Improving post-TB treatment of bacterial respiratory infections

Tuberculosis is the leading global infectious cause of death after COVID-19. In high TB burden countries (predominately in the Global South), TB programmes have been severely disrupted by COVID-19-related health service interruptions. Treatment of tuberculosis (TB) involves prolonged treatment with combination antimicrobials. However, people who have completed TB treatment (TB survivors) often experience long-term respiratory morbidity after discharge from TB care, including respiratory function impairment, repeated infections and treatment with antibiotics, and poor quality of life. There is very little knowledge of the main organisms causing respiratory infection after completion of TB treatment, nor how TB treatment affects the efficacy of subsequent antimicrobial treatment, as it is likely a strong selection for resistant bacteria and/or mobile resistance elements. A better understanding of the causative agents of post-tuberculosis infections, and how antimicrobial susceptibility is affected, could inform the development of antimicrobial guidelines for TB survivors, provide a considerable improvement for TB survivor care, and reduce the use of likely ineffective antimicrobials that might be at high risk to be resistant against following the long-term TB treatment.

Tuberculosis is the leading global infectious cause of death after COVID-19. In high TB burden countries (predominately in the Global South), TB programmes have been severely disrupted by COVID-19-related health service interruptions. Treatment of tuberculosis (TB) involves prolonged treatment with combination antimicrobials. However, people who have completed TB treatment (TB survivors) often experience long-term respiratory morbidity after discharge from TB care, including respiratory function impairment, repeated infections and treatment with antibiotics, and poor quality of life. There is very little knowledge of the main organisms causing respiratory infection after completion of TB treatment, nor how TB treatment affects the efficacy of subsequent antimicrobial treatment, as it is likely a strong selection for resistant bacteria and/or mobile resistance elements. A better understanding of the causative agents of post-tuberculosis infections, and how antimicrobial susceptibility is affected, could inform the development of antimicrobial guidelines for TB survivors, provide a considerable improvement for TB survivor care, and reduce the use of likely ineffective antimicrobials that might be at high risk to be resistant against following the long-term TB treatment.

You will be based predominantly in Malawi at the Malawi-Liverpool Wellcome Trust Clinical Research Programme (MLW) in Blantyre, where the Public Health Research Group led by Dr. Peter MacPherson has a long-standing ongoing programme of TB research, with well-characterised clinical cohorts recruited from hospitals and primary clinics across the city. You will work on exploring the prevalence and risk factors for respiratory infections by non-TB agents in TB survivors and to identify the main causative agents of post-TB lung infections and in addition assess on a population genomics level how these pathogen populations compare with other circulating infections like bloodstream infections for relevant species.

Key research questions and short overview of the study design outline:
1. Cross-sectional study with respiratory sampling of PTB survivors at TB treatment completion to understand colonising microbiology / resistance patterns, and differences in those with / without residual abnormalities on CXR imaging.
2. Case cohort
TB survivors experiencing deterioration in respiratory symptoms in the 1-yr after treatment completion to return for assessment /resampling (estimated ~15% from prevalence work) and identify organisms associated with exacerbations or respiratory decline. This is planned to be matched with patients that do not experience decline on several indicators like HIV status and X-ray changes.
3. Retreatment patients
Enriched sampling of patients with recurrent TB disease with respiratory sampling.

Bacterial isolates will then be sequenced, and their antimicrobial resistance profile will be assessed both by computational predictions and resistance testing. This will give a large data resource and provide highly relevant insights into what is causing respiratory illness. The results can also be linked in with ongoing studies on bloodstream infections at MLW, providing a unique opportunity to link the disease profiles circulating in the area and assess differences as well as identify putative co-circulating strains and pathogens. Dr. Meghji is an expert on post-TB lung damage and has contributed some of the first analyses of long-term ill health in patients after TB clearance and has an ongoing programme of work around the surveillance and management of post-TB lung health at MLW.

Sequencing will be performed using short- and long-read sequencing set up in house, and this as well as the follow-up computational analyses which will be supervised by Dr. Heinz, who is regularly visiting MLW and working on several collaborative projects with scientists at MLW (Prof. Feasey, Dr. Musicha, Dr. Cornick) on bloodstream infections, providing a direct link to assess the results in this additional larger context beyond lung diseases.

Where does the project lie on the Translational Pathway?

T2 – Human/Clinical Research, T3 – Evidence into Practice

Expected Outputs

The project will produce high quality REF returnable 3*/4* publications and will provide the evidence base for large scale research council funding in a global priority area. Previous and current PhD students from the supervisor team have all published one or several high-quality first-author papers, including Thorax, Lancet Global Health, Lancet Public Health, PLOS Medicine, Molecular Microbiology, PLoS Pathogens, Microbial Genomics and Nucleic Acids Research, and have all moved to postdoctoral positions or are working as programmers in industry.

 

There is clear scope for translational impact, and this project is in an emerging research area with a unique combination of supervisors in the lung health and antimicrobial resistance area. There is a strong interest in antimicrobial resistance research from funders and public health institutions, and the impact of long-term treatments for other diseases on follow-up infections is highly understudied.

Training Opportunities

The student will receive a highly sought-after combination of skills in i) bioinformatics, including comparative genomics and molecular evolution, ii) clinical microbiology working with respiratory samples and diagnostics protocols, and iii) epidemiological skills to design a patient study. This will provide a comprehensive set of skills to address this as well as future questions in the field of respiratory disease, in particular the effect of long-term drug treatments of unrelated diseases on follow-up infections with opportunistic bacterial pathogens and their resistance profile.

Skills Required

Basic knowledge of and strong interest in bioinformatics, clinical microbiology and respiratory disease.

Key Publications associated with this project

2021      Bacterial genomic epidemiology with mixed samples. Tommi Mäklin, Teemu Kallonen, Jarno Alanko, Ørjan Samuelsen, Kristin Hegstad, Veli Mäkinen, Jukka Corander, Eva Heinz, Antti Honkela. Microbial Genomics Nov;7(11) doi: 10.1099/mgen.0.000691

2019       rPinecone: Define sub-lineages of a clonal expansion via a phylogenetic tree. Alexander M Wailan, Francesc Coll, Eva Heinz, Gerry Tonkin-Hill, Jukka Corander, Nicholas A Feasey, Nicholas R Thomson. Apr;5(4):e000264. doi: 10.1099/mgen.0.000264

2021      Community-based active case-finding interventions for tuberculosis: a systematic review

Rachael M Burke, Marriott Nliwasa, Helena R A Feasey, Lelia H Chaisson, Jonathan E Golub, Fahd Naufal, Adrienne E Shapiro, Maria Ruperez, Lily Telisinghe, Helen Ayles, Elizabeth L Corbett, Peter MacPherson. Lancet Public Health May;6(5):e283-e299. doi: 10.1016/S2468-2667(21)00033-5

2021       The long term effect of pulmonary tuberculosis on income and employment in a low income, urban setting. Jamilah Meghji, Stefanie Gregorius, Jason Madan, Fatima Chitimbe, Rachael Thomson, Jamie Rylance, Ndaziona Pk Banda, Stephen B Gordon, Elizabeth L Corbett, Kevin Mortimer, Stephen Bertel Squire. Thorax Apr;76(4):387-395. doi: 10.1136/thoraxjnl-2020-215338

2021        Computer-aided X-ray screening for tuberculosis and HIV testing among adults with cough in Malawi (the PROSPECT study): A randomised trial and cost-effectiveness analysis. Peter MacPherson, Emily L. Webb, Wala Kamchedzera, Elizabeth Joekes, Gugu Mjoli, David G. Lalloo, Titus H. Divala, Augustine T. Choko, Rachael M. Burke, Hendramoorthy Maheswaran, Madhukar Pai, S. Bertel Squire, Marriott Nliwasa, Elizabeth L. Corbett. PLoS Medicine. https://doi.org/10.1371/journal.pmed.1003752

Now Accepting Applications 

CLOSING DATE FOR APPLICATIONS: Application Portal closes: Wednesday 9th February 2022 (12:00 noon UK time)

Shortlisting complete by: End Feb/early March 2022

Interviews by: Late March/early April 2022

For more information on Eligibility, funding and how to apply please visit the MRC DTP/CASE pages