All Title Author
Keywords Abstract

PLOS ONE  2013 

Challenges in the Development of an Immunochromatographic Interferon-Gamma Test for Diagnosis of Pleural Tuberculosis

DOI: 10.1371/journal.pone.0085447

Full-Text   Cite this paper   Add to My Lib

Abstract:

Existing diagnostic tests for pleural tuberculosis (TB) have inadequate accuracy and/or turnaround time. Interferon-gamma (IFNg) has been identified in many studies as a biomarker for pleural TB. Our objective was to develop a lateral flow, immunochromatographic test (ICT) based on this biomarker and to evaluate the test in a clinical cohort. Because IFNg is commonly present in non-TB pleural effusions in low amounts, a diagnostic IFNg-threshold was first defined with an enzyme-linked immunosorbent assay (ELISA) for IFNg in samples from 38 patients with a confirmed clinical diagnosis (cut-off of 300pg/ml; 94% sensitivity and 93% specificity). The ICT was then designed; however, its achievable limit of detection (5000pg/ml) was over 10-fold higher than that of the ELISA. After several iterations in development, the prototype ICT assay for IFNg had a sensitivity of 69% (95% confidence interval (CI): 50-83) and a specificity of 94% (95% CI: 81-99%) compared to ELISA on frozen samples. Evaluation of the prototype in a prospective clinical cohort (72 patients) on fresh pleural fluid samples, in comparison to a composite reference standard (including histopathological and microbiologic test results), showed that the prototype had 65% sensitivity (95% CI: 44-83) and 89% specificity (95% CI: 74-97). Discordant results were observed in 15% of samples if testing was repeated after one freezing and thawing step. Inter-rater variability was limited (3%; 1out of 32). In conclusion, despite an iterative development and optimization process, the performance of the IFNg ICT remained lower than what could be expected from the published literature on IFNg as a biomarker in pleural fluid. Further improvements in the limit of detection of an ICT for IFNg, and possibly combination of IFNg with other biomarkers such as adenosine deaminase, are necessary for such a test to be of value in the evaluation of pleural tuberculosis.

References

[1]  Seibert AF, Haynes J Jr., Middleton R, Bass JB Jr. (1991) Tuberculous pleural effusion. Twenty-year experience. Chest 99: 883-886. doi:10.1378/chest.99.4.883. PubMed: 1901261.
[2]  Udwadia ZF, Sen T (2010) Pleural tuberculosis: an update. Curr Opin Pulm Med 16: 399-406. doi:10.1097/MCP.0b013e328339cf6e. PubMed: 20531085.
[3]  Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E et al. (2007) A systematic review of rapid diagnostic tests for the detection of tuberculosis infection. Health Technol Assess 11: 1-314. PubMed: 17266837.
[4]  Porcel JM (2009) Tuberculous pleural effusion. Lung 187: 263-270. doi:10.1007/s00408-009-9165-3. PubMed: 19672657.
[5]  Pai M, Flores LL, Hubbard A, Riley LW, Colford JM Jr. (2004) Nucleic acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis. BMC Infect Dis 4: 6. doi:10.1186/1471-2334-4-6. PubMed: 15102325.
[6]  Christopher DJ, Schumacher SG, Michael JS, Luo R, Balamugesh T et al. (2013) Performance of Xpert MTB/RIF on pleural tissue for the diagnosis of pleural tuberculosis. Eur Respir J 42: 1427-1429. doi:10.1183/09031936.00103213. PubMed: 23900990.
[7]  Friedrich SO, von Groote-Bidlingmaier F, Diacon AH (2011) Xpert MTB/RIF assay for diagnosis of pleural tuberculosis. J Clin Microbiol 49: 4341-4342. doi:10.1128/JCM.05454-11. PubMed: 21998430.
[8]  Tortoli E, Russo C, Piersimoni C, Mazzola E, Dal Monte P et al. (2012) Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. Eur Respir J 40: 442-447. doi:10.1183/09031936.00176311. PubMed: 22241741.
[9]  Jiang J, Shi HZ, Liang QL, Qin SM, Qin XJ (2007) Diagnostic value of interferon-gamma in tuberculous pleurisy: a metaanalysis. Chest 131: 1133-1141. doi:10.1378/chest.06-2273. PubMed: 17426220.
[10]  Liang QL, Shi HZ, Wang K, Qin SM, Qin XJ (2008) Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis. Respir Med 102: 744-754. doi:10.1016/j.rmed.2007.12.007. PubMed: 18222681.
[11]  Goto M, Noguchi Y, Koyama H, Hira K, Shimbo T et al. (2003) Diagnostic value of adenosine deaminase in tuberculous pleural effusion: a meta-analysis. Ann Clin Biochem 40: 374-381. doi:10.1258/000456303766477011. PubMed: 12880538.
[12]  Greco S, Girardi E, Masciangelo R, Capoccetta GB, Saltini C (2003) Adenosine deaminase and interferon gamma measurements for the diagnosis of tuberculous pleurisy: a meta-analysis. Int J Tuberc Lung Dis 7: 777-786. PubMed: 12921155.
[13]  Pérez-Rodríguez E, Pérez Walton IJ, Sanchez Hernández JJ, Pallarés E, Rubi J et al. (1999) ADA1/ADAp ratio in pleural tuberculosis: an excellent diagnostic parameter in pleural fluid. Respir Med 93: 816-821. doi:10.1016/S0954-6111(99)90267-6. PubMed: 10603631.
[14]  Buel E, MacQuarrie R (1981) Purification of adenosine deaminase from human red blood cells. Prep Biochem 11: 363-380. doi:10.1080/00327488108065529. PubMed: 7312831.
[15]  Ungerer JP, Oosthuizen HM, Bissbort SH, Vermaak WJ (1992) Serum adenosine deaminase: isoenzymes and diagnostic application. Clin Chem 38: 1322-1326. PubMed: 1623598.
[16]  Ruddy M, Balabanova Y, Graham C, Fedorin I, Malomanova N et al. (2005) Rates of drug resistance and risk factor analysis in civilian and prison patients with tuberculosis in Samara Region, Russia. Thorax 60: 130-135. doi:10.1136/thx.2004.026922. PubMed: 15681501.
[17]  Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75: 163-189. PubMed: 14525967.
[18]  Pant Pai N, Balram B, Shivkumar S, Martinez-Cajas JL, Claessens C et al. (2012) Head-to-head comparison of accuracy of a rapid point-of-care HIV test with oral versus whole-blood specimens: a systematic review and meta-analysis. Lancet Infect Dis 12: 373-380. doi:10.1016/S1473-3099(11)70368-1. PubMed: 22277215.
[19]  Posthuma-Trumpie GA, Korf J, van Amerongen A (2009) Lateral flow (immuno)assay: its strengths, weaknesses, opportunities and threats. A literature survey. Anal Bioanal Chem 393: 569-582. doi:10.1007/s00216-008-2287-2. PubMed: 18696055.
[20]  Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP et al. (2003) The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Ann Intern Med 138: W1-12. doi:10.7326/0003-4819-138-1-200301070-00012-?w1. PubMed: 12513067.
[21]  Ioannidis JP, Panagiotou OA (2011) Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses. JAMA 305: 2200-2210. doi:10.1001/jama.2011.713. PubMed: 21632484.
[22]  Klarkowski DB, Wazome JM, Lokuge KM, Shanks L, Mills CF et al. (2009) The evaluation of a rapid in situ HIV confirmation test in a programme with a high failure rate of the WHO HIV two-test diagnostic algorithm. PLOS ONE 4: e4351. doi:10.1371/journal.pone.0004351. PubMed: 19197370.
[23]  Lee VJ, Tan SC, Earnest A, Seong PS, Tan HH et al. (2007) User acceptability and feasibility of self-testing with HIV rapid tests. J Acquir Immune Defic Syndr 45: 449-453. doi:10.1097/QAI.0b013e318095a3f3. PubMed: 17554213.
[24]  Denkinger CM, Grenier J, Minion J, Pai M (2012) Promise versus reality: optimism bias in package inserts for tuberculosis diagnostics. J Clin Microbiol 50: 2455-2461. doi:10.1128/JCM.00842-12. PubMed: 22573592.
[25]  Ioannidis JP (2008) Why most discovered true associations are inflated. Epidemiology 19: 640-648. doi:10.1097/EDE.0b013e31818131e7. PubMed: 18633328.
[26]  Porcel JM, Vives M (2003) Differentiating tuberculous from malignant pleural effusions: a scoring model. Med Sci Monit 9: CR175-180.
[27]  Villegas MV, Labrada LA, Saravia NG (2000) Evaluation of polymerase chain reaction, adenosine deaminase, and interferon-gamma in pleural fluid for the differential diagnosis of pleural tuberculosis. Chest 118: 1355-1364. doi:10.1378/chest.118.5.1355. PubMed: 11083686.

Full-Text

comments powered by Disqus