A Controlled Study of Tuberculosis Diagnosis in HIV-Infected and Uninfected Children in Peru.
BACKGROUND
Diagnosing tuberculosis in children is challenging because specimens are difficult to obtain and contain low tuberculosis concentrations, especially with HIV-coinfection. Few studies included well-controls so test specificities are poorly defined. We studied tuberculosis diagnosis in 525 children with and without HIV-infection.


RESULTS
'Cases' were children with suspected pulmonary tuberculosis (n = 209 HIV-negative; n = 81 HIV-positive) and asymptomatic 'well-control' children (n = 200 HIV-negative; n = 35 HIV-positive). Specimens (n = 2422) were gastric aspirates, nasopharyngeal aspirates and stools analyzed by a total of 9688 tests. All specimens were tested with an in-house hemi-nested IS6110 PCR that took <24 hours. False-positive PCR in well-controls were more frequent in HIV-infection (P≤0.01): 17% (6/35) HIV-positive well-controls versus 5.5% (11/200) HIV-negative well-controls; caused by 6.7% (7/104) versus 1.8% (11/599) of their specimens, respectively. 6.7% (116/1719) specimens from 25% (72/290) cases were PCR-positive, similar (P>0.2) for HIV-positive versus HIV-negative cases. All specimens were also tested with auramine acid-fast microscopy, microscopic-observation drug-susceptibility (MODS) liquid culture, and Lowenstein-Jensen solid culture that took ≤6 weeks and had 100% specificity (all 2112 tests on 704 specimens from 235 well-controls were negative). Microscopy-positivity was rare (0.21%, 5/2422 specimens) and all microscopy-positive specimens were culture-positive. Culture-positivity was less frequent (P≤0.01) in HIV-infection: 1.2% (1/81) HIV-positive cases versus 11% (22/209) HIV-negative cases; caused by 0.42% (2/481) versus 4.7% (58/1235) of their specimens, respectively.


CONCLUSIONS
In HIV-positive children with suspected tuberculosis, diagnostic yield was so low that 1458 microscopy and culture tests were done per case confirmed and even in children with culture-proven tuberculosis most tests and specimens were false-negative; whereas PCR was so prone to false-positives that PCR-positivity was as likely in specimens from well-controls as suspected-tuberculosis cases. This demonstrates the importance of control participants in diagnostic test evaluation and that even extensive laboratory testing only rarely contributed to the care of children with suspected TB.


BACKGROUND
This study did not meet Peruvian and some other international criteria for a clinical trial but was registered with the ClinicalTrials.gov registry: ClinicalTrials.gov NCT00054769.
Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States of America.
Richard A
RA
Oberhelman
Asociación Benéfica Proyectos en Informatica, Salud, Medicina, y Agricultura (PRISMA), Lima, Peru; US Naval Medical Research Unit Six, Lima, Peru.
Giselle
G
Soto-Castellares
Asociación Benéfica Proyectos en Informatica, Salud, Medicina, y Agricultura (PRISMA), Lima, Peru; Department of Microbiology, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia, Lima, Peru; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Robert H
RH
Gilman
Infectious Diseases Service, Instituto Nacional de Salud del Niño, Lima, Peru; Department of Pediatrics, Faculty of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru.
Maria E
ME
Castillo
Infectious Diseases Service, Instituto Nacional de Salud del Niño, Lima, Peru.
Lenka
L
Kolevic
Infectious Diseases Service, Instituto Nacional de Salud del Niño, Lima, Peru.
Trinidad
T
Delpino
Asociación Benéfica Proyectos en Informatica, Salud, Medicina, y Agricultura (PRISMA), Lima, Peru; Department of Microbiology, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia, Lima, Peru.
Mayuko
M
Saito
Department of Pediatrics, Hospital Nacional Cayetano Heredia, Lima, Peru.
Eduardo
E
Salazar-Lindo
Department of Pediatrics, Hospital Nacional Cayetano Heredia, Lima, Peru.
Eduardo
E
Negron
Universidad de Concepción, Concepción, Chile.
Sonia
S
Montenegro
US Naval Medical Research Unit Six, Lima, Peru.
V Alberto
VA
Laguna-Torres
Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
Paola
P
Maurtua-Neumann
Department of Microbiology, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia, Lima, Peru; Infectious Diseases & Immunity, Imperial College London, and Wellcome Trust Imperial College Centre for Global Health Research, London, United Kingdom; IFHAD: Innovation For Health And Development, London, United Kingdom.
Sumona
S
Datta
Department of Microbiology, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia, Lima, Peru; Infectious Diseases & Immunity, Imperial College London, and Wellcome Trust Imperial College Centre for Global Health Research, London, United Kingdom; IFHAD: Innovation For Health And Development, London, United Kingdom.
Carlton A
CA
Evans
D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000175:diagnosis* / Q000453:epidemiology; D006801:Humans; D007223:Infant; D008297:Male; D010568:Peru / Q000453:epidemiology; D016133:Polymerase Chain Reaction / Q000379:methods; D014376:Tuberculosis / Q000150:complications / Q000175:diagnosis* / Q000453:epidemiology