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Published on: August 11, 2008
A Controlled Study of Tuberculosis Diagnosis in HIV-Infected and Uninfected Children in Peru
Richard A Oberhelman1, Giselle Soto-Castellares2, Robert H Gilman3
1Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States of America.
Insights
Diagnosing childhood tuberculosis is difficult, especially with HIV. PCR tests showed high false-positive rates in healthy children, while cultures were often negative in sick children, limiting diagnostic utility.
Area of Science:
- Pediatric infectious diseases
- Mycobacteriology
- Diagnostic test evaluation
Background:
- Diagnosing tuberculosis (TB) in children presents challenges due to difficulties in specimen collection and low bacterial loads, particularly in HIV-coinfected individuals.
- Limited studies have included well-controlled groups, leading to poorly defined test specificities for pediatric TB diagnostics.
- This study investigated TB diagnostic methods in a cohort of 525 children, including those with and without HIV infection.
Purpose of the Study:
- To evaluate the diagnostic performance of PCR, microscopy, and culture for tuberculosis in children, with a specific focus on the impact of HIV coinfection.
- To assess the specificity of diagnostic tests by including asymptomatic well-control participants.
- To determine the clinical utility of extensive laboratory testing in the diagnosis of suspected pediatric TB.
Main Methods:
- Analyzed 2422 specimens (gastric aspirates, nasopharyngeal aspirates, stools) from 525 children (suspected TB cases and well-controls, with and without HIV).
- Utilized in-house hemi-nested IS6110 PCR (results <24 hours) and compared with auramine microscopy, MODS liquid culture, and Lowenstein-Jensen solid culture (results ≤6 weeks).
- Assessed PCR false-positive rates in well-controls and culture positivity rates in cases, stratified by HIV status.
Main Results:
- PCR showed higher false-positive rates in HIV-positive well-controls (17%) compared to HIV-negative well-controls (5.5%).
- PCR positivity in suspected TB cases was similar across HIV-positive (6.7%) and HIV-negative children (6.7%).
- Culture positivity was significantly lower in HIV-positive cases (1.2%) versus HIV-negative cases (11%), with microscopy positivity being rare (0.21%).
Conclusions:
- PCR tests exhibited high false-positive rates, making PCR positivity as likely in well-controls as in suspected TB cases, especially in HIV-infected children.
- Traditional methods (microscopy and culture) demonstrated 100% specificity but had low sensitivity, particularly in HIV-positive children, with a high number of tests required per confirmed case.
- Extensive laboratory testing provided limited contribution to the care of children with suspected TB, highlighting the need for improved diagnostic strategies.
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 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.
Trial Registration:
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.
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