Diagnosis of childhood tuberculosis and host RNA expression in Africa.
BACKGROUND
Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV).


METHODS
The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood.


RESULTS
We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%.


CONCLUSIONS
RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).
Suzanne T
ST
Anderson
Myrsini
M
Kaforou
Andrew J
AJ
Brent
Victoria J
VJ
Wright
Claire M
CM
Banwell
George
G
Chagaluka
Amelia C
AC
Crampin
Hazel M
HM
Dockrell
Neil
N
French
Melissa S
MS
Hamilton
Martin L
ML
Hibberd
Florian
F
Kern
Paul R
PR
Langford
Ling
L
Ling
Rachel
R
Mlotha
Tom H M
THM
Ottenhoff
Sandy
S
Pienaar
Vashini
V
Pillay
J Anthony G
JAG
Scott
Hemed
H
Twahir
Robert J
RJ
Wilkinson
Lachlan J
LJ
Coin
Robert S
RS
Heyderman
Michael
M
Levin
Brian
B
Eley
D000349:Africa; D000465:Algorithms; D001431:Bacteriological Techniques; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007223:Infant; D055985:Latent Tuberculosis / Q000175:diagnosis; D008297:Male; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000302:isolation & purification; D020411:Oligonucleotide Array Sequence Analysis; D012329:RNA, Bacterial / Q000097:blood*; D012306:Risk; D012680:Sensitivity and Specificity; D059467:Transcriptome; D014376:Tuberculosis / Q000150:complications / Q000175:diagnosis* / Q000235:genetics
D012329:RNA, Bacterial