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Mycobacterium Tuberculosis Blood Stream Infection Prevalence, Diagnosis, and Mortality Hazard in HIV-Positive Adults: A Systematic Review and Meta-Analysis of Individual Patient Data

47 Pages Posted: 20 May 2019

See all articles by David A. Barr

David A. Barr

University of Liverpool - Institute of Infection and Global Health; University of Cape Town (UCT) - Institute for Infectious Disease & Molecular Medicine; Liverpool School of Tropical Medicine

Joseph M. Lewis

Liverpool School of Tropical Medicine; Queen Elizabeth Central Hospital

Nicholas Feasey

Liverpool School of Tropical Medicine; Queen Elizabeth Central Hospital

Charlotte Schutz

University of Cape Town (UCT)

Andrew D. Kerkhoff

University of California, San Francisco (UCSF)

Shevin T. Jacob

Liverpool School of Tropical Medicine

Ben Andrews

Vanderbilt University - School of Medicine

Paul Kelly

Queen Mary University of London

Shabir Lakhi

University of Zambia (UNZA)

Levy Muchemwa

University of Zambia (UNZA); Defence Force School of Health Sciences

Helio A. Bacha

Institute of Infectious Diseases Emilio Ribas

David J. Hadad

Federal University of Espirito Santo

Richard Bedell

Dignitas International; University of British Columbia (UBC)

Monique van Lettow

Dignitas International; University of Toronto - Dalla Lana School of Public Health

Rony Zachariah

Doctors Without Borders (MSF)

John A. Crump

University of Otago; Duke University - Medical Center; Kilimanjaro Christian Medical University College - Kilimanjaro Christian Medical Centre

David Alland

Rutgers, The State University of New Jersey - New Jersey Medical School

Elizabeth L. Corbett

London School of Hygiene and Tropical Medicine; Queen Elizabeth Central Hospital

Krishnamoorthy Gopinath

Max Planck Institute for Infection Biology

Sarman Singh

All India Institute of Medical Sciences (AIIMS)

Rulan Griesel

University of Cape Town (UCT) - Department of Medicine

Gary Maartens

University of Cape Town (UCT) - Department of Medicine

Marc Mendelson

University of Cape Town (UCT)

Amy Ward

University of Cape Town (UCT)

Christopher M. Parry

University of Liverpool - Institute of Infection and Global Health; Nagasaki University - School of Tropical Medicine and Global Health

Elizabeth A. Talbot

Dartmouth College - Dartmouth Medical School

Patricia Munseri

Muhimbili University of Health and Allied Sciences

Susan E. Dorman

Johns Hopkins University - Center for Tuberculosis Research

Neil Martinson

Johns Hopkins University - Center for Tuberculosis Research; University of the Witwatersrand

Maunank Shah

Johns Hopkins University - Center for Tuberculosis Research

Kevin Cain

Government of the United States of America - Centers for Disease Control and Prevention (CDC)

Charles M. Heilig

Government of the United States of America - Centers for Disease Control and Prevention (CDC)

Jay Varma

Government of the United States of America - Centers for Disease Control and Prevention (CDC)

Anne von Gottberg

National Health Laboratory Services (NHLS) - National Institute for Communicable Diseases; University of the Witwatersrand - School of Pathology

Leonard Sacks

Government of the United States of America - Food and Drug Administration (FDA)

Douglas Wilson

University of KwaZulu-Natal

S. Bertel Squire

Liverpool School of Tropical Medicine

David G. Lalloo

University of Malawi, College of Medicine, Malawi-Liverpool-Wellcome Trust Clinical Research Programme; Liverpool School of Tropical Medicine

Geriant R. Davies

University of Liverpool - Institute of Infection and Global Health

Graeme Meintjes

University of Cape Town (UCT); University of Cape Town (UCT) - Institute for Infectious Disease & Molecular Medicine; University of Cape Town (UCT) - Department of Medicine

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Abstract

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis blood stream infection (MTB-BSI) is incompletely understood. We hypothesised that MTB-BSI prevalence has been underestimated, that MTB-BSI independently predicts death, and sputum Xpert has suboptimal diagnostic yield for MTB-BSI.

Methods: We conducted a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood-culture (TBBC), including HIV-positive adults aged ≥13-years with suspected tuberculosis. Predicted probabilities of MTB-BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum (Xpert or culture if Xpert unavailable) and urinelipoarabinomannan for MTB-BSI were obtained by two-level random-effect meta-analysis, mortality hazard of MTB-BSI by mixed-effect Cox proportional-hazard modelling, and effect of treatment delay with propensity-score analysis.

Findings 5751 patients met inclusion criteria. Predicted probability of MTB-BSI was 45% (95%CI 38-52%) for danger-sign positive tuberculosis inpatients with cohort median CD4 count of 76 cells/μL. Diagnostic yield of sputum was 77% (95%CI 63–87%), rising to 89% (95%CI 80-94%) when combined with urinelipoarabinomannan testing. MTB-BSI increased hazard of death before 30-days (aHR2·5, 95%CI 2·1–3·1). In a propensity-score matched cohort (n=630), mortality increased with treatment delay >4 days in MTB-BSI (OR 3·2, 95%CI 1·1–10·3).

Interpretation: In critically-ill adults with HIV-tuberculosis, MTB-BSI is a very frequent manifestation of tuberculosis and strongly predicts mortality. Better diagnostic yield in patients with MTB-BSI can be achieved by parallel use of sputum-Xpert and urine-LAM. Treatment delay may increase mortality hazard.

Funding Statement: This study was supported by Wellcome fellowships 109105z/15/a, 105165/Z14/A.

Charlotte Schutz was funded by the South African Medical Research Council under the National Health Scholars Programme. Moshi, Tanzania research was supported by an International Studies on AIDS Associated Co-infections (ISAAC) award, a program funded by the US National Institutes of Health (NIH) (U01 AI062563). John A. Crump receives support from US NIH R01AI121378. Elizabeth L. Corbett is supported by a Wellcome trust senior fellowship in clinical science (WT200901). Gary Maartens was supported in part by National Research Fund incentive funding (UID: 85810). Susan E. Dorman was supported by contract #HHSN2722000900050C and grant K24AI104830 (to SED), both from the US National Institutes of Health. Douglas Wilson was supported by BMS Secure the Future. Graeme Meintjes was supported by the Wellcome Trust (098316 and 203135/Z/16/Z), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787), NRF incentive funding (UID: 85858) and the South African Medical Research Council through its TB and HIV Collaborating Centres Programme with funds received from the National Department of Health (RFA# SAMRC-RFA-CC: TB/HIV/AIDS-01-2014).

Declaration of Interests: David Alland is on the Scientific Advisory Board of Specific Technologies and receives a portion of the licensing income paid by Cepheid to Rutgers University for sales of the Xpert Ultra assay. Neil Martinson has received institutional grants for collection of specimens for Roche and Becton Dickinson, and from Pfizer for assessing incident pneumonia. All other authors declare no competing interests.

Ethics Approval Statement: PROSPERO registration: CRD42016050022.

Keywords: Tuberculosis; HIV; blood stream infection; bacteraemia; sepsis; mortality

Suggested Citation

Barr, David A. and Lewis, Joseph M. and Feasey, Nicholas and Schutz, Charlotte and Kerkhoff, Andrew D. and Jacob, Shevin T. and Andrews, Ben and Kelly, Paul and Lakhi, Shabir and Muchemwa, Levy and Bacha, Helio A. and Hadad, David J. and Bedell, Richard and van Lettow, Monique and Zachariah, Rony and Crump, John A. and Alland, David and Corbett, Elizabeth L. and Gopinath, Krishnamoorthy and Singh, Sarman and Griesel, Rulan and Maartens, Gary and Mendelson, Marc and Ward, Amy and Parry, Christopher M. and Talbot, Elizabeth A. and Munseri, Patricia and Dorman, Susan E. and Martinson, Neil and Shah, Maunank and Cain, Kevin and Heilig, Charles M. and Varma, Jay and von Gottberg, Anne and Sacks, Leonard and Wilson, Douglas and Squire, S. Bertel and Lalloo, David G. and Davies, Geriant R. and Meintjes, Graeme, Mycobacterium Tuberculosis Blood Stream Infection Prevalence, Diagnosis, and Mortality Hazard in HIV-Positive Adults: A Systematic Review and Meta-Analysis of Individual Patient Data (May 14, 2019). Available at SSRN: https://ssrn.com/abstract=3388829

David A. Barr (Contact Author)

University of Liverpool - Institute of Infection and Global Health ( email )

8 West Derby Street
Liverpool, L69 7BE
United Kingdom

University of Cape Town (UCT) - Institute for Infectious Disease & Molecular Medicine ( email )

Rondebosch, Western Cape
South Africa

Liverpool School of Tropical Medicine ( email )

Liverpool
United Kingdom

Joseph M. Lewis

Liverpool School of Tropical Medicine

Liverpool
United Kingdom

Queen Elizabeth Central Hospital

Malawi

Nicholas Feasey

Liverpool School of Tropical Medicine

Liverpool
United Kingdom

Queen Elizabeth Central Hospital

Malawi

Charlotte Schutz

University of Cape Town (UCT)

Private Bag X3
Rondebosch, Western Cape 7701
South Africa

Andrew D. Kerkhoff

University of California, San Francisco (UCSF)

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Shevin T. Jacob

Liverpool School of Tropical Medicine

Liverpool
United Kingdom

Ben Andrews

Vanderbilt University - School of Medicine

Nashville, TN 37232-0685
United States

Paul Kelly

Queen Mary University of London

Mile End Rd
Mile End Road
London, London E1 4NS
United Kingdom

Shabir Lakhi

University of Zambia (UNZA)

Zambia

Levy Muchemwa

University of Zambia (UNZA)

Zambia

Defence Force School of Health Sciences

Zambia

Helio A. Bacha

Institute of Infectious Diseases Emilio Ribas

Brazil

David J. Hadad

Federal University of Espirito Santo

Av. Fernando Ferrari, 514
No. 514, Goiabeiras
Vitória, Espirito Santo 29075
Brazil

Richard Bedell

Dignitas International

Malawi

University of British Columbia (UBC)

2329 West Mall
Vancouver, British Columbia BC V6T 1Z4
Canada

Monique Van Lettow

Dignitas International

Malawi

University of Toronto - Dalla Lana School of Public Health

Toronto, Ontario
Canada

Rony Zachariah

Doctors Without Borders (MSF)

United States

John A. Crump

University of Otago

P.O. Box 56
Dunedin, Otago 9010
New Zealand

Duke University - Medical Center

100 Fuqua Drive
Durham, NC 27715
United States

Kilimanjaro Christian Medical University College - Kilimanjaro Christian Medical Centre

Moshi
Tanzania

David Alland

Rutgers, The State University of New Jersey - New Jersey Medical School

NJ
United States

Elizabeth L. Corbett

London School of Hygiene and Tropical Medicine

Keppel Street
London, WC1E 7HT
United Kingdom

Queen Elizabeth Central Hospital

Malawi

Krishnamoorthy Gopinath

Max Planck Institute for Infection Biology

Virchowweg 12
10117 Berlin
Germany

Sarman Singh

All India Institute of Medical Sciences (AIIMS)

Aurobindo Marg
Ansari Nagar East
New Delhi, New Delhi 110029
India

Rulan Griesel

University of Cape Town (UCT) - Department of Medicine

Private Bag X3
Rondebosch, 7701
South Africa

Gary Maartens

University of Cape Town (UCT) - Department of Medicine

Private Bag X3
Rondebosch, 7701
South Africa

Marc Mendelson

University of Cape Town (UCT)

Private Bag X3
Rondebosch, Western Cape 7701
South Africa

Amy Ward

University of Cape Town (UCT)

Private Bag X3
Rondebosch, Western Cape 7701
South Africa

Christopher M. Parry

University of Liverpool - Institute of Infection and Global Health

8 West Derby Street
Liverpool, L69 7BE
United Kingdom

Nagasaki University - School of Tropical Medicine and Global Health

Nagasaki
Japan

Elizabeth A. Talbot

Dartmouth College - Dartmouth Medical School

Hanover, NH 03755
United States

Patricia Munseri

Muhimbili University of Health and Allied Sciences

Tanzania

Susan E. Dorman

Johns Hopkins University - Center for Tuberculosis Research

600 N. Wolfe Street
Baltimore, MD
United States

Neil Martinson

Johns Hopkins University - Center for Tuberculosis Research

600 N. Wolfe Street
Baltimore, MD
United States

University of the Witwatersrand

1 Jan Smuts Avenue
Johannesburg, Gauteng 2000
South Africa

Maunank Shah

Johns Hopkins University - Center for Tuberculosis Research

600 N. Wolfe Street
Baltimore, MD
United States

Kevin Cain

Government of the United States of America - Centers for Disease Control and Prevention (CDC)

1600 Clifton Rd., NE
Atlanta, GA 30333
United States

Charles M. Heilig

Government of the United States of America - Centers for Disease Control and Prevention (CDC)

1600 Clifton Rd., NE
Atlanta, GA 30333
United States

Jay Varma

Government of the United States of America - Centers for Disease Control and Prevention (CDC)

1600 Clifton Rd., NE
Atlanta, GA 30333
United States

Anne Von Gottberg

National Health Laboratory Services (NHLS) - National Institute for Communicable Diseases

Johannesburg
South Africa

University of the Witwatersrand - School of Pathology

Johannesburg, 2000
South Africa

Leonard Sacks

Government of the United States of America - Food and Drug Administration (FDA)

5600 Fishers Lane
Rockville, MD 20857-0001
United States

Douglas Wilson

University of KwaZulu-Natal

Umbilo Road
Durban 4000, KZN 4000
South Africa

S. Bertel Squire

Liverpool School of Tropical Medicine

Liverpool
United Kingdom

David G. Lalloo

University of Malawi, College of Medicine, Malawi-Liverpool-Wellcome Trust Clinical Research Programme

P.O. Box 30096, Chichiri
Blantyre 3, Malawi
Blantyre
Malawi

Liverpool School of Tropical Medicine

Liverpool
United Kingdom

Geriant R. Davies

University of Liverpool - Institute of Infection and Global Health

8 West Derby Street
Liverpool, L69 7BE
United Kingdom

Graeme Meintjes

University of Cape Town (UCT)

Private Bag X3
Rondebosch, Western Cape 7701
South Africa

University of Cape Town (UCT) - Institute for Infectious Disease & Molecular Medicine

Rondebosch, Western Cape
South Africa

University of Cape Town (UCT) - Department of Medicine

Private Bag X3
Rondebosch, 7701
South Africa

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