Sumona Datta

Clinical Evaluation of Tuberculosis Viability Microscopy for Assessing Treatment Response

Tuberculosis viability microscopy predicted, within 1 hour, quantitative culture results that became available weeks later. Viability microscopy provides promising results for informing decisions concerning drug susceptibility testing, treatment changes, and infection control measures in resource-constrained settings where most tuberculosis occurs.

A score to predict and stratify risk of tuberculosis in adult contacts of tuberculosis index cases: a prospective derivation and external validation cohort study

BACKGROUND Contacts of tuberculosis index cases are at increased risk of developing tuberculosis. Screening, preventive therapy, and surveillance for tuberculosis are underused interventions in contacts, particularly adults. We developed a score to predict risk of tuberculosis in adult contacts of tuberculosis index cases. METHODS In 2002-06, we recruited contacts aged 15 years or older of index cases with pulmonary tuberculosis who lived in desert shanty towns in Ventanilla, Peru. We followed up contacts for tuberculosis until February, 2016. We used a Cox proportional hazards model to identify index case, contact, and household risk factors for tuberculosis from which to derive a score and classify contacts as low, medium, or high risk. We validated the score in an urban community recruited in Callao, Peru, in 2014-15. FINDINGS In the derivation cohort, we identified 2017 contacts of 715 index cases, and median follow-up was 10·7 years (IQR 9·5-11·8). 178 (9%) of 2017 contacts developed tuberculosis during 19 147 person-years of follow-up (incidence 0·93 per 100 person-years, 95% CI 0·80-1·08). Risk factors for tuberculosis were body-mass index, previous tuberculosis, age, sustained exposure to the index case, the index case being in a male patient, lower community household socioeconomic position, indoor air pollution, previous tuberculosis among household members, and living in a household with a low number of windows per room. The 10-year risks of tuberculosis in the low-risk, medium-risk, and high-risk groups were, respectively, 2·8% (95% CI 1·7-4·4), 6·2% (4·8-8·1), and 20·6% (17·3-24·4). The 535 (27%) contacts classified as high risk accounted for 60% of the tuberculosis identified during follow-up. The score predicted tuberculosis independently of tuberculin skin test and index-case drug sensitivity results. In the external validation cohort, 65 (3%) of 1910 contacts developed tuberculosis during 3771 person-years of follow-up (incidence 1·7 per 100 person-years, 95% CI 1·4-2·2). The 2·5-year risks of tuberculosis in the low-risk, medium-risk, and high-risk groups were, respectively, 1·4% (95% CI 0·7-2·8), 3·9% (2·5-5·9), and 8·6%· (5·9-12·6). INTERPRETATION Our externally validated risk score could predict and stratify 10-year risk of developing tuberculosis in adult contacts, and could be used to prioritise tuberculosis control interventions for people most likely to benefit. FUNDING Wellcome Trust, Department for International Development Civil Society Challenge Fund, Joint Global Health Trials consortium, Bill & Melinda Gates Foundation, Imperial College National Institutes of Health Research Biomedical Research Centre, Foundation for Innovative New Diagnostics, Sir Halley Stewart Trust, WHO, TB REACH, and Innovation for Health and Development.

A randomized controlled study of socioeconomic support to enhance tuberculosis prevention and treatment, Peru.

Abstract Objective To evaluate the impact of socioeconomic support on tuberculosis preventive therapy initiation in household contacts of tuberculosis patients and on treatment success in patients. Methods A non-blinded, household-randomized, controlled study was performed between February 2014 and June 2015 in 32 shanty towns in Peru. It included patients being treated for tuberculosis and their household contacts. Households were randomly assigned to either the standard of care provided by Peru’s national tuberculosis programme (control arm) or the same standard of care plus socioeconomic support (intervention arm). Socioeconomic support comprised conditional cash transfers up to 230 United States dollars per household, community meetings and household visits. Rates of tuberculosis preventive therapy initiation and treatment success (i.e. cure or treatment completion) were compared in intervention and control arms. Findings Overall, 282 of 312 (90%) households agreed to participate: 135 in the intervention arm and 147 in the control arm. There were 410 contacts younger than 20 years: 43% in the intervention arm initiated tuberculosis preventive therapy versus 25% in the control arm (adjusted odds ratio, aOR: 2.2; 95% confidence interval, CI: 1.1–4.1). An intention-to-treat analysis showed that treatment was successful in 64% (87/135) of patients in the intervention arm versus 53% (78/147) in the control arm (unadjusted OR: 1.6; 95% CI: 1.0–2.6). These improvements were equitable, being independent of household poverty. Conclusion A tuberculosis-specific, socioeconomic support intervention increased uptake of tuberculosis preventive therapy and tuberculosis treatment success and is being evaluated in the Community Randomized Evaluation of a Socioeconomic Intervention to Prevent TB (CRESIPT) project.

Comparison of sputum collection methods for tuberculosis diagnosis: a systematic review and pairwise and network meta-analysis

Summary Background The performance of laboratory tests to diagnose pulmonary tuberculosis is dependent on the quality of the sputum sample tested. The relative merits of sputum collection methods to improve tuberculosis diagnosis are poorly characterised. We therefore aimed to investigate the effects of sputum collection methods on tuberculosis diagnosis. Methods We did a systematic review and meta-analysis to investigate whether non-invasive sputum collection methods in people aged at least 12 years improve the diagnostic performance of laboratory testing for pulmonary tuberculosis. We searched PubMed, Google Scholar, ProQuest, Web of Science, CINAHL, and Embase up to April 14, 2017, to identify relevant experimental, case-control, or cohort studies. We analysed data by pairwise meta-analyses with a random-effects model and by network meta-analysis. All diagnostic performance data were calculated at the sputum-sample level, except where authors only reported data at the individual patient-level. Heterogeneity was assessed, with potential causes identified by logistic meta-regression. Findings We identified 23 eligible studies published between 1959 and 2017, involving 8967 participants who provided 19 252 sputum samples. Brief, on-demand spot sputum collection was the main reference standard. Pooled sputum collection increased tuberculosis diagnosis by microscopy (odds ratio [OR] 1·6, 95% CI 1·3–1·9, p<0·0001) or culture (1·7, 1·2–2·4, p=0·01). Providing instructions to the patient before sputum collection, during observed collection, or together with physiotherapy assistance increased diagnostic performance by microscopy (OR 1·6, 95% CI 1·3–2·0, p<0·0001). Collecting early morning sputum did not significantly increase diagnostic performance of microscopy (OR 1·5, 95% CI 0·9–2·6, p=0·2) or culture (1·4, 0·9–2·4, p=0·2). Network meta-analysis confirmed these findings, and revealed that both pooled and instructed spot sputum collections were similarly effective techniques for increasing the diagnostic performance of microscopy. Interpretation Tuberculosis diagnoses were substantially increased by either pooled collection or by providing instruction on how to produce a sputum sample taken at any time of the day. Both interventions had a similar effect to that reported for the introduction of new, expensive laboratory tests, and therefore warrant further exploration in the drive to end the global tuberculosis epidemic. Funding Wellcome Trust, Joint Global Health Trials consortium, Innovation For Health and Development, and Bill & Melinda Gates Foundation.

Dynamics of Cough Frequency in Adults Undergoing Treatment for Pulmonary Tuberculosis.

Summary This is the first research to evaluate cough frequency continuously over 24-hour periods and to characterize associations with mycobacterial load and treatment. This study provides novel information on the circadian cycle of cough frequency and risk factors for increased cough frequency.

Sputum microscopy with fluorescein diacetate predicts tuberculosis infectiousness

Summary Fluorescein diacetate microscopy was used to assess Mycobacterium tuberculosis metabolic activity in pretreatment sputa. Lower results predicted greater infectiousness in transmitting tuberculosis to household contacts. Fluorescein diacetate microscopy–negative bacteria may be better adapted to airborne tuberculosis transmission and consequently more contagious.

A Controlled Study of Tuberculosis Diagnosis in HIV-Infected and Uninfected Children in Peru

Background Diagnosing tuberculosis in children is challenging because specimens are difficult to obtain and contain low tuberculosis concentrations, especially with HIV-coinfection. Few studies included well-controls so test specificities are poorly defined. We studied tuberculosis diagnosis in 525 children with and without HIV-infection. Methods and Findings ‘Cases’ were children with suspected pulmonary tuberculosis (n = 209 HIV-negative; n = 81 HIV-positive) and asymptomatic ‘well-control’ children (n = 200 HIV-negative; n = 35 HIV-positive). Specimens (n = 2422) were gastric aspirates, nasopharyngeal aspirates and stools analyzed by a total of 9688 tests. All specimens were tested with an in-house hemi-nested IS6110 PCR that took <24 hours. False-positive PCR in well-controls were more frequent in HIV-infection (P≤0.01): 17% (6/35) HIV-positive well-controls versus 5.5% (11/200) HIV-negative well-controls; caused by 6.7% (7/104) versus 1.8% (11/599) of their specimens, respectively. 6.7% (116/1719) specimens from 25% (72/290) cases were PCR-positive, similar (P>0.2) for HIV-positive versus HIV-negative cases. All specimens were also tested with auramine acid-fast microscopy, microscopic-observation drug-susceptibility (MODS) liquid culture, and Lowenstein-Jensen solid culture that took ≤6 weeks and had 100% specificity (all 2112 tests on 704 specimens from 235 well-controls were negative). Microscopy-positivity was rare (0.21%, 5/2422 specimens) and all microscopy-positive specimens were culture-positive. Culture-positivity was less frequent (P≤0.01) in HIV-infection: 1.2% (1/81) HIV-positive cases versus 11% (22/209) HIV-negative cases; caused by 0.42% (2/481) versus 4.7% (58/1235) of their specimens, respectively. Conclusions In HIV-positive children with suspected tuberculosis, diagnostic yield was so low that 1458 microscopy and culture tests were done per case confirmed and even in children with culture-proven tuberculosis most tests and specimens were false-negative; whereas PCR was so prone to false-positives that PCR-positivity was as likely in specimens from well-controls as suspected-tuberculosis cases. This demonstrates the importance of control participants in diagnostic test evaluation and that even extensive laboratory testing only rarely contributed to the care of children with suspected TB. Trial Registration This study did not meet Peruvian and some other international criteria for a clinical trial but was registered with the ClinicalTrials.gov registry: ClinicalTrials.gov NCT00054769

Socioeconomic support to improve initiation of tuberculosis preventive therapy and increase tuberculosis treatment success in Peru: a household-randomised, controlled evaluation

Abstract Background For the first time in the modern era of tuberculosis control, the WHOs End TB strategy specifically integrates socioeconomic support for people affected by tuberculosis with existing biomedical interventions. However, there is little evidence of the impact of this approach on tuberculosis outcomes. We designed and implemented one of the worlds first tuberculosis-specific socioeconomic support interventions, assessed its impact on tuberculosis prevention measures and treatment success, and refined the support for use in the Community Randomized Evaluation of a Socioeconomic Intervention to Prevent Tuberculosis (CRESIPT) project. Methods This unmasked household-randomised controlled study was done in 32 peri-urban shanty towns in Callao, Peru. Households with patients treated for tuberculosis by Perus Tuberculosis Program were randomly assigned (1:1, computer-assisted randomisation) to receive the Peruvian Tuberculosis Program standard of care (control group) or to additionally receive socioeconomic support (intervention group). Socioeconomic support consisted of conditional cash transfers (≤US

Addressing social determinants to end tuberculosis

230) and social support (household visits and community meetings). Primary outcome was initiation of tuberculosis preventive therapy in contacts younger than 20 years available for follow-up assessment. 400 contacts were needed for 80% power at the 95% (two-sided) confidence level to detect a 50% increase in the primary outcome. Secondary outcome was treatment success in patients with tuberculosis by intention to treat. Ethics approval was given by the ethics committees of DIRESA Callao (Regional Ministry of Health) and Asociacion Benefica PRISMA, Lima, Peru, and Imperial College London, UK. All participants gave written informed consent. This study has been registered with the ISCTRN registry, number pending. Findings From Feb 10 to Aug 14, 2014, 282 patients (410 eligible contacts) were recruited. 135 patients were randomised to the intervention group (206 eligible contacts) and 147 to the control group (204 eligible contacts). Follow-up continued to June 30, 2015. Compared with controls, intervention contacts were more likely to start preventive therapy (91/206 [44%] vs 53/204 [26%], adjusted odds ratio 2·2 [95% CI 1·1–4·2]; p=0·02); and intervention patients were more likely to have treatment success (87 [64%] vs 78 [53%], 1·8 [1·1–2·9]; p=0·02). Interpretation Tuberculosis-specific socioeconomic support improved initiation of tuberculosis preventive therapy and treatment success. The CRESIPT study will now evaluate the impact of this socioeconomic support on tuberculosis control. Funding Joint Global Health Trials consortium of Wellcome Trust, Medical Research Council, and Department For International Development; British Infection Association; Bill and Melinda Gates Foundation; Innovation For Health And Development; Wellcome Trust.

Pragmatic tuberculosis prevention policies for primary care in low- and middle-income countries

Leave no one behind. This is the overarching pledge of the Sustainable Development Goals; a pledge that is far from being realised. In 2016, more than 4 million people with tuberculosis were estimated to be undiagnosed or their care and treatment were unknown.1 In the same year, nearly a fifth of the people who were diagnosed and known to be treated for tuberculosis had adverse outcomes, including 1·3 million deaths.1 One reason that millions of people affected by tuberculosis are left behind is an absence of coordinated, international action to combat poverty and inequality.