Trends and risk factors for death and excess all-cause mortality among notified tuberculosis patients in the UK: an analysis of surveillance data.

INTRODUCTION: In the UK, several hundred patients notified with tuberculosis (TB) die every year. The aim of this article is to describe trends in deaths among notified TB patients, explore risk factors associated with death and compare all-cause mortality in TB patients with age-specific mortality rates in the general UK population. METHODS: We used 2001-2014 data from UK national TB surveillance to explore trends and risk factors for death, and population mortality data to compare age-specific death rates among notified TB patients with annual death rates in the UK general population. RESULTS: The proportion of TB patients in the UK who died each year declined steadily from 7.1% in 2002 to 5.5% in 2014. One in five patients (21.3%) was diagnosed with TB post-mortem. Where information was available, almost half of the deaths occurred within 2 months of starting treatment. Risk factors for death included demographic, disease-specific and social risk factors. Age had by far the largest effect, with patients aged ≥80 years having a 70 times increased risk of death compared with those aged <15 years. In contrast, excess mortality determined by incidence ratios comparing all-cause mortality among TB patients with that of the general population was highest among children and the working-age population (15-64 years old). CONCLUSIONS: Efforts to control TB and improve diagnosis and treatment outcomes in the UK need to be sustained. Control efforts need to focus on socially deprived and vulnerable groups. There is a need for further in-depth analysis of deaths of TB patients in the UK to identify potentially preventable factors

Does antiretroviral treatment increase the infectiousness of smear-positive pulmonary tuberculosis?

BACKGROUND: Understanding of the effects of human immunodeficiency virus (HIV) infection and antiretroviral treatment (ART) on Mycobacterium tuberculosis transmission dynamics remains limited. We undertook a cross-sectional study among household contacts of smear-positive pulmonary tuberculosis (TB) cases to assess the effect of established ART on the infectiousness of TB. METHOD: Prevalence of tuberculin skin test (TST) positivity was compared between contacts of index cases aged 2-10 years who were HIV-negative, HIV-positive but not on ART, on ART for <1 year and on ART for 1 year. Random-effects logistic regression was used to take into account clustering within households. RESULTS: Prevalence of M. tuberculosis infection in contacts of HIV-negative patients, HIV-positive patients on ART 1 year and HIV-positive patients not on ART/on ART <1 year index cases was respectively 44%, 21% and 22%. Compared to contacts of HIV-positive index cases not on ART or recently started on ART, the odds of TST positivity was similar in contacts of HIV-positive index cases on ART 1 year (adjusted OR [aOR] 1.0, 95%CI 0.3-3.7). The odds were 2.9 times higher in child contacts of HIV-negative index cases (aOR 2.9, 95%CI 1.0-8.2). CONCLUSIONS: We found no evidence that established ART increased the infectiousness of smear-positive, HIV-positive index cases

What happens to ART-eligible patients who do not start ART? Drop out between screening and ART initiation: a cohort study in Karonga, Malawi

BACKGROUND: Routine ART programme statistics generally only provide information about individuals who start treatment. We aimed to investigate the outcome of those who are eligible but do not start ART in the Malawi programme, factors associated with this dropout, and reasons for not starting treatment, in a prospective cohort study.METHODS: Individuals having a first screening visit at the ART clinic at Karonga District Hospital, northern Malawi, between September 2005 and July 2006 were interviewed. Study follow-up to identify treatment outcomes was conducted at the clinic and in the community. Logistic regression models were used to identify factors associated with dropout before ART initiation among participants identified as clinically eligible for ART.RESULTS: 88 participants eligible for ART at their first screening visit (out of 633, 13.9%) defaulted before starting ART. Participants with less education, difficulties in dressing, a more delayed ART initiation appointment, and mid-upper arm circumference (MUAC) &lt; 22 cm were significantly less likely to have visited the clinic subsequently. Thirty-five (58%) of the 60 participants who defaulted and were tracked at home had died, 21 before their ART initiation appointment.CONCLUSIONS: MUAC and reported difficulties in dressing may provide useful screening indicators to identify sicker ART-eligible individuals at high risk of dropping out of the programme who might benefit from being brought back quickly or admitted to hospital for observation. Individuals with less education may need adapted health information at screening. Deaths of ART-eligible individuals occurring prior to ART initiation are not included in routine programme statistics. Considering all those who are eligible for ART as a denominator for programme indicators would help to highlight this vulnerable group, in order to identify new opportunities for further improving ART programmes

Chronic lung disease in HIV-infected children established on antiretroviral therapy.

Respiratory disease is a major cause of morbidity and mortality in HIV-infected children. Despite antiretroviral therapy (ART), children suffer chronic symptoms. We investigated symptom prevalence, lung function, and exercise capacity among older children established on ART, and an age-matched HIV-uninfected group. A cross-sectional study in Zimbabwe of: 1) HIV-infected children aged 6-16 years receiving ART for over six months; 2) HIV-uninfected children attending primary health clinics from the same area. Standardised questionnaire, spirometry, Incremental Shuttle Walk Testing (ISWT), CD4 count, HIV viral load, and sputum culture for tuberculosis were performed. 202 HIV-infected and 150 uninfected participants (median age 11.1 years in each group) were recruited. Median age at HIV diagnosis and ART initiation was 5.5 (IQR 2.8-7.5) and 6.1 years (IQR 3.6-8.4) respectively. Median CD4 count was 726 cells/μl, and 79% had HIV viral load&lt;400copies/ml. Chronic respiratory symptoms were rare in HIV-uninfected children (n = 1 [0.7%]), but common in HIV-infected participants (51 [25%]), especially cough (30 [15%]) and dyspnoea (30 [15%]). HIV-infected participants were more commonly previously treated for tuberculosis (76 [38%] versus 1 [0.7%], p &lt; 0.001), had lower exercise capacity (mean ISWT distance 771m versus 889m respectively, p &lt; 0.001), and more frequently abnormal spirometry (43 [24.3%] versus 15 [11.5%], p = 0.003) compared to HIV-uninfected participants. HIV diagnosis at an older age was associated with lung function abnormality (p = 0.025). No participant tested positive for M. tuberculosis. In children, despite ART, HIV is associated with significant respiratory symptoms and functional impairment. Understanding pathogenesis is key, as new treatment strategies are urgently required

Turnaround time of whole genome sequencing for mycobacterial identification and drug susceptibility testing in routine practice.

OBJECTIVES: Until recently whole genome sequencing (WGS) for mycobacteria has been restricted mostly to the research setting. However, in 2017 Public Health England has implemented WGS for routine mycobacterial identification and susceptibility testing for Mycobacterium tuberculosis. Our objective was to evaluate the impact of this change on the laboratory turnaround times and availability of results. METHODS: Over the years 2016 and 2017, the period 1 January to 30 April was selected to represent before and after implementation of WGS. Prior to 2017, line probe assays were used for mycobacterial species identification. Turnaround times for the different steps of the diagnostic process were evaluated for all positive mycobacterial cultures that were sent from our hospital to the Reference Laboratory during the study period. RESULTS: A total of 161 positive mycobacterial cultures were sent to the Reference Laboratory. Half of the isolates (n=81/161, 50%) were M. tuberculosis and 80/161 (50%) were non-tuberculous mycobacteria. The median number of workdays for mycobacterial species identification was 1 day (interquartile range (IQR) 1-3) in 2016 and 6 days (IQR 5-7) in 2017, p <0.001. For M. tuberculosis complex, the median time to drug susceptibility testing results, either molecular or phenotypic, was 12 days (IQR 11-18) in 2016 and 8 days (IQR 7-10) in 2017, p <0.001. CONCLUSIONS: Routine WGS performed well in this setting for mycobacterial identification and susceptibility testing for M. tuberculosis and decreased time to drug susceptibility testing results. There was an increase in turnaround times for species identification using WGS, when compared with the previous methods

Risk factors for Mycobacterium tuberculosis infection in 2-4 year olds in a rural HIV-prevalent setting.

BACKGROUND: Mycobacterium tuberculosis infection in children acts as a sentinel for infectious tuberculosis. OBJECTIVE: To assess risk factors associated with tuberculous infection in pre-school children. METHOD: We conducted a population-wide tuberculin skin test (TST) survey from January to December 2012 in Malawi. All children aged 2-4 years residing in a demographic surveillance area were eligible. Detailed demographic data, including adult human immunodeficiency virus (HIV) status, and clinical and sociodemographic data on all diagnosed tuberculosis (TB) patients were available. RESULTS: The prevalence of M. tuberculosis infection was 1.1% using a TST induration cut-off of 15 mm (estimated annual risk of infection of 0.3%). The main identifiable risk factors were maternal HIV infection at birth (adjusted OR [aOR] 3.6, 95%CI 1.1-12.2), having three or more adult members in the household over a lifetime (aOR 2.4, 95%CI 1.2-4.8) and living in close proximity to a known case of infectious TB (aOR 1.6, 95%CI 1.1-2.4), modelled as a linear variable across categories (>200 m, 100-200 m, <100 m, within household). Less than 20% of the infected children lived within 200 m of a known diagnosed case. CONCLUSION: Household and community risk factors identified do not explain the majority of M. tuberculosis infections in children in our setting

Delivery of index-linked HIV testing for children: learnings from a qualitative process evaluation of the B-GAP study in Zimbabwe

Background Index-linked HIV testing for children, whereby HIV testing is offered to children of individuals living with HIV, has the potential to identify children living with undiagnosed HIV. The “Bridging the Gap in HIV Testing and Care for Children in Zimbabwe” (B-GAP) study implemented and evaluated the provision of index-linked HIV testing for children aged 2–18 years in Zimbabwe. We conducted a process evaluation to understand the considerations for programmatic delivery and scale-up of this strategy. Methods We used implementation documentation to explore experiences of the field teams and project manager who delivered the index-linked testing program, and to describe barriers and facilitators to index-linked testing from their perspectives. Qualitative data were drawn from weekly logs maintained by the field teams, monthly project meeting minutes, the project coordinator’s incident reports and WhatsApp group chats between the study team and the coordinator. Data from each of the sources was analysed thematically and synthesised to inform the scale-up of this intervention. Results Five main themes were identified related to the implementation of the intervention: (1) there was reduced clinic attendance of potentially eligible indexes due to community-based differentiated HIV care delivery and collection of HIV treatment by proxy individuals; (2) some indexes reported that they did not live in the same household as their children, reflecting the high levels of community mobility; (3) there were also thought to be some instances of ‘soft refusal’; (4) further, delivery of HIV testing was limited by difficulties faced by indexes in attending health facilities with their children for clinic-based testing, stigma around community-based testing, and the lack of familiarity of indexes with caregiver provided oral HIV testing; (5) and finally, test kit stockouts and inadequate staffing also constrained delivery of index-linked HIV testing. Conclusions There was attrition along the index-linked HIV testing cascade of children. While challenges remain at all levels of implementation, programmatic adaptations of index-linked HIV testing approaches to suit patterns of clinic attendance and household structures may strengthen implementation of this strategy. Our findings highlight the need to tailor index-linked HIV testing to subpopulations and contexts to maximise its effectiveness