Clinical Significance of Interferon $\gamma$ Release Assay for Diagnosis of Tuberculosis in Children

소아 결핵 진단에 있어서 결핵 특이항원자극 인터페론 감마 측정검사의 임상적 의의

  • Lee, Hee Woo (Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University) ;
  • Park, Hwa Young (Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University) ;
  • Ahn, Young Min (Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University) ;
  • Sohn, Keun Chan (Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University)
  • 이희우 (을지대학교 의과대학 소아과학교실) ;
  • 박화영 (을지대학교 의과대학 소아과학교실) ;
  • 안영민 (을지대학교 의과대학 소아과학교실) ;
  • 손근찬 (을지대학교 의과대학 소아과학교실)
  • Received : 2010.08.12
  • Accepted : 2010.10.17
  • Published : 2010.12.25

Abstract

Purpose : The purpose of this study is to evaluate the usefulness and limitation of QuantiFERON-TB Gold (QTB) for diagnosis of latent tuberculosis in children. Methods : The medical records of 112 children who were tested by tuberculin skin test (TST) and QTB for detection of latent tuberculosis (TB) in Eulji General Hospital during the period from January 2007 to June 2009 were retrospectively reviewed. Results : Of the 112 participants, the clinical TB group included 15 (13.4%), the contact group included 43 (38.4%), and the non-contact group included 54 (48.2%). Positive rates of TST and QTB were 100% and 80% in the clinical TB group, 64% and 14% in the close contact group, 27% and 0% in the casual contact group, and 52% and 2% in the non-contact group, respectively. Sensitivity of QTB was 80.0% and specificity was 92.6%. Agreement between QTB and TST was poor ($\kappa$=0.209). We also confirmed that the positive rate of QTB increased as the age of the patient increased (P=0.011). A QTB indeterminate result was observed in 11 (9.8%) subjects. QTB was retested in 15 subjects. In 5 of the 6 subjects who had positive results initially, positive results persisted for a median 2.2 months after termination of treatment. Conclusion : Although QTB was associated with several problems, including low sensitivity and a high rate of indeterminate results, it had clinical importance due to its high specificity. We found good correlation with regard to exposure and QTB positivity, including that of young children under 5 years of age. However, clinical application of interferon-$\gamma$ releasing assay for young children for diagnosis of active and latent tuberculosis will require additional prospective studies.

목적 : 본 연구는 소아에서 QuantiFERON-TB Gold(QTB) 검사의 임상적 유용성과 문제점을 평가하기 위해 시행되었다. 방 법: 2007년 1월부터 2009년 6월까지 본원에서 TST와 QTB를 시행 받은 소아청소년 112명의 의무 기록을 후향적으로 조사하였다. 결과 : TST와 QTB의 양성률은 각각 59.8%, 15.2%였고, 두 검사의 일치도는 낮았다($\kappa$=0.209). QTB의 민감도와 특이도는 각각 80.0%, 92.6%였다. QTB 양성율은 임상적 결핵군, 긴밀 접촉군, 일반 접촉군, 비접촉군에서 각각 80%, 14%, 0%, 2% 였으며, 판정보류의 빈도는 9.8%였다. QTB 추적 관찰이 시행된 환자 중, 초기 QTB 양성이었던 6명 중 5명은 치료 종료 후 평균 2.2개월까지 양성이 지속되었다. 결론 : 소아에서 QTB는 민감도가 낮고, 판정보류의 빈도가 높다는 단점이 있으나, 특이도가 높은 장점이 있으므로, TST의 특이도가 낮은 점을 보완하여 결핵의 진단 및 치료 결정에 활용될 수 있을 것으로 생각된다.

Keywords

References

  1. World Health Organization. Global tuberculosis control: surveilance, planning, financing. Geneva, Switzerland: World Health Organization, 2002.
  2. Shim TS, Koh WJ, Yim JJ, WJ. L. Diagnosis and treatment of latent tuberculosis infection in Korea. Tuberc Respir Dis 2004;282:677-86.
  3. Shin KC. Report on the seventh national tuberculosis prevalence survey. The Korean Academy of Tuberculosis and Respiratory diseases 1997;85:171-7.
  4. Marais BJ, Gie RP, Schaaf HS, Beyers N, Donald PR, Starke JR. Childhood pulmonary tuberculosis: old wisdom and new challenges. Am J Respir Crit Care Med 2006;173:1078-90. https://doi.org/10.1164/rccm.200511-1809SO
  5. Huebner RE, Schein MF, Bass JB, Jr. The tuberculin skin test. Clin Infect Dis 1993;17:968-75. https://doi.org/10.1093/clinids/17.6.968
  6. Lighter J, Rigaud M, Eduardo R, Peng CH, Pollack H. Latent tuberculosis diagnosis in children by using the QuantiFERON-TB Gold In-Tube test. Pediatrics 2009; 123:30-7. https://doi.org/10.1542/peds.2007-3618
  7. Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340-54. https://doi.org/10.7326/0003-4819-146-5-200703060-00006
  8. Chee CB, KhinMar KW, Gan SH, Barkham TM, Pushparani M, Wang YT. Latent tuberculosis infection treatment and T-cell responses to Mycobacterium tuberculosis- specific antigens. Am J Respir Crit Care Med 2007; 175(3):282-7. https://doi.org/10.1164/rccm.200608-1109OC
  9. Ferrara G, Losi M, D'Amico R, Roversi P, Piro R, Meacci M, et al. Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study. Lancet 2006;367:1328-34. https://doi.org/10.1016/S0140-6736(06)68579-6
  10. Goletti D, Vincenti D, Carrara S, Butera O, Bizzoni F, Bernardini G, et al. Selected RD1 peptides for active tuberculosis diagnosis: comparison of a gamma interferon whole-blood enzyme-linked immunosorbent assay and an enzyme-linked immunospot assay. Clin Diagn Lab Immunol 2005;12:1311-6.
  11. Okada K, Mao TE, Mori T, Miura T, Sugiyama T, Yoshiyama T, et al. Performance of an interferon-gamma release assay for diagnosing latent tuberculosis infection in children. Epidemiol Infect 2008;136:1179-87.
  12. Nakaoka H, Lawson L, Squire SB, Coulter B, Ravn P, Brock I, et al. Risk for tuberculosis among children. Emerg Infect Dis 2006;12:1383-8. https://doi.org/10.3201/eid1209.051606
  13. Liebeschuetz S, Bamber S, Ewer K, Deeks J, Pathan AA, Lalvani A. Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study. Lancet 2004;364:2196-203. https://doi.org/10.1016/S0140-6736(04)17592-2
  14. Haustein T, Ridout DA, Hartley JC, Thaker U, Shingadia D, Klein NJ, et al. The likelihood of an indeterminate test result from a whole-blood interferon-gamma release assay for the diagnosis of Mycobacterium tuberculosis infection in children correlates with age and immune status. Pediatr Infect Dis J 2009;28:669-73. https://doi.org/10.1097/INF.0b013e3181a16394
  15. Lewinsohn DA. Embracing interferon-gamma release assays for diagnosis of latent tuberculosis infection. Pediatr Infect Dis J 2009;28:674-5. https://doi.org/10.1097/INF.0b013e3181ad547d
  16. Powell DA. Interferon gamma release assays in the evaluation of children with possible Mycobacterium tuberculosis infection: a view to caution. Pediatr Infect Dis J 2009;28:676-7. https://doi.org/10.1097/INF.0b013e3181ad5490
  17. Mazurek GH, Jereb J, Vernon A, Lobue P, Goldberg S, Castro K. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010. CDC Morbidity and Mortality weekly report 2010;59:1-24.
  18. Sung JY, Kim JH, Yang MA, Kim SH, Eun BW, Kim NH, et al. Usefulness of interferon gamma measurement following stimulation of tuberculosis-specific antigens for diagnosis of latent tuberculosis infection in children exposed to pulmonary tuberculosis. Korean J Pediatr Infect Dis 2008;15:51-7.
  19. Chun JK, Kim CK, Kim HS, Jung GY, Linton JA, Kim KH, et al. Comparison of a whole blood Interferon gamma assay and A tuberculin skin test for detecting latent tuberculosis infection in children. Korean J Pediatr 2008;51:971-6. https://doi.org/10.3345/kjp.2008.51.9.971
  20. Kim YJ, Lee JS. Comparison of Interferon gamma assays with the tuberculin skin test in children. Pediatr Allergy Respir Dis (Korea) 2010;20:10-6.
  21. Han YM, Kim HS, Kim CH, Kang HJ, Lee KM. Analysis of patients with positive acid-fast bacilli culture and negative T-SPOT.TB results. Korean J Lab Med 2010; 30:414-9. https://doi.org/10.3343/kjlm.2010.30.4.414
  22. Kim BS, Hwang MH, Kim CH, Park JO, Shin SM. The effect of percutaneous multiple puncture BCG vaccination on PPD 1TU, 2TU and 5TU tuberculin skin test. Korean J Pediatr Infect Dis 2001;8:175-80.
  23. Kim WS, Kim CH, Lee DH, Shin SM. Conversion rates of tuberculin test according to BCG vaccination methods. J Korean Pediatr 1997;40:489-96.
  24. Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006;10:1192-204.
  25. American Academy of Pediatrics, Committee on Infectious Diseases. Red book. report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village: American Academy of Pediatrics, 2003:642-60.
  26. Connell TG, Curtis N, Ranganathan SC, Buttery JP. Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children. Thorax 2006;61:616-20. https://doi.org/10.1136/thx.2005.048033
  27. Cehovin A, Cliff JM, Hill PC, Brookes RH, Dockrell HM. Extended culture enhances sensitivity of a gamma interferon assay for latent Mycobacterium tuberculosis infection. Clin Vaccine Immunol 2007;14:796-8. https://doi.org/10.1128/CVI.00093-07
  28. Leyten EM, Arend SM, Prins C, Cobelens FG, Ottenhoff TH, van Dissel JT. Discrepancy between Mycobacterium tuberculosis-specific gamma interferon release assays using short and prolonged in vitro incubation. Clin Vaccine Immunol 2007;14:880-5. https://doi.org/10.1128/CVI.00132-07
  29. Grare M, Derelle J, Dailloux M, Laurain C. Difficulties of TB diagnosis in children: QuantiFERON TB Gold[R] In-Tube as useful tool. Arch Pediatr 2010;17:77-85.
  30. Bianchi L, Galli L, Moriondo M, Veneruso G, Becciolini L, Azzari C, et al. Interferon-gamma release assay improves the diagnosis of tuberculosis in children. Pediatr Infect Dis J 2009;28:510-4. https://doi.org/10.1097/INF.0b013e31819abf6b
  31. Kobashi Y, Sugiu T, Mouri K, Obase Y, Miyashita N, Oka M. Indeterminate results of QuantiFERON TB-2G test performed in routine clinical practice. Eur Respir J 2009;33:812-5. https://doi.org/10.1183/09031936.00075008
  32. Mazurek GH, Jereb J, Lobue P, Iademarco MF, Metchock B, Vernon A. Guidelines for using the Quanti- FERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep 2005;54(RR-15):49-55.
  33. Ferrara G, Losi M, Meacci M, Meccugni B, Piro R, Roversi P, et al. Routine hospital use of a new commercial whole blood interferon-gamma assay for the diagnosis of tuberculosis infection. Am J Respir Crit Care Med 2005;172:631-5. https://doi.org/10.1164/rccm.200502-196OC
  34. Luetkemeyer AF, Charlebois ED, Flores LL, Bangsberg DR, Deeks SG, Martin JN, et al. Comparison of an interferon- gamma release assay with tuberculin skin testing in HIV-infected individuals. Am J Respir Crit Care Med 2007;175:737-42. https://doi.org/10.1164/rccm.200608-1088OC
  35. Frenkel L, Bryson YJ. Ontogeny of phytohemagglutinininduced gamma interferon by leukocytes of healthy infants and children: evidence for decreased production in infants younger than 2 months of age. J Pediatr 1987; 111:97-100. https://doi.org/10.1016/S0022-3476(87)80353-0
  36. Miyawaki T, Seki H, Taga K, Sato H, Taniguchi N. Dissociated production of interleukin-2 and immune (gamma) interferon by phytohaemagglutinin stimulated lymphocytes in healthy infants. Clin Exp Immunol 1985; 59:505-11.
  37. Bosshard V, Roux-Lombard P, Perneger T, Metzger M, Vivien R, Rochat T, et al. Do results of the T-SPOT.TB interferon-gamma release assay change after treatment of tuberculosis? Respir Med 2009;103:30-4. https://doi.org/10.1016/j.rmed.2008.09.012
  38. Dheda K, Pooran A, Pai M, Miller RF, Lesley K, Booth HL, et al. Interpretation of Mycobacterium tuberculosis antigen-specific IFN-gamma release assays (T-SPOT.TB) and factors that may modulate test results. J Infect 2007; 55:169-73. https://doi.org/10.1016/j.jinf.2007.02.005
  39. 39) Kobashi Y, Sugiu T, Ohue Y, Mouri K, Obase Y, Miyashita N, et al. Long-term follow-up of the Quanti FERON TB-2G test for active tuberculosis disease. Intern Med 2008;47:1957-61. https://doi.org/10.2169/internalmedicine.47.1313