Urinary lipoarabinomannan (LAM)
detection as a diagnostic test for TB
Dr Ankur Gupta-Wright
Clinical Research Fellow
London School Hygiene & Tropical Medicine/Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Overview
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What is LAM?
How do we detect LAM?
How accurate are urine LAM assays for diagnosing TB?
How does LAM end up in the urine of TB patients?
In whom should and shouldn’t we use LAM assays?
Can using LAM assays impact patient outcomes?
Background
• HIV-TB still causes significant
morbidity and mortality
• TB causes between 1/3 and 2/3
deaths in HIV+ adults admitted to
hospital in SSA
• 50% of this TB disease is
undiagnosed at the time of death
• Current (sputum-based) diagnostics
are inadequate in this population
• Need improved diagnostic
strategies to reduce TB deaths
What is lipoarabinomannan (LAM)?
How do we detect LAM in urine?
Determine TB-LAM Ag assay
Negative
Positive
Control band
Patient sample
result
Sample
pad
Lawn et al Lancet Infect Dis 2012
Positive
How accurate is Urine TB-LAM testing?
100
• Overall sensitivity is ‘inadequate’ (<30%
sensitivity)
• Moderate to good sensitivity in advanced
HIV, linked to CD4 cell count
• Good specificity (>99%) when correct
reference standard is used
• Diagnoses sickest patients at the highest
risk of death
90
80
Sensitivity (%)
70
60
50
40
30
20
10
0
<50
50-150
>150
All patients
Lawn et al. JAIDS 2012
How does LAM end-up in urine of TB patients?
• Filtration of LAM from blood in the
kidney was the early hypothesis
• Bound LAM is too large to be filtered by
healthy kidneys
• Evidence of renal TB from post-mortem
studies (e.g. Cox et al PLoS One 2015)
• Microbiology supports the renal TB
hypothesis
-evidence of whole TB bacilli in urine of
LAM positive patients
-strong association with MTB
bacteraemia
Images courtesy of Prof. Sebastian Lucas
Observations explained by
haematogenous renal TB
• Utility of the assay is restricted to HIV+ patients with low CD4 cell counts
-target the correct patient population
• Urine-LAM antigenuria is a predictor of mortality in HIV-TB
• Specificity is sub-optimal when the reference standard does not include extra-pulmonary
samples
In whom should and shouldn’t we use LAM assays?
• WHO policy guidance November 2015
• Shouldn’t be used for the diagnosis of TB except…
• may be used to assist in the diagnosis of TB in HIV
positive adult in-patients with signs and symptoms of
TB who have a CD4 <100 cells/µL, are seriously unwell
(conditional recommendation; low quality of
evidence)
• Shouldn’t be used as a screening test for TB
Can using LAM assays impact patient outcomes?
• LAM RCT- adjunctive LAM testing for
hospitalised patients ‘suspected of
having TB’
• 4 sites (SA, Zim, Zambia, Tanzania)
• Randomised 2659 patients
• 2 month mortality:
-no LAM arm 24.9%
-LAM arm 20.8%
-aRR 0.83 (95%CI 0.03-0.96,
p=0.012)
• One of the first trials of a TB
diagnostic to show an impact on
mortality
STAMP trial
• RAPID URINEBASED SCREENING
FOR TB TO REDUCE
AIDS-RELATED
MORTALITY IN
HOSPITALIZED
PATIENTS IN
AFRICA
• 2 sites:
-Zomba, Malawi
-PMB, South Africa
Summary
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Need for better diagnostics for HIV-associated TB
Detectable LAM in urine is a marker of renal TB
Potential utility in advanced HIV (when disseminated/renal TB is more common)
Needs to be applied to the correct patient population
Potential to improve patient outcomes, as demonstrated by a recent RCT
Questions?
• Thanks for listening
• Thanks to funders:
Global Health Trials (MRC/WT/DfID)
Royal College of Physicians London
• Thanks to my supervisors:
Prof Stephen Lawn
Prof Liz Corbett