TY - JOUR
T1 - A controlled study of tuberculosis diagnosis in HIV-infected and uninfected children in Peru
AU - Oberhelman, Richard A.
AU - Soto-Castellares, Giselle
AU - Gilman, Robert H.
AU - Castillo, Maria E.
AU - Kolevic, Lenka
AU - Delpino, Trinidad
AU - Saito, Mayuko
AU - Salazar-Lindo, Eduardo
AU - Negron, Eduardo
AU - Montenegro, Sonia
AU - Laguna-Torres, V. Alberto
AU - Maurtua-Neumann, Paola
AU - Datta, Sumona
AU - Evans, Carlton A.
N1 - Funding Information:
This research study was supported entirely by National Institutes of Health grant 1 RO1 AI- 49139. Collaborators and the diagnostic laboratory for this research were also funded by: USAID TB Award HRN-5986-A-00-6006-00; NIH ITREID grant 5D43- TW00910; Fogarty-NIH AIDS training program 3T22- TW00016-05S3; NIAID tutorial training grant 5T35- AI07646-02; IFHAD: Innovation For Health And Development; Joint Global Health Trials consortium (Wellcome Trust/MRC/DFID); The Wellcome Trust; and Imperial College Biomedical Research Centre. NAMRU-6 work was supported by Work Unit Number 62787 S17 H B0002. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. In memoriam Luz Caviedes, who led the laboratory aspects of this research project with great enthusiasm, skill and dedication. We thank Dr. David A. J. Moore for his advice and encouragement, and we thank the participants, their families and the personnel of the regional and national health systems in Peru for supporting this research. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. Copyright Statement: V. Alberto Laguna-Torres and Giselle Soto-Castellares are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. § 105 provides that ''Copyright protection under this title is not available for any work of the United States Government''. Title 17 U.S.C. § 101.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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. Methods and Findings '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 HIVpositive). 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 wellcontrols 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 cultureproven 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.
AB - 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. Methods and Findings '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 HIVpositive). 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 wellcontrols 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 cultureproven 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.
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U2 - 10.1371/journal.pone.0120915
DO - 10.1371/journal.pone.0120915
M3 - Article
C2 - 25927526
AN - SCOPUS:84957837920
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 4
M1 - e0120915
ER -