Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study

Handle URI:
http://hdl.handle.net/10754/622901
Title:
Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study
Authors:
Dheda, Keertan; Limberis, Jason D; Pietersen, Elize; Phelan, Jody; Esmail, Aliasgar; Lesosky, Maia; Fennelly, Kevin P; te Riele, Julian; Mastrapa, Barbara; Streicher, Elizabeth M; Dolby, Tania; Abdallah, Abdallah; Ben Rached, Fathia; Simpson, John; Smith, Liezel; Gumbo, Tawanda; van Helden, Paul; Sirgel, Frederick A; McNerney, Ruth; Theron, Grant; Pain, Arnab ( 0000-0002-1755-2819 ) ; Clark, Taane G; Warren, Robin M
Abstract:
Background: The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies. Methods: In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179). Findings: Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 μm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid. Interpretation: More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing. Funding: UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Pathogen Genomics Laboratory
Citation:
Dheda K, Limberis JD, Pietersen E, Phelan J, Esmail A, et al. (2017) Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study. The Lancet Respiratory Medicine. Available: http://dx.doi.org/10.1016/S2213-2600(16)30433-7.
Publisher:
Elsevier BV
Journal:
The Lancet Respiratory Medicine
Issue Date:
19-Jan-2017
DOI:
10.1016/S2213-2600(16)30433-7
Type:
Article
ISSN:
2213-2600
Sponsors:
Medical Research Council[grant no MR/K000551/1, MR/M01360X/1, MR/N010469/1]
Additional Links:
http://www.sciencedirect.com/science/article/pii/S2213260016304337
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorDheda, Keertanen
dc.contributor.authorLimberis, Jason Den
dc.contributor.authorPietersen, Elizeen
dc.contributor.authorPhelan, Jodyen
dc.contributor.authorEsmail, Aliasgaren
dc.contributor.authorLesosky, Maiaen
dc.contributor.authorFennelly, Kevin Pen
dc.contributor.authorte Riele, Julianen
dc.contributor.authorMastrapa, Barbaraen
dc.contributor.authorStreicher, Elizabeth Men
dc.contributor.authorDolby, Taniaen
dc.contributor.authorAbdallah, Abdallahen
dc.contributor.authorBen Rached, Fathiaen
dc.contributor.authorSimpson, Johnen
dc.contributor.authorSmith, Liezelen
dc.contributor.authorGumbo, Tawandaen
dc.contributor.authorvan Helden, Paulen
dc.contributor.authorSirgel, Frederick Aen
dc.contributor.authorMcNerney, Ruthen
dc.contributor.authorTheron, Granten
dc.contributor.authorPain, Arnaben
dc.contributor.authorClark, Taane Gen
dc.contributor.authorWarren, Robin Men
dc.date.accessioned2017-02-15T08:32:15Z-
dc.date.available2017-02-15T08:32:15Z-
dc.date.issued2017-01-19en
dc.identifier.citationDheda K, Limberis JD, Pietersen E, Phelan J, Esmail A, et al. (2017) Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study. The Lancet Respiratory Medicine. Available: http://dx.doi.org/10.1016/S2213-2600(16)30433-7.en
dc.identifier.issn2213-2600en
dc.identifier.doi10.1016/S2213-2600(16)30433-7en
dc.identifier.urihttp://hdl.handle.net/10754/622901-
dc.description.abstractBackground: The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies. Methods: In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179). Findings: Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 μm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid. Interpretation: More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing. Funding: UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology.en
dc.description.sponsorshipMedical Research Council[grant no MR/K000551/1, MR/M01360X/1, MR/N010469/1]en
dc.publisherElsevier BVen
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S2213260016304337en
dc.titleOutcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort studyen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentPathogen Genomics Laboratoryen
dc.identifier.journalThe Lancet Respiratory Medicineen
dc.contributor.institutionDivision of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africaen
dc.contributor.institutionDepartment of Medicine, University of Cape Town, Cape Town, South Africaen
dc.contributor.institutionFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UKen
dc.contributor.institutionDivision of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africaen
dc.contributor.institutionPulmonary Clinical Medicine Section, Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USAen
dc.contributor.institutionBrooklyn Chest Hospital, Cape Town, South Africaen
dc.contributor.institutionHarry Surtie Hospital, Upington, South Africaen
dc.contributor.institutionDST/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, Cape Town, South Africaen
dc.contributor.institutionNational Health Laboratory Services, Green Point, Cape Town, South Africaen
dc.contributor.institutionCenter for Infectious Diseases Research and Experimental Therapeutics, Baylor University Medical Center, Dallas, TX, USAen
dc.contributor.institutionFaculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UKen
kaust.authorAbdallah, Abdallahen
kaust.authorBen Rached, Fathiaen
kaust.authorPain, Arnaben
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