infection among adolescents and young adults in the HPTN 071 (PopART) trial communities in Zambia and South Africa.

HPTN071 (PopART) was a cluster randomized trial conducted in Zambian and South African (SA) communities, between 2013-2018. The PopART intervention (universal HIV-testing and treatment (UTT) combined with population-level TB symptom screening) was implemented in 14 communities. The TREATS study (2017-2021) was conducted to evaluate the impact of the PopART intervention on TB outcomes. We report on the impact of the combined TB/HIV intervention on the incidence of TB infection in a cohort of adolescents and young adults (AYA) aged 15-24 years. A random sample of AYA was enrolled between July 2018 and July 2019 in 7 intervention vs 7 standard-of-care communities. We collected questionnaire data on risk factors for TB, and blood for measuring TB infection using QuantiFERON (QFT) Plus. AYA were seen at months 12 and 24 with all procedures repeated. Primary outcome was incidence of TB infection comparing intervention and standard-of-care communities. An incident case was defined as a participant with QFT interferon-gamma response of < 0.2 IU/ml plasma ('negative') at baseline and a QFT interferon-gamma response of > = 0.7 IU/ml ('positive') at follow up. We enrolled 4,648 AYA, 2,223 (47.8%) had a negative QFT-plus result at baseline, 1,902 (85.6%) had a follow up blood sample taken at 12 months or 24 months. Among the 1,902 AYA, followed for 2,987 person-years, 213 had incident TB infection giving (7.1 per 100 person-years). TB infection incidence rates were 8.7 per 100 person-years in intervention communities compared to 6.0 per 100 person-years in standard-of-care communities. There was no evidence the intervention reduced the transmission of TB (incidence-rate-ratio of 1.45, 95%CI 0.97-2.15, p = 0.063). In our trial setting, we found no evidence that UTT combined with TB active case finding reduced the incidence of TB infection at population level. Our data will inform future modelling work to better understand the population level dynamics of HIV and TB.

A study of an Incidence of tuberculosis is linked to elevated hepcidin at HIV diagnosis

Background: Hepcidin prevents ferroportin-mediated iron efflux, which results in intracellular macrophage iron retention and may encourage Mycobacterium tuberculosis nutrient absorption and TB pathogenesis. Aims &amp; Objectives: In order to research into the relationship between incident pulmonary and extrapulmonary TB and plasma hepcidin levels, a retrospective cohort of HIV-positive, antiretroviral-native individuals had their plasma hepcidin levels tested at HIV diagnosis. Methods &amp; Materials: Between 5 August 2017 and 1 June 2019, 140 individuals were monitored, and 34 incident TB cases were found. Discussion: After a median time to TB of 7 months, higher hepcidin was linked to a significantly increased chance of TB. Conclusion: The need for time-sensitive biomarkers that can detect individual variations in TB risk and the elucidation of iron-related causative pathways cannot be overstated.

Contribution of remote M.tuberculosis infection to tuberculosis disease: A 30-year population study.

The importance of remote infection with M.tuberculosis as a cause of tuberculosis disease (TB) is unclear, with limited evidence of impact on TB rates beyond 10 years. Our objective was to assess rates of tuberculosis over 30 years by M.tuberculosis infection status at baseline in Karonga District, Northern Malawi. Population-based surveys of tuberculin skin testing (TST) from the 1980s were linked with follow-up and TB surveillance in Karonga district. We compared rates of microbiologically-confirmed TB by baseline TST induration <5mm (no evidence of M.tuberculosis infection) and those with baseline TST >17mm (evidence of M.tuberculosis infection), using hazard ratios by time since baseline and attributable risk percent. The attributable risk percent was calculated to estimate the proportion of TB in those infected that can be attributed to that prior infection. We analysed whole genome sequences of M.tuberculosis strains to identify recent transmission. Over 412,959 person-years, 208 incident TB episodes were recorded. Compared to the small induration group, rates of TB were much higher in the first two years in the large induration group, and remained higher to 20 years: age, sex and area-adjusted hazard ratios (HR) 2-9 years post-TST 4.27 (95%CI 2.56-7.11); 10-19 years after TST 2.15 (1.10-4.21); ≥20 years post-TST 1.88 (0.76-4.65). The attributable risk percent of remote infection was 76.6% (60.9-85.9) 2-9 years post-TST, and 53.5% (9.1-76.2) 10-19 years post-TST. Individuals with large TST indurations had higher rates of unique-strain TB (HR adjusted for age, sex and area = HR 6.56 (95% CI 1.96-22.99)), suggesting disease following remote infection, but not of linked-strain TB (recent transmission). M.tuberculosis infection can increase the risk of TB far beyond 10 years, accounting for a substantial proportion of TB occurring among those remotely infected.

Comorbidities and New Onset of Type 2 Diabetes Mellitus among Women Living with HIV Receiving Antiretroviral Therapy in Lagos, Nigeria

Background: There is limited gender stratified data in many type 2 diabetes mellitus (T2DM) studies in Africa. This study aimed to determine the prevalence of Comorbidities, New Onset of T2DM and risk factors influencing predisposition to T2DM among women living with HIV (WLWH) and receiving Antiretroviral Therapies. Methods: This was a cross-sectional study of females who were 15 years and above with HIV and/or without pulmonary TB attending HIV and TB DOTS clinics in Lagos, Nigeria from January 2019 to October 2021. The socio-demographic data of participants were obtained using questionnaire. Participants who were not known diabetic cases were tested for diabetes based on WHO and ADA standards using glycated haemoglobin (HbA1c) test, fasting plasma glucose and 2 hour 75 g oral glucose post prandial test. CD4 and CD8 counts were carried out using flow cytometer and their cytokines’ levels were determine using ELISA technique. HIV positive patients with signs and symptoms of TB (presumptive TB) were tested using sputum smear microscopy method and gene X-pert technique. We measured Body mass index (BMI) using International System of Units (kg/m2). Information on age, gender, Antiretroviral therapy (ART), values of CD4, weight, height, viral load and cholesterol test results less than 6 months were obtained from the patients’ folders. Results: A total of 187 WLWH were studied. Their mean age was 41.93±10.32 years. Fifty-five (27.9%) had BMI values of ≥ 30 kg/m2. Twenty-one (11.2%) had impaired glucose level. Those with T2DM at baseline were 5(2.7%), 17(9.1%) later developed T2DM. There was strong association between newly developed T2DM and obesity odd ratio (OR) 8.21(95% CI 1.30-51.99), interleukin (IL-): IL-6 OR 4.50 (95% CI 0.58-35.15), viral load with OR as 1.34(0.48-3.75), knowledge of diabetes OR 2.24 (95% CI 0.43-11.62), consumption of alcohol OR 2.03(95% CI 0.60-6.90). Twenty (10.7%) WLWH developed pulmonary TB while receiving ART. Co-morbidities recorded were: HIV/T2DM 14(7.5%), HIV/TB 21(11.2%), HIV/TB/T2DM 7(3.7%). A total of 42(22.7%) were on 2nd line ART. Conclusion: Prevalence of HIV/TB co-infection, HIV/T2DM comorbidity and HIV/TB/T2DM multimorbidity were high. Also the prevalence of incident TB and new cases of T2DM among the study population were high. There was positive association between development of T2DM while receiving ART and obesity, IL-6, knowledge of diabetes and alcohol consumption. Protease inhibitors were found to influence the development of T2DM among WLWH while receiving ART. Recommendation: There is need for promoting awareness of T2DM and its risk factors among WLWH who are receiving ART.

A spatial-mechanistic model to estimate subnational tuberculosis burden with routinely collected data: An application in Brazilian municipalities.

Reliable subnational estimates of TB incidence would allow national policy makers to focus disease control resources in areas of highest need. We developed an approach for generating small area estimates of TB incidence, and the fraction of individuals missed by routine case detection, based on available notification and mortality data. We demonstrate the feasibility of this approach by creating municipality-level burden estimates for Brazil. We developed a mathematical model describing the relationship between TB incidence and TB case notifications and deaths, allowing for known biases in each of these data sources. We embedded this model in a regression framework with spatial dependencies between local areas, and fitted the model to municipality-level case notifications and death records for Brazil during 2016-2018. We estimated outcomes for 5568 municipalities. Incidence rate ranged from 8.6 to 57.2 per 100,000 persons/year for 90% of municipalities, compared to 44.8 (95% UI: 43.3, 46.8) per 100,000 persons/year nationally. Incidence was concentrated geographically, with 1% of municipalities accounting for 50% of incident TB. The estimated fraction of incident TB cases receiving diagnosis and treatment ranged from 0.73 to 0.95 across municipalities (compared to 0.86 (0.82, 0.89) nationally), and the rate of untreated TB ranged from 0.8 to 72 cases per 100,000 persons/year (compared to 6.3 (4.8, 8.3) per 100,000 persons/year nationally). Granular disease burden estimates can be generated using routine data. These results reveal substantial subnational differences in disease burden and other metrics useful for designing high-impact TB control strategies.

A retrospective longitudinal study on tuberculosis disease among people with HIV

The use of Isoniazid Prevention Therapy (IPT) helps normalize the health issues of patients with TB. The majority of patients suffering from these diseases are from a low-income group with poor education. They do not have adequate knowledge related to prevention and approaches that reduce the occurrence of TB disease soon after ART initiation where risk is higher. The study aims to determine the incidence of tuberculosis disease among patients with HIV while taking IPT and after its completion. This is a retrospective, observational, longitudinal study that used existing records of patients from Department of Pulmonary Medicine, D Y Patil Medical College, Nerul, Navimumbai, Maharashtra, India. The period of the study was from January 2020 to June 2021. STATA statistical software Version 12 was used to analyse the data. The sample size was estimated based on simple proportion formula taking incident TB disease after starting IPT 1.5% based on the study in a similar setting. In this study, 960 patients were involved with mean age of 30 years, ranged between 25-37 years. TB was developed in 9.2% patients, out of which, 2.2% of patients were diagnosed while receiving IPT and 6.97% after IPT. Moreover, 55.2% of patients were on this treatment at the last observation. The unfavourable count of patients was 152 (15.8%). Most of the patients with unfavourable follow-up outcomes were lost to follow-up. 0.6% of patients have stopped treatment during the follow-up and 28.9% was transferred out. Finally, 4.7% of patients died and remaining were recovered. Breakthrough TB was uncommon and shown a significant proportion of it occurrence in the first month of treatment. This could be due to difficulty in diagnosing TB disease with HIV. The proper screening of patients is essential for offering treatment and providing effective care services.

Management of childhood MDR-TB in Europe and Central Asia: report of a Regional WHO meeting.

BACKGROUND: As the WHO European Region has the highest proportion of multidrug-resistant TB (MDR-TB) among total incident TB cases, many children and adolescents are at risk of MDR-TB infection and disease.METHODS: We performed an electronic survey of clinicians and TB programme personnel who attended the 2020 Regional Consultation on child and adolescent TB organised by the WHO Regional Office. We characterised access to diagnostics and drugs, and practices in the prevention and management of child and adolescent MDR-TB.RESULTS: Children and adolescents are inconsistently represented in national guidelines and budgets; child-friendly drug formulations for MDR-TB treatment are insufficiently available in 57% of countries, and 32% of countries reported paediatric drug stock-outs. The novel drugs, bedaquiline and delamanid, are accessible by respectively 80% and 60% of respondent countries. Respondents were asked how many children were diagnosed with MDR-TB in 2019, and a comparison of this number to modelled estimates of incidence (to identify the case detection gap) and WHO notifications (to identify the case reporting gap) showed substantial differences in both comparisons.CONCLUSIONS: Better representation of this patient group in guidelines and budgets, greater access to drugs and improved reporting are essential to reach TB elimination in this Region.

Attributable is preventable: Corrected and revised estimates of population attributable fraction of TB related to undernutrition in 30 high TB burden countries

IntroductionThe Global TB Report 2020 estimated the population attributable fractions (PAF) for the major risk factors of TB. Undernourishment emerged as the leading risk factor accounting for 19% of the cases. The WHO however used the terms undernourishment and undernutrition interchangeably in its computation of PAF. Undernourishment is an indirect model derived estimate of decreased per capita energy availability, while undernutrition is defined by direct anthropometric measurements of nutritional status. An estimate of PAF for a risk factor should use the prevalence and the risk ratio of the same risk factor, which is not the case with the current methodology. MethodsWe re- estimated the PAF of undernutrition (instead of undernourishment) in 30 high TB burden countries as defined by WHO for the period 2016–2020, using the prevalence of undernutrition (age standardized estimate of BMI < 18.5 kg/m2 in adults for both sexes), and the relative risk (RR) of 3.2. Further, we revised PAF estimates of undernutrition with an RR of 4.49 (95% CI: 2.28, 8.86), in light of recent evidence. FindingsIn 30 high TB burden countries, 24.1% (95% CI: 17.6,30.0) of incident TB is attributable to undernutrition. The PAF of undernutrition was highest in Asian countries, unlike the PAF of undernourishment that was highest in Africa. The corrected estimate led up to 65% increase in number of cases attributable to undernutrition in Asian countries. If a revised relative risk was used, 33.0% (95% CI: 10.1, 60.1) of incident TB cases in the selected countries could be attributable to undernutrition. More than one-third to nearly half of incident TB cases in India could be attributable to undernutrition. InterpretationEstimation of the PAF of TB related to undernutrition is methodologically valid and operationally relevant, rather than PAF related to undernourishment, and should be used for future Global TB reports by WHO. Addressing undernutrition, the leading driver of TB in high TB burden countries (especially Asia) could enable achievement of END TB milestones of TB incidence for 2025.

Clinical predictors of pulmonary tuberculosis among South African adults with HIV.

SummaryBackgroundTuberculosis (TB) clinical prediction rules rely on presence of symptoms, however many undiagnosed cases in the community are asymptomatic. This study aimed to explore the utility of clinical factors in predicting TB among people with HIV not seeking care.MethodsBaseline data were analysed from an observational cohort of ambulant adults with HIV in South Africa. Participants were tested for Mycobacterium tuberculosis (Mtb) sensitisation (interferon-γ release assay, IGRA) and microbiologically-confirmed prevalent pulmonary TB disease at baseline, and actively surveilled for incident TB through 15 months. Multivariable LASSO regression with post-selection inference was used to test associations with Mtb sensitisation and TB disease.FindingsBetween March 22, 2017, and May 15, 2018, 861 participants were enrolled; Among 851 participants included in the analysis, 94·5% were asymptomatic and 45·9% sensitised to Mtb. TB prevalence was 2·0% at baseline and incidence 2·3/100 person-years through 15 months follow-up. Study site was associated with baseline Mtb sensitisation (p < 0·001), prevalent (p < 0·001), and incident TB disease (p = 0·037). Independent of site, higher CD4 counts (per 50 cells/mm3, aOR 1·48, 95%CI 1·12–1·77, p = 0·006) were associated with increased IGRA positivity, and participants without TB disease (aOR 0·80, 95%CI 0·69–0·94, p = 0·006) had reduced IGRA positivity; no variables were independently associated with prevalent TB. Mixed ancestry (aHR 1·49, 95%CI 1·30–>1000, p = 0·005) and antiretroviral initiation (aHR 1·48, 95%CI 1·01–929·93, p = 0·023) were independently associated with incident TB. Models incorporating clinical features alone performed poorly in diagnosing prevalent (AUC 0·65, 95%CI 0·44–0·85) or predicting progression to incident (0·67, 0·46–0·88) TB.InterpretationCD4 count and antiretroviral initiation, proxies for immune status and HIV stage, were associated with Mtb sensitisation and TB disease. Inadequate performance of clinical prediction models may reflect predominantly subclinical disease diagnosed in this setting and unmeasured local site factors affecting transmission and progression.FundingThe CORTIS-HR study was funded by the Bill & Melinda Gates Foundation (OPP1151915) and by the Strategic Health Innovation Partnerships Unit of the South African Medical Research Council with funds received from the South African Department of Science and Technology. The regulatory sponsor was the University of Cape Town.

Association of Micronutrients with Tuberculosis Development in HIV Infected Patients.

Human immunodeficiency virus (HIV) infection associated with weakened immune system due to decreased CD4 T cell count favors development of tuberculosis. Effector immune responses are also associated with micronutrient status due to their prominent role in maintaining immune functions. Micronutrient deficiencies are quite common among HIV patients that further result into compromised immunity thus making the conditions even more favorable for mycobacteria to establish disease. So, current study was designed to assess association of different micronutrients with development of TB in HIV patients. Micronutrient levels were measured in asymptomatic HIV patients who were monitored for the development of TB during follow up period (incident TB) within one month to one year and also in symptomatic microbiologically confirmed HIV-TB patients. Among various micronutrients assessed, levels of ferritin were found to be significantly increased (p < 0.05) with significant decreased zinc (p < 0.05) and selenium (p < 0.05) levels in incident TB group as well as in HIV-TB subjects compared to asymptomatic HIV patients who did not develop TB in the follow up period. Importantly, increased levels of ferritin and decreased levels of selenium were significantly associated with development of tuberculosis in HIV patients.

The effect of new Mycobacterium tuberculosis infection on the sensitivity of prognostic TB signatures.

BACKGROUND: Tests that identify individuals at greatest risk of TB will allow more efficient targeting of preventive therapy. The WHO target product profile for such tests defines optimal sensitivity of 90% and minimum sensitivity of 75% for predicting incident TB. The CORTIS (Correlate of Risk Targeted Intervention Study) evaluated a blood transcriptomic signature (RISK11) for predicting incident TB in a high transmission setting. RISK11 is able to predict TB disease progression but optimal prognostic performance was limited to a 6-month horizon.METHODS: Using a mathematical model, we estimated how subsequent Mycobacterium tuberculosis (MTB) infection may have contributed to the decline in sensitivity of RISK11. We calculated the effect at different RISK11 thresholds (60% and 26%) and for different assumptions about the risk of MTB infection.RESULTS: Modelled sensitivity over 15 months, excluding new infection, was 28.7% (95% CI 12.3-74.1) compared to 25.0% (95% CI 12.7-45.9) observed in the trial. Modelled sensitivity exceeded the minimum criteria (>75%) over a 9-month horizon at the 60% threshold and over 12 months at the 26% threshold.CONCLUSIONS: The effect of new infection on prognostic signature performance is likely to be small. Signatures such as RISK11 may be most useful in individuals, such as household contacts, where probable time of infection is known.

A prospective study of spectrum of pulmonary tuberculosis in HIV sero positive patients

Background: Tuberculosis is the leading cause of death in India contributing to 30% of total global burden. Approximately 0.5 million people dies of TB annually and 5% of the incident TB cases in India have HIV. So it is important to understand the effect of tuberculosis and HIV on each other. HIV epidemics have leads to increased number of tuberculosis cases with various presentations.Methods: It is an observational cross-sectional study of patients with HIV positive and pulmonary TB. Patients were investigated for HIV positivity by HIV coomb's test, if positive confirmed by capillaries and tridot method. Some patients, who are diagnosed as having pulmonary Koch, are sent for HIV testing. CD4 cells count as tested in all patients with HIV positive and severity of pulmonary TB and relation with CD count is studied in all patients.Results: In chest x-ray of patients we have observed that upper zone infiltration was found in 10 (16.67%) patients, mid and lower zone infiltration was found in 19 (31.67%) patients, bilateral infiltration and miliary tuberculosis was found in 22 (36.67%). We have found that 9 (15%) patients were presented with fibro cavitary lesion.Conclusions: From present study we can conclude that tuberculosis and HIV is common between 3rd and 5th decade of life with male predominance. It was more common in daily labourer and BMI was 18.22±3.21 kg/m2. Fever, weight loss and cough was most common presentation and present in more than 90% patients pallor and lymphadenopathy was common finding and present in more than 50% patients.

Monocyte-to-lymphocyte ratio as a predictor of TB among people living with HIV.

BACKGROUND: Diagnostic tools to identify incipient or subclinical TB stages will be helpful for preventive intervention. A simple biomarker to predict TB may be the monocytes to lymphocytes ratio (ML ratio) in peripheral blood.METHODS: We assessed the relationship between multiple time-updated ML ratio measurements and incidence of TB in people living with HIV (PLWH) after antiretroviral therapy (ART) was initiated. The ML ratio was updated at least every 6 months. TB incidence with corresponding 95% confidence intervals stratified according to time-updated ML ratio was calculated using ML ratio in quartiles.RESULTS: A total of 1305 PLWH were included in the analyses: 46 had incident TB and 1259 remained TB-free. The TB incidence rate was 10.3 (95% CI 7.1-14.9) cases/1000 patient-years (PYR) among participants with ML ratio ≥0.25 compared with 1.1/1000 PYR (95% CI 0.4-2.9) among those with ML ratio <0.15. At cut-point 0.23, the ML ratio provided a diagnostic area under the receiver operating characteristics curve (AROC) of 0.849 (95% CI 0.784-0.914) and a sensitivity of 85% and specificity of 71%.CONCLUSION: Increased ML ratio was predictive of incident TB among PLWH on or after ART. The ML ratio can be a simple tool to stratify the risk of TB in PLWH.

Effectiveness of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis at various stand-alone laboratories in Delhi

BackgroundGlobally, EPTB accounts for 15% of the notified incident TB cases. Laboratory confirmation of EPTB is challenging and majority of the cases remain undetected for a longer time. A major breakthrough in the diagnosis of EPTB was the introduction of nucleic acid amplification tests (NAAT). One such test-the Xpert MTB/RIF assay also known as Cartridge based nucleic acid amplification test (CBNAAT) was endorsed by the Scientific and Technical Advisory Board of the WHO for the diagnosis of Tuberculosis. The present study was conduct to evaluate the outcome of various extrapulmonary samples tested in the year 2019 at different standalone NAAT laboratories in Delhi. Materials and methodsA total of 20,238 samples consisting mainly of Pus (21.77%), Cerebrospinal fluid (CSF) (14.96%), Biopsies (13.87%), Pleural fluid (10.49%), Lymph node aspirations (FNAC aspirates) (6.75%), synovial fluid (0.54%) and gastric aspirates (26.4%) tested at 22 standalone NAAT laboratories were included in this study. ResultsMycobacterium tuberculosis was detected in 3496 samples and resistance to rifampicin was detected in 329 of the samples. The overall yield of all the specimens combined was 17.2%. Highest yield was seen in Lymph nodes aspirates (FNAC) (36.0%), followed by pus (35.4%), tissues (15.7%), synovial fluid (13.5%), Endometrial tissues (10.7%), Pleural fluid (9.5%), Gastric aspirates (9.4%) and CSF (6.5%). The lowest yield was seen in Cavitary fluids (6.2%). ConclusionThe results of this study highlight the usefulness of Xpert MTB/RIF assay in the diagnosis of EPTB. In particular, this assay proved to be of great utility while testing pus samples, tissue samples and lymph node FNACs.

Effect of anti-tuberculosis treatment on the systemic levels of tissue inhibitors of metalloproteinases in tuberculosis – Diabetes co-morbidity

ObjectivesTo study the association of Tissue inhibitors of matrix metalloproteinases (TIMP) levels with tuberculosis-diabetes comorbidity (TB-DM) comorbidity at baseline and in response to anti-TB treatment (ATT). MethodsWe examined the levels of TIMP-1, -2, -3 and -4 in pulmonary tuberculosis alone (TB) or TB-DM at baseline and after ATT. ResultsTIMP-1, -3 and -4 were significantly increased in TB-DM compared to TB at baseline and after ATT. ATT resulted in a significant reduction in TIMP-2 and -3 levels and a significant increase in TIMP-1 in both TB and TB-DM. TIMP-1, -3 and -4 were also significantly increased in TB-DM individuals with bilateral, cavitary disease and also exhibited a positive relationship with bacterial burden in TB-DM and HbA1c in all TB individuals. Within the TB-DM group, those known to be diabetic before incident TB (KDM) exhibited higher levels of TIMP-1, -2, -3 and -4 at baseline and TIMP-2 at post-treatment compared to those newly diagnosed with DM (NDM). KDM individuals on metformin treatment exhibited lower levels of TIMP-1, -2 and -4 at baseline and of TIMP-4 at post-treatment. ConclusionsTIMP levels were elevated in TB-DM, associated with disease severity and bacterial burden, correlated with HbA1c levels and modulated by duration of DM and metformin treatment.