The TBPod

In this extraordinary episode we speak with renowned historian Professor Christoph Gradmann about the life and work of German physician Robert Koch. In this episode we look at how Koch came to discover tuberculosis and what it meant for the field of medicine in the late 19th century.

REFERENCES:
Gradmann, Christoph. "Robert Koch and the pressures of scientific research: tuberculosis and tuberculin." Medical history 45.1 (2001): 1-32.

Gradmann, Christoph. "Robert Koch and the white death: from tuberculosis to tuberculin." Microbes and Infection 8.1 (2006): 294-301.

Gradmann, Christoph. "Robert Koch and the invention of the carrier state: tropical medicine, veterinary infections and epidemiology around 1900." Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences 41.3 (2010): 232-240.

Gradmann, Christoph. "Money and microbes: Robert Koch, tuberculin and the Foundation of the Institute for Infectious Diseases in Berlin in 1891." History and philosophy of the life sciences (2000): 59-79.

Gradmann, Christoph. "A spirit of scientific rigour: Koch's postulates in twentieth-century medicine." Microbes and infection 16.11 (2014): 885-892.

Gradmann, Christoph. "A harmony of illusions: clinical and experimental testing of Robert Koch’s tuberculin 1890–1900." Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences 35.3 (2004): 465-481.

Gradmann, Christoph, Mark Harrison, and Anne Rasmussen. "Typhoid and the Military in the Early 20th Century." Clinical Infectious Diseases 69.Supplement_5 (2019): S385-S387.

Gradmann, Christoph. "The traveling laboratory: Robert Koch investigates cholera 1883/84." Medizinhistorisches Journal38.1 (2003): 35-56.

Gradmann, Christoph. "Laboratory disease: Robert Koch's medical bacteriology." Isis 102 (2011).

Today we have the pleasure of speaking to both Professor Leonard (Respiratory physician and director of the sarcoidosis service for Manchester Foundation Trust) and Dr Montero (director of cellular pathology for Wythenshawe Hospital) about the complex interplay between these two illnesses and how best to approach complex patients with uncertain diagnosis of granulomatous disease.

REFERENCES:
Agrawal, Rupesh, et al. "Tuberculosis or sarcoidosis: opposite ends of the same disease spectrum?." Tuberculosis 98 (2016): 21-26.

Baughman, Robert P., et al. "ERS clinical practice guidelines on treatment of sarcoidosis." European respiratory journal58.6 (2021).

Fang, Chuling, Hui Huang, and Zuojun Xu. "Immunological evidence for the role of mycobacteria in sarcoidosis: a meta-analysis." PLoS One 11.8 (2016): e0154716.

Malkova, Anna, et al. "The opposite effect of human leukocyte antigen genotypes in sarcoidosis and tuberculosis: A narrative review of the literature." ERJ Open Research 6.3 (2020).

Mortaz, Esmaeil, Ian M. Adcock, and Peter J. Barnes. "Sarcoidosis: Role of non-tuberculosis mycobacteria and Mycobacterium tuberculosis." International journal of mycobacteriology 3.4 (2014): 225-229.

Today I had the privilege of speak with Professor Christoph Lange, Secretary General of the Union, founding chairman of TBNet and is the clinical lead for the Unite4TB Consortium. Professor Lange spoke to us about where we're up to with our EndTB Goals. Professor Lange spoke about the significant barriers that remain, where our shortfalls have come, where our successes have arisen, and what exciting opportunities lay in the years ahead for tuberculosis.

REFERENCES
Lange, Christoph, et al. "Perspective for precision medicine for tuberculosis." Frontiers in Immunology 11 (2020): 566608

Lange, Christoph, et al. "Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement." (2014): 23-63.

Günther, Gunar, et al. "Relative cost of multidrug-resistant TB medicines in Europe." The international journal of tuberculosis and lung disease 27.5 (2023): 341-344.

Koehler, Niklas, et al. "Pretomanid-resistant tuberculosis." Journal of Infection 86.5 (2023): 520-524.

Domínguez, José, et al. "Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement." The Lancet Infectious Diseases 23.4 (2023): e122-e137.

Heyckendorf, Jan, et al. "Method for diagnosis and treatment monitoring and individual therapy end decision in tuberculosis infection." U.S. Patent Application No. 17/904,544

Villar-Hernández, Raquel, et al. "Tuberculosis: current challenges and beyond." Breathe 19.1 (2023)

Günther, Gunar, et al. "Availability and costs of medicines for the treatment of tuberculosis in Europe." Clinical microbiology and infection 29.1 (2023): 77-84

DiNardo, Andrew R., et al. "Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes." European Respiratory Journal 60.3 (2022).

Günther, Gunar, et al. "Cost and availability of drugs and treatment regimens and availability of drug resistance testing for tuberculosis in Europe." medRxiv (2022): 2022-02

Boeree, M. J., et al. "UNITE4TB: a new consortium for clinical drug and regimen development for TB." The International Journal of Tuberculosis and Lung Disease 25.11 (2021): 886

Lönnroth, Knut, N. Sarita Shah, and Christoph Lange. "State-of-the-art series on tuberculosis and migration." The international journal of tuberculosis and lung disease 20.10 (2016): 1280-1281.

DiNardo, Andrew R., et al. "Tuberculosis endotypes to guide stratified host-directed therapy." Med 2.3 (2021): 217-232.

Today I had the pleasure of speaking with Dr Emily MacLean about the exciting modern tests both commercially available and in research development for diagnosing tuberculosis. Emily talked to us about how GeneXpert has evolved and how we can get the most out of this amazing test but also about the extraordinary diagnostic tests being investigated at the moment from blood tests of host response to bacilli to AI learning cough acoustic markers of tuberculosis!

REFERENCES:
MacLean, Emily, et al. "Diagnostic accuracy of stool Xpert MTB/RIF for detection of pulmonary tuberculosis in children: a systematic review and meta-analysis." Journal of clinical microbiology 57.6 (2019): e02057-18.

Singhroy, Diane N., et al. "Adoption and uptake of the lateral flow urine LAM test in countries with high tuberculosis and HIV/AIDS burden: current landscape and barriers." Gates open research 4 (2020).

MacLean, Emily Lai-Ho, et al. "Integrating tuberculosis and COVID-19 molecular testing in Lima, Peru: a cross-sectional, diagnostic accuracy study." The Lancet Microbe (2023).

Zifodya, Jerry S., et al. "Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis." Cochrane Database of Systematic Reviews 2 (2021).
APA |

Mishra, Hridesh, et al. "Xpert MTB/RIF Ultra and Xpert MTB/RIF for diagnosis of tuberculosis in an HIV-endemic setting with a high burden of previous tuberculosis: a two-cohort diagnostic accuracy study." The Lancet Respiratory Medicine 8.4 (2020): 368-382.
APA |

Kohli, Mikashmi, et al. "Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults." Cochrane Database of Systematic Reviews 1 (2021).
APA |

Branigan D. Tuberculosis Diagnostics. Nov 2022. Available at:https://www.treatmentactiongroup.org/wp-content/uploads/2022/11/pipeline_TB_diagnostics_2022.pdf

MacLean, Emily, et al. "Advances in molecular diagnosis of tuberculosis." Journal of clinical microbiology 58.10 (2020): e01582-19.

Sweeney, Timothy E., et al. "Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis." The Lancet Respiratory Medicine 4.3 (2016): 213-224.

Sutherland, Jayne S., et al. "Diagnostic accuracy of the Cepheid 3-gene host response fingerstick blood test in a prospective, multi-site study: interim results." Clinical Infectious Diseases 74.12 (2022): 2136-2141.

Moreira, Flora Martinez Figueira, et al. "Blood-based host biomarker diagnostics in active case finding for pulmonary tuberculosis: A diagnostic case-control study." EClinicalMedicine 33 (2021): 100776.

Peter, Jonny G., et al. "Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial." The Lancet 387.10024 (2016): 1187-1197.

Today I had the pleasure of speaking with Dr Geoff Eather from the Princess Alexandra Hospital in Brisbane about his work and research on TST and IGRA screening for tuberculosis. This was a fantastic experience to learn more about these incredibly common tests from an expert in this field of research.

REFERENCES:
Auguste, Peter, et al. "Comparing interferon-gamma release assays with tuberculin skin test for identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review and meta-analysis." BMC infectious diseases 17 (2017): 1-13.

Campbell, Jonathon R., Nicholas Winters, and Dick Menzies. "Absolute risk of tuberculosis among untreated populations with a positive tuberculin skin test or interferon-gamma release assay result: systematic review and meta-analysis." bmj 368 (2020).

Dobler, Claudia C., et al. "Risk of tuberculosis in patients with solid cancers and haematological malignancies: a systematic review and meta-analysis." European Respiratory Journal 50.2 (2017).

Mulenga, Humphrey, et al. "Performance of diagnostic and predictive host blood transcriptomic signatures for Tuberculosis disease: A systematic review and meta-analysis." PLoS One 15.8 (2020): e0237574.

Rangaka, Molebogeng X., et al. "Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis." The Lancet infectious diseases12.1 (2012): 45-55.

Tagmouti, Saloua, et al. "Reproducibility of interferon gamma (IFN-γ) release assays. A systematic review." Annals of the American Thoracic Society 11.8 (2014): 1267-1276.

Today I had the pleasure of speaking to Hojoon Sohn, an associate professor in infectious disease epidemiologist at the Seoul National University College of Medicine. Hojoon is an expert in TB modelling and speaks to us about his research in decentralised models of testing. This was a fascinating podcast about an area of Tuberculosis not often encountered in the clinical sphere and Hojoon gives a wonderful insight into how and why we implement diagnostic testing.

REFERENCES
Sohn, Hojoon, et al. "Informing decision-making for universal access to quality tuberculosis diagnosis in India: an economic-epidemiological model." BMC medicine 17 (2019): 1-11.

XPEL-TB: Cattamanchi, Adithya, et al. "Multicomponent strategy with decentralised molecular testing for tuberculosis." New England Journal of Medicine 385.26 (2021): 2441-2450.

Mungai, Brenda Nyambura, et al. "‘If not TB, what could it be?’Chest X-ray findings from the 2016 Kenya Tuberculosis Prevalence Survey." Thorax 76.6 (2021): 607-614.

Vessière, Aurélia, et al. "Impact of systematic early tuberculosis detection using Xpert MTB/RIF Ultra in children with severe pneumonia in high tuberculosis burden countries (TB-Speed pneumonia): a stepped wedge cluster randomized trial." BMC pediatrics 21 (2021): 1-12.

Thompson, Ryan R., et al. "Multicomponent strategy with decentralised molecular testing for tuberculosis in Uganda: a cost and cost-effectiveness analysis." The Lancet Global Health 11.2 (2023): e278-e286.

Today we speak to Professor Jan-Willem Alffenaar from Westmead Hospital and the University of Sydney about Therapeutic Drug Monitoring in Tuberculosis. Professor Alffenaar reviews the PK/PD issues with common TB medications, the strengths and weaknesses of TDM and how best to utilise TDM in the treatment of TB patients.

REFERENCES
1) personalised dosing of TB drugs
Clinical standards for the dosing and management of TB drugs
Alffenaar JW, Stocker SL, Forsman LD, Garcia-Prats A, Heysell SK, Aarnoutse RE, Akkerman OW, Aleksa A, van Altena R, de Onata WA, Bhavani PK. Clinical standards for the dosing and management of TB drugs. The International Journal of Tuberculosis and Lung Disease. 2022 Jun 1;26(6):483-99.

Population Pharmacokinetics and Bayesian Dose Adjustment to Advance TDM of Anti-TB Drugs.
Sturkenboom MG, Märtson AG, Svensson EM, Sloan DJ, Dooley KE, van den Elsen SH, Denti P, Peloquin CA, Aarnoutse RE, Alffenaar JW. Population pharmacokinetics and Bayesian dose adjustment to advance TDM of anti-TB drugs. Clinical pharmacokinetics. 2021 Jun;60:685-710.

2) drug exposure - pathogen susceptibility - treatment outcome
Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China.
Zheng X, Forsman LD, Bao Z, Xie Y, Ning Z, Schön T, Bruchfeld J, Xu B, Alffenaar JW, Hu Y. Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China. European Respiratory Journal. 2022 Mar 1;59(3).

Drug Exposure and Minimum Inhibitory Concentration Predict Pulmonary Tuberculosis Treatment Response.
Zheng X, Bao Z, Forsman LD, Hu Y, Ren W, Gao Y, Li X, Hoffner S, Bruchfeld J, Alffenaar JW. Drug exposure and minimum inhibitory concentration predict pulmonary tuberculosis treatment response. Clinical Infectious Diseases. 2021 Nov 1;73(9):e3520-8.

3) TDM framework
Therapeutic Drug Monitoring of Anti-infective Drugs: Implementation Strategies for 3 Different Scenarios.
Kim HY, Byashalira KC, Heysell SK, Märtson AG, Mpagama SG, Rao P, Sturkenboom MG, Alffenaar JW. Therapeutic drug monitoring of anti-infective drugs: implementation strategies for 3 different scenarios. Therapeutic Drug Monitoring. 2022 Feb 1;44(1):3-10.

4) point of care TDM
A mobile microvolume UV/visible light spectrophotometer for the measurement of levofloxacin in saliva.
Alffenaar JW, Jongedijk EM, van Winkel CA, Sariko M, Heysell SK, Mpagama S, Touw DJ. A mobile microvolume UV/visible light spectrophotometer for the measurement of levofloxacin in saliva. Journal of Antimicrobial Chemotherapy. 2021 Feb;76(2):423-9.

Levofloxacin pharmacokinetics in saliva as measured by a mobile microvolume UV spectrophotometer among people treated for rifampicin-resistant TB in Tanzania.
Mohamed S, Mvungi HC, Sariko M, Rao P, Mbelele P, Jongedijk EM, van Winkel CA, Touw DJ, Stroup S, Alffenaar JW, Mpagama S. Levofloxacin pharmacokinetics in saliva as measured by a mobile microvolume UV spectrophotometer among people treated for rifampicin-resistant TB in Tanzania. Journal of Antimicrobial Chemotherapy. 2021 Jun;76(6):1547-52.

Today we speak with Professor Jann-Yuan Wang, a clinician and researcher in Taiwan, about his work in latent tuberculosis. Professor Wang speaks about his experience using 3HP and the challenges of systemic drug reactions. Professor Wang talks about his research into predicting which patients will experience systemic drug reactions based on research algorithms of clinical characteristics, plasma drug levels and transcriptomic factors.

REFERENCES:
1) Lee, Ming‐Chia, et al. "Isoniazid level and flu‐like symptoms during rifapentine‐based tuberculosis preventive therapy: A population pharmacokinetic analysis." British journal of clinical pharmacology (2022).
2) Peng, Tzu-Rong, et al. "Advantages of short-course rifamycin-based regimens for latent tuberculosis infection: an updated network meta-analysis." Journal of Global Antimicrobial Resistance 29 (2022): 378-385.
3) Huang, Hung-Ling, et al. "Whole-blood 3-gene Signature as a Decision Aid for Rifapentine-based TB Preventive Therapy." Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America (2022).
4) Huang, Hung-Ling, et al. "Impact of age on outcome of rifapentine-based weekly therapy for latent tuberculosis infection." Clinical Infectious Diseases 73.5 (2021): e1064-e1071.
5) Lee, Meng-Rui, et al. "Isoniazid concentration and NAT2 genotype predict risk of systemic drug reactions during 3HP for LTBI." Journal of clinical medicine 8.6 (2019): 812.
6) Sun, Hsin-Yun, et al. "Twelve-dose weekly rifapentine plus isoniazid for latent tuberculosis infection: A multicentre randomised controlled trial in Taiwan." Tuberculosis 111 (2018): 121-126.
7) Lee, Meng-Rui, et al. "Plasma Concentration of Isoniazid and Single-Nucleotide Polymorphisms of N-Acetyltransferase 2 Predict Risk of Systemic Drug Reactions During Weekly Rifapentine and Isoniazid Therapy for Latent Tuberculosis Infection: A Prospective Observational Cohort Study." Available at SSRN 3297903 (2018).

Drug Resistant TB is a growing problem with some exciting advances over the past decade. With the recent Rapid Communication from the WHO and the advent of the B-PALMS regimen, drug resistant TB is a changing and exciting field of tuberculosis around the world.

In this episode Professor Greg Fox from the University of Sydney speaks with Dr Jack Callum about the latest changes in the treatment of Drug Resistant TB in light of the WHO Rapid Communication as well as the NIX, ZeNIX and TB Practecal Trials. Professor Fox also addressing the implications for clinical practice and what the future might hold in this ever challenging field of TB.

1) Gegia, Medea, et al. "Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis." The Lancet Infectious Diseases 17.2 (2017): 223-234.

2) NIX Study: Conradie, Francesca, et al. "Treatment of highly drug-resistant pulmonary tuberculosis." New England Journal of Medicine382.10 (2020): 893-902.

3) ZeNIX Study: Conradie, Francesca, et al. "Bedaquiline–pretomanid–linezolid Regimens for drug-resistant tuberculosis." New England Journal of Medicine 387.9 (2022): 810-823.

4) TB Practecal Trial (not yet published but study protocol available):  Berry, Catherine, et al. "TB-PRACTECAL: study protocol for a randomised, controlled, open-label, phase II–III trial to evaluate the safety and efficacy of regimens containing bedaquiline and pretomanid for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis." Trials 23.1 (2022): 1-16.

5) WHO Guidelines for DR TB Update: World Health Organization. Rapid communication: key changes to the treatment of drug-resistant tuberculosis. No. WHO/UCN/TB/2022.2. World Health Organization, 2022.

6) Commentary on the WHO Update: Migliori, G. B., and S. Tiberi. "WHO drug-resistant TB guidelines 2022: what is new?." The International Journal of Tuberculosis and Lung Disease: the Official Journal of the International Union Against Tuberculosis and Lung Disease26.7 (2022): 590-591.

BCG has long been the only widely used vaccination strategy since it's initial use over 100 years ago. In high TB burden settings it is still recommended in children to protect against disseminated disease though the lasting protection offered by BCG vaccination has been poor at best.

Today, Emeritus Professor Warwick Britton AO FAHMS from the Centenary Institute and the University of Sydney speaks with Professor Greg Fox about how the BCG vaccine works and where it's utility lies. Professor Britton also explores exciting research in tuberculosis vaccines and what developments may be required to control tuberculosis in the future.

REFERENCES:
Hart, D'Arcy, and Sutherland. "BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life." Br Med J 2.6082 (1977): 293-295.

Nemes, Elisa, et al. "Prevention of M. tuberculosis infection with H4: IC31 vaccine or BCG revaccination." New England Journal of Medicine 379.2 (2018): 138-149. 

Darrah, Patricia, et al. "Prevention of tuberculosis in macaques after intravenous BCG immunization." Nature 577.7788 (2020): 95-102.