Researchers from the Universities of Cape Town, Stanford, Oxford and the London School of Hygiene & Tropical Medicine have shown that a blood test usually used to detect tuberculosis infection in adults can predict the onset of tuberculosis disease in young children.
QuantiFERON testing and tuberculosis risk among young children: an observational cohort study describes how infants with very high results of the QuantiFERON blood tests, more than 10 times the cut-off value for a positive test, had exceptionally high risk of tuberculosis disease in subsequent months.
The QuantiFERON test is commonly used in adults, particularly in developed countries, and conversion from a negative to positive test indicates recent infection with tuberculosis, often triggering drug treatment to prevent disease. The researchers analysed QuantiFERON results from a large tuberculosis vaccine trial conducted by the South African Tuberculosis Vaccine Initiative (SATVI) among more than 2,700 children in Worcester, near Cape Town, South Africa.
Until now, there has been scant evidence to suggest that the QuantiFERON test could or should be used in young children from tuberculosis endemic countries as an indication for preventative treatment.
The new findings show that young South African children with very high QuantiFERON results, more than 10 times the recommended adult cut-off value for a positive test, had more than 40 times greater risk of developing tuberculosis disease than children with a negative test.
By contrast children with a positive test at the usual adult cut-off value were likely to change back to negative when next tested.
“These findings confirm that the QuantiFERON test performs very differently in young children than in adults. More importantly, we now know that a very high QuantiFERON result can be used to identify those children who are at highest risk of developing tuberculosis disease and who would benefit most from investigation and treatment,” said SATVI Professor Mark Hatherill.
If confirmed in other studies these findings could lead to a revision of international guidelines for QuantiFERON testing and provide an opportunity to prevent at risk children from developing tuberculosis.
Summary
Background: The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. We aimed to investigate the relation between QuantiFERON-TB Gold In-Tube (QFT) conversion interferon-γ values and risk of subsequent active tuberculosis disease and of QFT reversion.
Methods: We analysed data from a reported vaccine efficacy trial of the tuberculosis vaccine MVA85A in South Africa. QFT negative, HIV uninfected young children aged 18–24 weeks were enrolled. We stratified participants by quantitative QFT result (interferon-γ <0·35 IU/mL, 0·35–4·00 IU/mL, and >4·00 IU/mL) at the intermediate study visit (day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6–24 months. No QFT differences were observed between placebo and MVA85A groups at day 336 or end of study; therefore, both groups were included in analyses. Study clinicians were not masked to QFT values, but strict case definitions were used that excluded QFT results. We used generalised additive models to evaluate the quantitative relation between day 336 QFT value and subsequent disease risk, and we compared disease rates between QFT strata using a two-sample Poisson test.
Findings: Among 2512 young children with QFT tests done at day 336, 172 (7%) were positive; 87 (7%) of 1267 in placebo group and 85 (7%) of 1245 in the MVA85A group (p=1·00). Compared with QFT non-converters (tuberculosis disease incidence 0·7 per 100 person-years [95% CI 0·4–1·1]), children with QFT conversion at interferon-γ values between 0·35–4·00 IU/mL did not have significantly increased risk of disease (2·5 per 100 person-years [95% CI 0·4–9·4]; incidence rate ratio (IRR) 3·7 (95% CI 0·4–15·8; p=0·23). However, QFT conversion at interferon-γ values higher than 4·00 IU/mL was associated with substantially increased disease incidence (28·0 per 100 person-years [95% CI 14·9–45·7]) compared with non-converters (IRR 42·5 [95% CI 17·2–99·7]; p<0·0001), and compared with children with interferon-γ values between 0·35–4·00 IU/mL (IRR 11·4 [95% CI 2·4–107·2]; p=0·00047). Among 91 QFT converters who were given a repeat test, 53 (58%) reverted from positive to negative. QFT reversion risk was inversely associated with interferon-γ value at QFT conversion and was highest with interferon-γ values less than 4·00 IU/mL (47 [77%] of 61). Interpretation: In young children, tuberculosis disease risk was not significantly increased, and QFT reversion was common, following QFT conversion at interferon-γ values up to 10 times the recommended test threshold (0·35 IU/mL). By contrast, QFT conversion at very high interferon-γ values (>4·00 IU/mL) warrants intensified diagnostic and preventive intervention because of the extremely high risk of tuberculosis disease in these young children.
Authors
Jason R Andrews, Elisa Nemes, Michele Tameris, Bernard S Landry, Hassan Mahomed, J Bruce McClain, Helen A Fletcher, Willem A Hanekom, Robin Wood, Helen McShane, Thomas J Scriba, Mark Hatherill
[link url="http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30060-7/fulltext"]The Lancet article summary[/link]