Enhanced tuberculosis diagnosis with computer-aided chest X-ray and urine LAM in adults with HIV admitted to hospital (CASTLE study): A cluster randomised trial

Rachael M Burke; Saulos K Nyirenda; Timeo Mtenga; Hussein H Twabi; Elizabeth Joekes; Naomi F Walker; Rose Nyirenda; Ankur Gupta-Wright; Marriott Nliwasa; Katherine Fielding; Peter MacPherson; Elizabeth L Corbett

doi:10.1093/cid/ciae273

Enhanced tuberculosis diagnosis with computer-aided chest X-ray and urine LAM in adults with HIV admitted to hospital (CASTLE study): A cluster randomised trial

Clin Infect Dis. 2024 May 15:ciae273. doi: 10.1093/cid/ciae273. Online ahead of print.

Authors

Rachael M Burke^{1

2}, Saulos K Nyirenda³, Timeo Mtenga¹, Hussein H Twabi^{2

4}, Elizabeth Joekes⁵, Naomi F Walker⁵, Rose Nyirenda⁶, Ankur Gupta-Wright^{1

7}, Marriott Nliwasa^{2

4}, Katherine Fielding⁸, Peter MacPherson^{1

2

5}, Elizabeth L Corbett^{1

2}

Affiliations

¹ Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, UK.
² Malawi Liverpool Wellcome Trust Clinical Research Programme, Malawi.
³ Zomba Central Hospital, Ministry of Health, Malawi.
⁴ Kamuzu University of Health Sciences, Malawi.
⁵ School of Health and Wellbeing, University of Glasgow, UK.
⁶ Department of HIV/AIDS, Ministry of Health, Malawi.
⁷ Institute for Global Health, University College London, UK.
⁸ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, UK.

PMID: 38748183
DOI: 10.1093/cid/ciae273

Abstract

Background: People with HIV (PHIV) admitted to hospital have high mortality, with tuberculosis (TB) being the major cause of death. Systematic use of new TB diagnostics could improve TB diagnosis and might improve outcomes.

Methods: We conducted a cluster randomised trial among adult PHIV admitted to Zomba Central Hospital, Malawi. Admission-days were randomly assigned to: enhanced TB diagnostics using urine lipoarabinomannan (LAM) antigen tests (SILVAMP-LAM, Fujifilm, Japan and Determine-LAM, Alere/Abbot, USA), digital chest X-ray with computer aided diagnosis (dCXR-CAD, CAD4TBv6, Delft, Netherlands), plus usual care ("enhanced TB diagnostics"); or usual care alone ("usual care"). The primary outcome was TB treatment initiation during admission. Secondary outcomes were 56-day mortality, TB diagnosis within 24-hours, and undiagnosed TB at discharge, ascertained by culture of one admission sputum sample.

Findings: Between 2 September 2020 and 15 February 2022, we recruited 419 people. Four people were excluded post-recruitment, leaving 415 adults recruited during 207 randomly assigned admission-days in modified intention-to-treat analysis. At admission, 90.8% (377/415) were taking antiretroviral therapy (ART) with median (IQR) CD4 cell count 240 cells/mm3. In the enhanced diagnostic arm, median CAD4TBv6 score was 60 (IQR: 51-71), 4.4% (9/207) had SILVAMP-LAM-positive and 14.4% (29/201) had Determine-LAM positive urine with three samples positive by both urine tests. TB treatment was initiated in 46/208 (22%) in enhanced TB diagnostics arm and 24/207 (12%) in usual care arm (risk ratio [RR] 1.92, 95% CI 1.20-3.08). There was no difference in mortality by 56 days (enhanced TB diagnosis: 54/208, 26%; usual care: 52/207, 25%; hazard ratio 1.05, 95% CI 0.72-1.53); TB treatment initiation within 24 hours (enhanced TB diagnosis: 8/207, 3.9%; usual care: 5/208, 2.4%; RR 1.61, 95% CI 0.53-4.71); or undiagnosed microbiological-confirmed TB at discharge (enhanced TB diagnosis, 0/207 (0.0%), usual care arm 2/208 (1.0%) (p = 0.50).

Interpretation: Urine SILVAMP-LAM/Determine-LAM plus dCXR-CAD diagnostics identified more hospitalised PHIV with TB than usual care. The increase in TB treatment appeared mainly due to greater use of Determine-LAM, rather than SILVAMP-LAM or dCXR-CAD. Poor concordance between Determine-LAM and SILVAMP-LAM urine tests requires further investigation. Inpatient mortality for adults with HIV remains unacceptability high.

Keywords: HIV; TB; advanced HIV disease; diagnostics; hospitalisation.

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