Non-Tuberculous Mycobacterial Pulmonary Disease identified during community-based screening for Mycobacterium Tuberculosis: a case report

There is a rising prevalence of Non-Tuberculous Mycobacterial (NTM) disease in sub-Saharan Africa identified on culture specimens. However, distinguishing mycobacterial colonisations from infection from identified NTMs on culture in the sub-Saharan Africa setting remains to be established. A 49-year-old man presented with the cardinal symptoms of tuberculosis (TB) in a community TB prevalence survey in Blantyre, Malawi. Mycobacteriology was atypical, prompting a line probe assay which revealed Mycobacterium avium complex (MAC) species. The epidemiology of Mycobacterium tuberculosis complex (MTBC) is better known than that of NTM. Up-scaling culture and speciation may be a solution to this gap in knowledge of the burden of disease of NTM. Like most resource-poor settings, TB culture is not routinely done in the diagnosis and management of TB in Malawi. Furthermore, the treatment of NTM is not analogous to that of MTBC. The multi-drug regimens used for NTM disease treatment includes a newer macrolide (azithromycin, clarithromycin), ethambutol, and rifamycin, and require prolonged durations of therapy aimed at facilitating clearance of the mycobacteria and minimizing the emergence of drug resistance. Clinicians must thus be aware of this rising burden of NTM disease and consider other diagnostic options to better investigate this disease in patients

Clinical, health systems and neighbourhood determinants of tuberculosis case fatality in urban Blantyre, Malawi : a multilevel epidemiological analysis of enhanced surveillance data

We investigated whether household to clinic distance was a risk factor for death on tuberculosis (TB) treatment in Malawi. Using enhanced TB surveillance data, we recorded all TB treatment initiations and outcomes between 2015 and 2018. Household locations were geolocated, and distances were measured by a straight line or shortest road network. We constructed Bayesian multi-level logistic regression models to investigate associations between distance and case fatality. A total of 479/4397 (10.9%) TB patients died. Greater distance was associated with higher (odds ratio (OR) 1.07 per kilometre (km) increase, 95% credible interval (CI) 0.99–1.16) odds of death in TB patients registered at the referral hospital, but not among TB patients registered at primary clinics (OR 0.98 per km increase, 95% CI 0.92–1.03). Age (OR 1.02 per year increase, 95% CI 1.01–1.02) and HIV-positive status (OR 2.21, 95% CI 1.73–2.85) were also associated with higher odds of death. Model estimates were similar for both distance measures. Distance was a risk factor for death among patients at the main referral hospital, likely due to delayed diagnosis and suboptimal healthcare access. To reduce mortality, targeted community TB screening interventions for TB disease and HIV, and expansion of novel sensitive diagnostic tests are required.Peer reviewe

Utility of broad-spectrum antibiotics for diagnosing pulmonary tuberculosis in adults : a systematic review and meta-analysis

Funding: Helse Nord RHF, Wellcome Trust, and the UK Commonwealth Scholarship Commission.Suboptimal diagnostics for pulmonary tuberculosis drive the use of the so-called trial of antibiotics, a course of broad-spectrum antibiotics without activity against Mycobacterium tuberculosis that is given to patients who are mycobacteriology negative but symptomatic, with the aim of distinguishing pulmonary tuberculosis from bacterial lower respiratory tract infection. The underlying assumption—that patients with lower respiratory tract infection will improve, whereas those with pulmonary tuberculosis will not—has an unclear evidence base for such a widely used intervention (at least 26·5 million courses are prescribed per year). We aimed to collate available evidence on the diagnostic performance of the trial of antibiotics.Publisher PDFPeer reviewe

Design and protocol for a pragmatic randomised study to optimise screening, prevention and care for tuberculosis and HIV in Malawi (PROSPECT Study)

Background: Adults seeking diagnosis and treatment for tuberculosis (TB) and HIV in low-resource settings face considerable barriers and have high pre-treatment mortality. Efforts to improve access to prompt TB treatment have been hampered by limitations in TB diagnostics, with considerable uncertainty about how available and new tests can best be implemented. Design and methods: The PROSPECT Study is an open, three-arm pragmatic randomised study that will investigate the effectiveness and cost-effectiveness of optimised HIV and TB diagnosis and linkage to care interventions in reducing time to TB diagnosis and prevalence of undiagnosed TB and HIV in primary care in Blantyre, Malawi. Participants (≥ 18 years) attending a primary care clinic with TB symptoms (cough of any duration) will be randomly allocated to one of three groups: (i) standard of care; (ii) optimised HIV diagnosis and linkage; or (iii) optimised HIV and TB diagnosis and linkage. We will test two hypotheses: firstly, whether prompt linkage to HIV care should be prioritised for adults with TB symptoms; and secondly, whether an optimised TB triage testing algorithm comprised of digital chest x-ray evaluated by computer-aided diagnosis software and sputum GeneXpert MTB/Rif can outperform clinician-directed TB screening. The primary trial outcome will be time to TB treatment initiation by day 56, and secondary outcomes will include prevalence of undiagnosed TB and HIV, mortality, quality of life, and cost-effectiveness. Conclusions: The PROSPECT Study will provide urgently-needed evidence under “real-life” conditions to inform clinicians and policy makers on how best to improve TB/HIV diagnosis and treatment in Africa

Durations of asymptomatic, symptomatic, and care-seeking phases of tuberculosis disease with a Bayesian analysis of prevalence survey and notification data

This work was supported by the Wellcome Trust (206575/Z/17/Z to PM, 200901/Z/16/Z to ELC) and the UK MRC (MR/P022081/1 to PJD). This UK funded award (PJD) is part of the EDCTP2 programme supported by the European Union. KCH is supported by the European Research Council (757699) and UK FCDO (“Leaving no-one behind: transforming gendered pathways to health for TB”). This research has been partially funded by UK aid from the UK government (to KCH).Background Ratios of bacteriologically positive tuberculosis (TB) prevalence to notification rates are used to characterise typical durations of TB disease. However, this ignores the clinical spectrum of tuberculosis disease and potentially long infectious periods with minimal or no symptoms prior to care-seeking. Methods We developed novel statistical models to estimate progression from initial bacteriological positivity including smear conversion, symptom onset and initial care-seeking. Case-detection ratios, TB incidence, durations, and other parameters were estimated by fitting the model to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework using Markov chain Monte Carlo methods. Results Analysis across 11 national datasets found asymptomatic tuberculosis durations in the range 4–8 months for African countries; three countries in Asia (Cambodia, Lao PDR, and Philippines) showed longer durations of > 1 year. For the six countries with relevant data, care-seeking typically began half-way between symptom onset and notification. For Kenya and Blantyre, Malawi, individual-level data were available. The sex-specific durations of asymptomatic bacteriologically-positive tuberculosis were 9.0 months (95% credible interval [CrI]: 7.2–11.2) for men and 8.1 months (95% CrI: 6.2–10.3) for women in Kenya, and 4.9 months (95% CrI: 2.6–7.9) for men and 3.5 months (95% CrI: 1.3–6.2) for women in Blantyre. Age-stratified analysis of data for Kenya showed no strong age-dependence in durations. For Blantyre, HIV-stratified analysis estimated an asymptomatic duration of 1.3 months (95% CrI: 0.3–3.0) for HIV-positive people, shorter than the 8.5 months (95% CrI: 5.0–12.7) for HIV-negative people. Additionally, case-detection ratios were higher for people living with HIV than HIV-negative people (93% vs 71%). Conclusion Asymptomatic TB disease typically lasts around 6 months. We found no evidence of age-dependence, but much shorter durations among people living with HIV, and longer durations in some Asian settings. To eradicate TB transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions.Peer reviewe

Suppression of host gene expression is associated with latent TB infection : a possible diagnostic biomarker

Funding:This work was Supported by the Wellcome Trust Institutional Strategic Support fund of the University of St Andrews, grant code 204821/Z/16/Z. Additional funding was obtained from Helse Nord Tuberculosis Initiative (HNTI), Pathology Department, Kamuzu University of Health Sciences and the Africa Centre for Public Health and Herbal Medicines (ACEPHEM), Kamuzu University of Health Sciences.The World Health Organization End TB strategy aims for a 90% reduction of tuberculosis (TB) incidence by 2035. Systematic testing and treatment of latent TB infection (LTBI) among contacts of active TB patients is recommended as one of the ways to curtail TB incidence. However, there is a shortage of tools to accurately diagnose LTBI. We assessed the appropriateness of whole blood host transcriptomic markers (TM) to diagnose LTBI among household contacts of bacteriologically confirmed index cases compared to HIV negative healthy controls (HC). QuantiFERON-TB Gold Plus Interferon gamma release assay (IGRA) and reverse-transcriptase quantitative PCR were used to determine LTBI and quantify TM expression respectively. Association between TM expression and LTBI was evaluated by logistic regression modelling. A total of 100 participants, 49 TB exposed (TBEx) household contacts and 51 HC, were enrolled. Twenty-five (51%) TBEx individuals tested positive by IGRA, and were denoted as LTBI individuals, and 37 (72.5%) HC were IGRA-negative. Expression of 11 evaluated TM was significantly suppressed among LTBI compared to HC. Out of the 11 TM, ZNF296 and KLF2 expression were strongly associated with LTBI and successfully differentiated LTBI from HC. Paradoxically, 21 (49%) TBEx participants who tested IGRA negative exhibited the same pattern of suppressed TM expression as IGRA positive (LTBI-confirmed individuals). Results suggest that suppression of gene expression underlies LTBI and may be a more sensitive diagnostic biomarker than standard-of-care IGRA.Peer reviewe

Sensitivity and specificity of using trial-of-antibiotics versus sputum mycobacteriology for diagnosis of tuberculosis : protocol for a systematic literature review

TD is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF. This review is part of his PhD work at London School of Hygiene & Tropical Medicine.Background:  Suboptimal diagnostics for pulmonary tuberculosis (PTB) drives use of ‘trial-of-antibiotics (non-tuberculosis)’ in an attempt to distinguish PTB patients from those with bacterial lower respiratory tract infection (LRTI). The underlying assumption—that patients with LRTI will report ‘response’ to broad-spectrum antibiotics, while those with PTB will not—has minimal evidence base for such a widely used intervention. Numerous potential causes of misclassification include bacterial super-infection of active PTB, placebo effect, and antimicrobial resistance (AMR). The main aim of this systematic review is to collate available evidence on the performance of trial-of-antibiotics as a diagnostic test and to explore the timing, interpretation, and decision-making process. Methods:  We will search MEDLINE, Embase, and Global Health using the Ovid platform for published studies that recruited adults being investigated for PTB, performed trial-of-antibiotics accompanied by mycobacteriological investigations, and reported both diagnostic test outcomes at the individual level. Following article selection, two authors will independently review titles and abstracts against eligibility criteria then perform full-text screening and extraction into a spreadsheet. We will conduct a risk of bias assessment at the level of the study using QUADAS-2 (University of Bristol) tool that assesses diagnostic evaluation work in four domains: (1) patient selection, (2) the index test, (3) the reference standard, and (4) patient flow and timing of tests. We will perform a narrative synthesis and, where possible, meta-analyses addressing our primary outcome. Our protocol adheres to the standards recommended by the PRISMA-P. Discussion:  Pooling all available evidence on the accuracy, approach, and interpretation of results of trial-of-antibiotics in the context of PTB diagnosis will meet an urgent need, considering the widespread utilisation and potential for antimicrobial resistance. We therefore believe that our findings will have impact on policy and that they will inform the design of future detailed investigations into this important diagnostic approach.Publisher PDFPeer reviewe

Effect of the duration of antimicrobial exposure on the development of antimicrobial resistance (AMR) for macrolide antibiotics: protocol for a systematic review with a network meta-analysis

THD is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF. This review is part of his PhD work at LSHTM. ELC is funded by a Wellcome Trust Senior Research Fellowship in Clinical Science: WT200901. HRS is supported by the Medical Research Council [MR/R008345/1].Background: Antimicrobial resistance generates a huge health and economic burden and has the potential to become the leading cause of death globally, but its underlying drivers are yet to be fully described. The association between a microbe’s exposure to antimicrobials and subsequent development of, or selection for, resistance is well documented, as are the exacerbating microbial and human factors. However, the nature and extent of this risk, and how it varies by antimicrobial class and duration of treatment, is poorly defined. The goal of our systematic review and network meta-analysis is to determine the relationship between the duration of antimicrobial exposure and selection for resistance. We will use macrolides as the antimicrobial class of interest and Streptococcus pneumoniae carriage as an indicator organism. Our secondary outcomes include duration of symptoms, risk of treatment failure and recurrence, and descriptions of resistance mechanisms. Methods:  We will conduct a systematic review, selecting studies if they are published randomised controlled trials (RCTs) which report the relationship between taking a macrolide for any indication and incidence of resistant Streptococcus pneumoniae in patients of any age group. We will use a predefined search strategy to identify studies meeting these eligibility criteria in MEDLINE, Embase, Global Health and the Cochrane Central Register of RCTs. Two authors will independently screen titles and abstracts, review the full texts and undertake data extraction. We will use the Cochrane Collaboration’s tool to assess the quality of included RCTs. If feasible, we will perform pair-wise meta-analysis modelling to determine the relationship between the duration of macrolide treatment and development of macrolide resistant Streptococcus pneumoniae. If the identified studies meet the assumptions for a network meta-analysis (NMA), we will additionally model this relationship using indirect comparisons. Our protocol utilises reporting guidance by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the extensions for protocols (PRISMA-P) and network meta-analyses (PRISMA for NMA). Our review will also report to these standards. Discussion:  Establishing the relationship between the duration of antimicrobial exposure and development of, or selection for, resistance will inform the design of antimicrobial prescriptions, treatment guidelines and the behaviour of both physicians and patients. This work will therefore be a strong contribution towards the full realisation of current antimicrobial resistance stewardship strategies.Publisher PDFPeer reviewe

Clinical, health systems and neighbourhood determinants of tuberculosis case fatality in urban Blantyre, Malawi: a multilevel epidemiological analysis of enhanced surveillance data

Abstract We investigated whether household to clinic distance was a risk factor for death on tuberculosis (TB) treatment in Malawi. Using enhanced TB surveillance data, we recorded all TB treatment initiations and outcomes between 2015 and 2018. Household locations were geolocated, and distances were measured by a straight line or shortest road network. We constructed Bayesian multi-level logistic regression models to investigate associations between distance and case fatality. A total of 479/4397 (10.9%) TB patients died. Greater distance was associated with higher (odds ratio (OR) 1.07 per kilometre (km) increase, 95% credible interval (CI) 0.99–1.16) odds of death in TB patients registered at the referral hospital, but not among TB patients registered at primary clinics (OR 0.98 per km increase, 95% CI 0.92–1.03). Age (OR 1.02 per year increase, 95% CI 1.01–1.02) and HIV-positive status (OR 2.21, 95% CI 1.73–2.85) were also associated with higher odds of death. Model estimates were similar for both distance measures. Distance was a risk factor for death among patients at the main referral hospital, likely due to delayed diagnosis and suboptimal healthcare access. To reduce mortality, targeted community TB screening interventions for TB disease and HIV, and expansion of novel sensitive diagnostic tests are required.</jats:p

"Are we getting the biometric bioethics right?" - the use of biometrics within the healthcare system in Malawi.

Biometrics is the science of establishing the identity of an individual based on their physical attributes. Ethical concerns surrounding the appropriate use of biometrics have been raised, especially in resource-poor settings. A qualitative investigation was conducted to explore biometrics clients (n = 14), implementers (n = 12) and policy makers as well as bioethicists (n = 4) perceptions of the ethical aspects of implementing biometrics within the healthcare system in Malawi. Informed use, privacy and confidentiality as well as perceptions of benefits and harms were identified as major issues in the application of biometrics. Implementation of biometrics within the healthcare system in Malawi poses a range of potential ethical issues and practical challenges that impact on equitable uptake. There is a need for more research to explore the benefits and harms of biometrics in practice. Improved community engagement and sensitization should be a required component of biometrics introduction in Malawi