Recent papers and highlights

These are some recent papers, with comments from the authors

Are mRNA based transcriptomic signatures ready for diagnosing tuberculosis in the clinic? - A review of evidence and the technological landscape. (2022) Hamada, Y., A. Penn-Nicholson, S. Krishnan, D. M. Cirillo, A. Matteelli, R. Wyss, C. M. Denkinger, M. X. Rangaka, M. Ruhwald and S. G. Schumacher. EBioMedicine 82: 104174 https://doi.org/10.1016/j.ebiom.2022.104174

This paper reviews published research to evaluate whether transcriptomics technologies, specifically mRNA transcriptomes, are sufficiently mature to develop next-generation TB diagnostic tests. We introduce the use cases for mRNA signatures for TB diagnostics and summarize the evidence for each. We discuss strengths and limitations in previous studies and provides recommendations to expedite the translation of mRNA-based technologies to TB diagnostics.

Estimating annual risk of infection with Mycobacterium tuberculosis(2022) Yates, T. A. and P. Y. Khan. Lancet Infect Dis 22(9): 1276-1277 https://doi.org/10.1016/S1473-3099(22)00454-6

September's Lancet Infectious Diseases contains an article by David Dowdy and Marcel Behr arguing that we may have been considerably underestimating the force of M. tuberculosis infection. In the same edition, there is lively correspondence about this article, with contributions from UCL-TB members and our friends at LSHTM.

Bedaquiline resistance in drug-resistant tuberculosis HIV co-infected patients. (2020) Nimmo, C., J. Millard, K. Brien, S. Moodley, L. van Dorp, K. Lutchminarain, A. Wolf, A. D. Grant, F. Balloux, A. S. Pym, N. Padayatchi and M. O'Donnell. Eur Respir J https://doi.org/10.1183/13993003.02383-2019.

Bedaquiline is a highly effective drug for tuberculosis (TB) and is an important part of current regimens for drug-resistant TB. Genetic mutations leading to bedaquiline resistance were found to be common at treatment baseline and frequently acquired during treatment. Given the key importance of bedaquiline in current and future TB treatment, routine resistance monitoring is urgently needed to prevent widespread transmission of bedaquiline-resistant tuberculosis.

Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis. (2020) Gupta, R. K., C. T. Turner, C. Venturini, H. Esmail, M. X. Rangaka, A. Copas, M. Lipman, I. Abubakar and M. Noursadeghi. Lancet Respir Med https://doi.org/10.1016/S2213-2600(19)30282-6

In a meta-analysis of >1100 samples, 8 blood transcriptional signatures (of 1-25 genes) identified incipient TB with equivalent accuracy. These achieved WHO TPP for predicting TB within 3-6 months. They reveal interferon and TNF activity prior to the onset of symptomatic disease.

Effectiveness of BCG Vaccination Against Mycobacterium tuberculosis Infection in Adults: A Cross-sectional Analysis of a UK-Based Cohort. (2020) Katelaris, A. L., C. Jackson, J. Southern, R. K. Gupta, F. Drobniewski, A. Lalvani, M. Lipman, P. Mangtani and I. Abubakar. J Infect Dis 221(1): 146-155 https://doi.org/10.1093/infdis/jiz430.

In this analysis of 3453 contacts of TB patients from the PREDICT TB cohort, BCG was found to be associated with lower prevalence of latent tuberculosis infection suggesting that, in addition to TB disease, BCG may protect against M. tuberculosis infection.

Evaluation of QuantiFERON-TB Gold Plus for Predicting Incident Tuberculosis among Recent Contacts: A Prospective Cohort Study. Gupta, R. K., H. Kunst, M. Lipman, M. Noursadeghi, C. Jackson, J. Southern, A. Imran, S. Lozewicz and I. Abubakar (2020). Ann Am Thorac Soc. DOI: https://doi.org/10.1513/AnnalsATS.201905-407RL.

In this prospective study, we test how well a new generation interferon-gamma release assay (“QuantiFERON Plus”) predicts development of TB among people with recent contact with a TB case. We find that this newer test is likely to perform very similarly to previous versions.

Blood transcriptomic stratification of short-term risk in contacts of tuberculosis.  (2019) Roe, J., C. Venturini, R. K. Gupta, C. Gurry, B. M. Chain, Y. Sun, J. Southern, C. Jackson, M. C. Lipman, R. F. Miller, A. R. Martineau, I. Abubakar and M. Noursadeghi  Clin Infect Dis https://doi.org/10.1093/cid/ciz252.

We describe a novel 3-gene transcriptional signature comprising BATF2, GBP5, and SCARF1 that achieved a positive predictive value (PPV) of 50% (15.7–84.3) and negative predictive value of 99.3% (97.5–99.9) for incident TB disease in UK cohort of 333 HIV-negative tuberculosis contacts with a median follow-up of 346 days.

IMPACT study on intervening with a manualised package to achieve treatment adherence in people with tuberculosis: protocol paper for a mixed-methods study, including a pilot randomised controlled trial.  (2019) Stagg, H. R., I. Abubakar, C. N. Campbell, A. Copas, M. Darvell, R. Horne, K. Kielmann, H. Kunst, M. Mandelbaum, E. Pickett, A. Story, N. Vidal, F. B. Wurie and M. Lipman  BMJ Open 9(12): e032760 https://doi.org/10.1136/bmjopen-2019-032760

Poor adherence to treatment for TB results in worse patient outcomes. It can be due to a number of factors including patient perceptions and beliefs about TB and its treatment. The IMPACT study uses a mixed-methods, patient-centred approach to develop an intervention to support adherence to treatment that is sensitive to the individual’s beliefs, cultural background and social circumstances, and can be routinely delivered within the NHS. This paper describes the study protocol.

Quantitative Interferon Gamma Release Assay and Tuberculin Skin Test Results to Predict Incident Tuberculosis: A Prospective Cohort Study. Gupta, R. K., M. Lipman, C. Jackson, A. Sitch, J. Southern, F. Drobniewski, J. J. Deeks, C. Y. Tsou, C. Griffiths, J. Davidson, C. Campbell, O. Stirrup, M. Noursadeghi, H. Kunst, P. Haldar, A. Lalvani and I. Abubakar (2019). Am J Respir Crit Care Med. DOI: https://doi.org/10.1164/rccm.201905-0969OC

It has been suggested that using higher test cut-offs for existing latent TB tests may help us to better predict people who are most likely to develop TB disease. In this extension of the UK PREDICT TB study, we extend the follow-up of the cohort of 9,610 recent TB contacts and migrants to an average now approaching 5 years. We show that implementing higher test cut-offs is not a helpful approach, since this leads to us missing the majority of people who go on to develop TB.