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Bacterial and host determinants of cough aerosol culture positivity in patients with drug-resistant versus drug-susceptible tuberculosis

Nature Medicine volume 26, pages 1435–1443 (2020)Cite this article

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Abstract

A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesized that lower proportions of patients with drug-resistant TB would have culturable Mycobacterium tuberculosis from respirable, cough-generated aerosols compared to patients with drug-susceptible TB, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated the colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with drug resistance), compared clinical characteristics, and performed mycobacterial whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of the patients with drug-resistant TB were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive, thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture positivity; however, this was not always rapid. These data question current paradigms, inform public health strategies and suggest the need to redirect TB transmission-associated research efforts toward host–pathogen interactions.

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Fig. 1: CASS used to measure culturable M. tuberculosis in cough aerosol droplets.
Fig. 2: Comparison of mycobacterial factors in CASS-positive and CASS-negative patients.
Fig. 3: Repeat cough aerosol sampling results in patients initially CASS-positive who were resampled until CASS-negative.

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Data availability

The deidentified datasets generated and/or analyzed during the study are available from the corresponding author without restriction. The sequencing data are available at the Sequence Read Archive under accession no. PRJNA600338). Source data for Figs. 1–3 and Extended Data Figs. 2–5 are included with this paper.

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Acknowledgements

We are indebted to the patients who participated. The study would not have been possible without the remarkable efforts of R. Wilson and G. Pretorius. We also thank for their invaluable assistance M. Pienaar and M. Pretorius, P. Spiller, M. Barnard, J. Simpson, T. Dolby, R. van Aarde, C. Clarke and B. Derendinger. The WGS computations were done using facilities provided by the University of Cape Town’s ICTS High Performance Computing team. The project was funded by the National Institutes of Health (grant no. 1R01AI104817-01), Wellcome Trust (grant no. 099854/Z/12/Z), South African Medical Research Council (Career Development Award, Self-initiated Research Award) and the National Research Foundation of South Africa. The content is solely the responsibility of the authors and does not necessarily represent the official views of the South African Medical Research Council. G.T. acknowledges funding from the South African Medical Research Council (grant no. RFA-IFSP-01-2013), the EDCTP2 programme supported by the European Union (grant no. SF1401, OPTIMAL DIAGNOSIS) and the Faculty of Medicine and Health Sciences, Stellenbosch University. K.D. acknowledges funding from the South African Medical Research Council (grant no. RFA-EMU-02-2017), EDCTP (grant nos. TMA-2015SF-1043, TMA-1051-TESAII and TMA-CDF2015), UK Medical Research Council (grant no. MR/S03563X/1) and the Wellcome Trust (grant no. MR/S027777/1). K.F. was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. We acknowledge the financial assistance of the National Research Foundation toward this research. The opinions expressed and conclusions arrived at are those of the author(s) and should not necessarily to be attributed to the National Research Foundation.

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Authors and Affiliations

  1. Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute & South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa

    Grant Theron, Jason Limberis, Liezel Smith, Elize Pietersen, Aliasgar Esmail, Greg Calligaro & Keertan Dheda

  2. DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and South African Medical Research Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Grant Theron, Rouxjeane Venter, Liezel Smith, Marianna de Kock, Paul van Helden & Robin Warren

  3. Brooklyn Chest Hospital, Cape Town, South Africa

    Julian te Riele

  4. Center for Infectious Diseases Research and Experimental Therapeutics, Baylor University Medical Center, Dallas, TX, USA

    Tawanda Gumbo

  5. Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK

    Taane G. Clark & Keertan Dheda

  6. Faculty of Epidemiology and Public Health, London School of Hygiene & Tropical Medicine, London, UK

    Taane G. Clark

  7. Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Kevin Fennelly

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Contributions

K.D., K.F., R.W. and G.T. conceived the study and acquired the funding. G.T., J.L., R.V., L.S., E.P., A.E., G.C., J.t.R. and M.d.K. acquired the data. K.D., P.v.H., T.G., T.G.C. and R.W. provided important research infrastructure. G.T., K.D., J.L., R.V. and L.S. carried out the analyses. G.T. prepared the first draft of the manuscript. All authors provided critical feedback.

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Correspondence to Keertan Dheda.

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Extended data

Extended Data Fig. 1 Study profile and participant overview.

Abbreviations: CASS, cough aerosol sampling system; DS, drug-susceptible; INH, isoniazid; MDR, multidrug-resistant; MGIT, mycobacterial growth indicator tube; RIF, rifampicin; TB, tuberculosis; XDR, extensively drug-resistant; VL, viral load; WGS, whole genome sequencing. *Done using Sensititre MYCOTB plates for isoniazid, rifampicin, ethambutol, ethionamide, kanamycin, ofloxacin, p-aminosalicylic acid, rifabutin, streptomycin, cycloserine, amikacin, and moxifloxacin.

Extended Data Fig. 2 M. tuberculosis CFU from cough aerosol particles at recruitment as a function of days on treatment before CASS stratified by regimen type.

Beyond eight days, no patients receiving the first-line regimen were CASS-positive, whereas patients receiving second-line regimens had CFU in their aerosol for months. The y-axis is logarithmic and one was added to CFU counts. Abbreviations: ACI, Andersen Cascade Impactor; CLF, clofazimine; FQ, fluoroquinolone; IQR, interquartile range; SLID, second-line injectable drug.

Source data

Extended Data Fig. 3

Relationships between sputum bacillary load (liquid culture time-to-positivity) and disease extent (a and b) and cavitation score (c), and between CASS-status and cavitation score (d) assessed by chest radiography using the standardised reporting system in Supplementary Table 2. No legend required in addition to title.

Source data

Extended Data Fig. 4 Maximum likelihood phylogenetic tree of baseline CASS isolates (n=318) rooted to Mycobacterium bovis BCG.

Heatmaps to the right of the tree denote from left to right CASS status (also denoted on the branch nodes), treatment duration, drug resistance group and M. tuberculosis lineage. No legend required in addition to title.

Source data

Extended Data Fig. 5 A Manhattan plot of multivariate genome wide association study (GWAS) using nsSNPs per gene for CASS-positivity including two principal components, patient age, TB symptom score, HIV-status, duration of treatment less than 48h, PCF, culture time to positivity, and drug-resistance category did not detect significant associations.

The horizontal dashed line represents the threshold of statistical significance.

Source data

Supplementary information

Supplementary Information

Supplementary Tables 1–22, results text and references.

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Theron, G., Limberis, J., Venter, R. et al. Bacterial and host determinants of cough aerosol culture positivity in patients with drug-resistant versus drug-susceptible tuberculosis. Nat Med 26, 1435–1443 (2020). https://doi.org/10.1038/s41591-020-0940-2

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