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Comparison of two diagnostic intervention packages for community-based active case finding for tuberculosis: an open-label randomized controlled trial

Nature Medicine volume 29, pages 1009–1016 (2023)Cite this article

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Abstract

Two in every five patients with active tuberculosis (TB) remain undiagnosed or unreported. Therefore community-based, active case-finding strategies require urgent implementation. However, whether point-of-care (POC), portable battery-operated, molecular diagnostic tools deployed at a community level, compared with conventionally used POC smear microscopy, can shorten time-to-treatment initiation, thus potentially curtailing transmission, remains unclear. To clarify this issue, we performed an open-label, randomized controlled trial in periurban informal settlements of Cape Town, South Africa, where we TB symptom screened 5,274 individuals using a community-based scalable mobile clinic. Some 584 individuals with HIV infection or symptoms of TB underwent targeted diagnostic screening and were randomized (1:1) to same-day smear microscopy (n = 296) or on-site DNA-based molecular diagnosis (n = 288; GeneXpert). The primary aim was to compare time to TB treatment initiation between the arms. Secondary aims included feasibility and detection of probably infectious people. Of participants who underwent targeted screening, 9.9% (58 of 584) had culture-confirmed TB. Time-to-treatment initiation occurred significantly earlier in the Xpert versus the smear-microscopy arm (8 versus 41 d, P = 0.002). However, overall, Xpert detected only 52% of individuals with culture-positive TB. Notably, Xpert detected almost all of the probably infectious patients compared with smear microscopy (94.1% versus 23.5%, P = <0.001). Xpert was associated with a shorter median time to treatment of probably infectious patients (7 versus 24 d, P = 0.02) and a greater proportion of infectious patients were on treatment at 60 d compared with the probably noninfectious patients (76.5% versus 38.2%, P < 0.01). Overall, a greater proportion of POC Xpert-positive participants were on treatment at 60 d compared with all culture-positive participants (100% versus 46.5%, P < 0.01). These findings challenge the traditional paradigm of a passive case-finding, public health strategy and argues for the implementation of portable DNA-based diagnosis with linkage to care as a community-oriented, transmission-interruption strategy. The study was registered with the South African National Clinical Trials Registry (application ID 4367; DOH-27-0317-5367) and ClinicalTrials.gov (NCT03168945).

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Fig. 1: Consort schematic summarizing the recruitment strategy and overall findings.
Fig. 2
Fig. 3: Proportion of probably infectious TB patients identified by Xpert and smear microscopy (only patients with a valid smear, chest X-ray and CASS results were included, that is n = 51).

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Data availability

Individual participant data will be made available to researchers who provide a protocol that is approved by their respective human research ethics committee. All protocols will be reviewed and approved by the XACT consortium trial steering committee up to 5 years after publication. A data sharing agreement will need to be concluded between the representatives of the requesting institution and the University of Cape Town Lung Institute. Data sharing requests should be directed to [email protected].

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Acknowledgements

This work was funded by the National Institutes of Health (grant no. CRDF-OISE-16-62105) and the South African Medical Research Council (grant no. RFA-EMU-02-2017). K.D.’s lab also acknowledges funding from the European and Developing Countries Clinical Trials Partnership (grant nos. TMA-2015SF-1043 and TMA-1051-TESAII), UK Medical Research Council (grant no. MR/S03563X/1) and the Wellcome Trust (grant no. MR/S027777/1). A.E. acknowledges funding from EDCTP (grant no. TMA-2015CDF-1052). The funders have not influenced the results of this trial in any way. We are indebted to the participants who took part in the this study. We thank the Health Directorate of the City of Cape Town for providing access to appropriate health care facilities. We further acknowledge the assistance of clinical staff at each of the TB clinics, the University of Cape Town Research Ethics Committee and community leaders and the University of Cape Town Lung Institute TB community advisory board for enabling this study. Lessons learned from patients during the conduct of the XACT-1 study were implemented in the design of the present study to facilitate acceptance of the XACT-2 active case finding model.

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Authors and Affiliations

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

    Aliasgar Esmail, Philippa Randall, Suzette Oelofse, Michele Tomasicchio, Anil Pooran, Richard Meldau, Edson Makambwa, Lynelle Mottay, Shameem Jaumdally, Gregory Calligaro, Stuart Meier & Keertan Dheda

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

    Marianna de Kock & Robin Mark Warren

  3. Praedicare Laboratories, Dallas, TX, USA

    Tawanda Gumbo

  4. Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

    Keertan Dheda

  5. Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK

    Keertan Dheda

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Contributions

K.D., A.E., P.R. and G.C. conceived the trial. K.D. was the principal investigator. K.D., A.E., P.R., S.O., M.T., A.P., R.M., E.M., R. W., M. K. and L.M. designed and performed the experiments. K.D., A.E., S.M., P.R., S.O., M.T. and A.P. analyzed the data and wrote the paper. All authors critically reviewed and approved the final version.

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Correspondence to Keertan Dheda.

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Nature Medicine thanks Gavin Churchyard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Farrell, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Cough Aerosol Sampling System (CASS) used to measure culturable M. tuberculosis in cough aerosol droplets as a surrogate for infectiousness.

The CASS system consisting of a six-stage Anderson cascade impactor (ACI) showing the median expected droplet diameter (µm) for each stage (Panel A).Patient sitting in a negative pressure cubical while coughing into a mouth piece that is attached to the ACI (Panel B).Culture plate that enables CFUs from individual aerosol droplets to be isolated (Panel C) The ACI was horizontally contained in a 10 litre autoclavable chamber (panel D).

Extended Data Fig. 2 Overview of the recruitment activities and procedures for the XACT-II study.

* A vast majority (235/288; 81.6%) of the participants in the Xpert arm of the study received their results on the same-day,thus, enabling ‘immediate’ (that is, same-visit) referral for TB treatment initiation during the same interaction while only a small proportion (42/296; 14.2%) of participants in the smear arm received their results in the same-day.

Supplementary information

Supplementary Information

Supplementary Tables 1–6, one figure, background information and summary table describing the contents of the XACT ACF model.

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Esmail, A., Randall, P., Oelofse, S. et al. Comparison of two diagnostic intervention packages for community-based active case finding for tuberculosis: an open-label randomized controlled trial. Nat Med 29, 1009–1016 (2023). https://doi.org/10.1038/s41591-023-02247-1

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