Abstract
Tuberculosis (TB) remains an important public health problem and a leading infectious cause of death. Diagnosis and treatment of latent tuberculosis infection (LTBI) is important for TB control and elimination. Nevertheless, the diagnosis of LTBI in both adults and children remains complex, since there is no gold standard. The development of interferon gamma release assays was a major breakthrough in the diagnosis of LTBI. The evaluation of IGRAs in the diagnosis of LTBI in children is proven to be difficult since childhood TB differs from adults as immune responses vary with age. Separate studies assessing IGRAs performance in children are still limited, and only a few of them divide results by narrow age groups Nevertheless, new approaches are being exploited by the ongoing research for the development of more efficient diagnostic tools. It is likely that many changes in both the diagnosis and management of LTBI will occur in the near future. We believe that better understanding of the immunopathology of latency can ultimately lead to the development of more effective strategies in TB control. In the present review we summarize current data on diagnosis of LTBI in children, underscoring the existing challenges and limitations.
Similar content being viewed by others
Abbreviations
- TB:
-
Tuberculosis
- LTBI:
-
Latent tuberculosis infection
- TST:
-
Tuberculin skin test
- IGRAS:
-
Interferon gamma release assays
- Mtb:
-
Mycobacterium tuberculosis
- BCG:
-
Bacillus Calmette-Guerin
- QFT:
-
QuantiFERON-TB test
- MDR:
-
Multidrug resistant
- IC:
-
Immunocompromised
References
Abgrall S, Del Giudice P, Melica G, Costagliola D; on behalf of FHDH-ANRS CO4 (2010) HIV-associated tuberculosis and immigration in a high-income country: incidence trends and risk factors in recent years. AIDS 24:763–771
Migliori GB, D'Arcy Richardson M, Sotgiu G, Lange C (2009) Multidrug-resistant and extensively drug-resistant tuberculosis in the West. Europe and United States: epidemiology, surveillance, and control. Clin Chest Med 30:637–665
Newton SM, Brent AJ, Anderson S, Whittaker E, Kampmann B (2008) Paediatric tuberculosis. Lancet Infect Dis 8:498–510
Marais BJ, Gie RP, Schaaf HS, Beyers N, Donald PR, Starke JR (2006) Childhood pulmonary tuberculosis: old wisdom and new challenges. Am J Respir Crit Care Med 173:1078–1090
Hollo V, Amato-Gauci A, Kodmon C, Manissero D (2009) Tuberculosis in the EU and EEA/EFTA countries: what is the latest data telling us? Euro Surveill 14:19151
Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D, Bossink A, Magdorf K, Hölscher C, Kampmann B, Arend SM, Detjen A, Bothamley G, Zellweger JP, Milburn H, Diel R, Ravn P, Cobelens F, Cardona PJ, Kan B, Solovic I, Duarte R, Cirillo DM, Lange C; TBNET (2009) LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J 33:956–973
Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Obihara CC, Starke JJ, Enarson DA, Donald PR, Beyers N (2004) The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 8:278–285
Marais BJ, Graham SM, Cotton MF, Beyers N (2007) Diagnostic and management challenges for childhood tuberculosis in the era of HIV. J Infect Dis 196(Suppl 1):76–85
Ozuah PO, Ozuah TP, Stein RE, Burton W, Mulvihill M (2001) Evaluation of a risk assessment questionnaire used to target tuberculin skin testing in children. JAMA 285:451–453
Vynnycky E, Fine PE (2000) Lifetime risks, incubation period, and serial interval of tuberculosis. Am J Epidemiol 152:247–263
Kruk A, Gie RP, Schaaf HS, Marais BJ (2008) Symptom-based screening of child tuberculosis contacts: improved feasibility in resource-limited settings. Pediatrics 121:1646–1652
Pai M, Dheda K, Cunningham J, Scano F, O'Brien R (2007) T-cell assays for the diagnosis of latent tuberculosis infection: moving the research agenda forward. Lancet Infect Dis 7:428–438
Centers for Disease Control and Prevention (2010) Updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection, United States. MMWR 59(No.RR-5):2–3
Menzies D, Pai M, Comstock G (2007) Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 146:340–354
Bakir M, Millington KA, Soysal A, Deeks JJ, Efee S, Aslan Y, Dosanjh DP, Lalvani A (2008) Prognostic value of a T-cell-based, interferon-gamma biomarker in children with tuberculosis contact. Ann Intern Med 149:777–787
Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A (2008) Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis. Am J Respir Crit Care Med 177:1164–1170
Okada K, Mao TE, Mori T, Miura T, Sugiyama T, Yoshiyama T, Mitarai S, Onozaki I, Harada N, Saint S, Kong KS, Chhour YM (2008) Performance of an interferon-gamma release assay for diagnosing latent tuberculosis infection in children. Epidemiol Infect 136:1179–1187
Haustein T, Ridout DA, Hartley JC, Thaker U, Shingadia D, Klein NJ, Novelli V, Dixon GL (2009) 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 28:669–673
Tsiouris SJ, Austin J, Toro P, Coetzee D, Weyer K, Stein Z, El-Sadr WM (2006) Results of a tuberculosis-specific IFN-gamma assay in children at high risk for tuberculosis infection. Int J Tuberc Lung Dis 10:939–941
Diel R, Loddenkemper R, Meywald-Walter K, Gottschalk R, Nienhaus A (2009) Comparative performance of tuberculin skin test, QuantiFERON-TB-Gold in Tube assay, and T-Spot.TB test in contact investigations for tuberculosis. Chest 135:1010–1018
Chun JK, Kim CK, Kim HS, Jung GY, Lee TJ, Kim KH, Kim DS (2008) The role of a whole blood interferon-gamma assay for the detection of latent tuberculosis infection in Bacille Calmette-Guérin vaccinated children. Diagn Microbiol Infect Dis 62:389–394
Diel R, Loddenkemper R, Nienhaus A (2010) Evidence-based comparison of commercial interferon-γ release assays for detecting active TB: a metaanalysis. Chest 137:952–968
Sester M, Sotgiu G, Lange C, Giehl C, Girardi E, Migliori GB, Bossink A, Dheda K, Diel R, Dominguez J, Lipman M, Nemeth J, Ravn P, Winkler S, Huitric E, Sandgren A, Manissero D (2011) Interferon-c release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J 37:100–111
Diel R, Goletti D, Ferrara G, Bothamley G, Cirillo D, Kampmann B, Lange C, Losi M, Markova R, Migliori GB, Nienhaus A, Ruhwald M, Wagner D, Zellweger JP, Huitric E, Sandgren A, Manissero D (2011) Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis. Eur Respir J 37:88–99
Diel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A (2011) Negative and positive predictive value of a whole-blood IGRA for developing active TB - an update. Am J Respir Crit Care Med 183:88–95
Stout JE, Menzies D (2008) Predicting tuberculosis: does the IGRA tell the tale? Am J Respir Crit Care Med 177:1055–1057
Detjen AK, Keil T, Roll S, Hauer B, Mauch H, Wahn U, Magdorf K (2007) Interferon-gamma release assays improve the diagnosis of tuberculosis and nontuberculous mycobacterial disease in children in a country with a low incidence of tuberculosis. Clin Infect Dis 45:322–328
Hill PC, Jackson-Sillah DJ, Fox A, Brookes RH, de Jong BC, Lugos MD, Adetifa IM, Donkor SA, Aiken AM, Howie SR, Corrah T, McAdam KP, Adegbola RA (2008) Incidence of tuberculosis and the predictive value of ELISPOT and Mantoux tests in Gambian case contacts. PLoS One 3:1379
Ewer K, Deeks J, Alvarez L, Bryant G, Waller S, Andersen P, Monk P, Lalvani A (2003) Comparison of T-cell based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 361:1168–1173
Arend SM, Thijsen SF, Leyten EM, Bouwman JJ, Franken WP, Koster BF, Cobelens FG, van Houte AJ, Bossink AW (2007) Comparison of two interferon–gamma assays and tuberculin skin test for tracing tuberculosis contacts. Am J Respir Crit Care Med 175:618–627
Liebeschuetz S, Bamber S, Ewer K, Deeks J, Pathan AA, Lalvani A (2004) Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study. Lancet 364:2196–2203
Bamford AR, Crook AM, Clark JE, Nademi Z, Dixon G, Paton JY, Riddell A, Drobniewski F, Riordan A, Anderson ST, Williams A, Walters S, Kampmann B (2010) Comparison of interferon-{gamma} release assays and tuberculin skin test in predicting active tuberculosis (TB) in children in the UK: a paediatric TB network study. Arch Dis Child 95:180–186
Nicol MP, Davies MA, Wood K, Hatherill M, Workman L, Hawkridge A, Eley B, Wilkinson KA, Wilkinson RJ, Hanekom WA, Beatty D, Hussey G (2009) Comparison of T-SPOT.TB assay and tuberculin skin test for the evaluation of young children at high risk for tuberculosis in a community setting. Pediatrics 123:38–43
Connell TG, Curtis N, Ranganathan SC, Buttery JP (2006) Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children. Thorax 61:616–620
Brock I, Weldingh K, Lillebaek T, Follmann F, Andersen P (2004) Comparison of tuberculin skin test and new specific blood test in tuberculosis contacts. Am J Respir Crit Care Med 170(1):65–69
Lewinsohn DA, Lobato MN, Jereb JA (2010) Interferon-gamma release assays: new diagnostic tests for Mycobacterium tuberculosis infection, and their use in children. Curr Opin Pediatr 22:71–76
Tsolia MN, Mavrikou M, Critselis E, Papadopoulos NG, Makrinioti H, Spyridis NP, Metsou F, Tsagaraki M, Koulouri M, Kafetzis DA (2010) Whole blood interferon gamma release assay is a useful tool for the diagnosis of tuberculosis infection particularly among Bacille Calmette Guerin-vaccinated children. Pediatr Infect Dis J 29:1137–1140
Richeldi L, Ewer K, Losi M, Bergamini BM, Roversi P, Deeks J, Fabbri LM, Lalvani A (2004) T cell-based tracking of multidrug resistant tuberculosis infection after brief exposure. Am J Respir Crit Care Med 170:288–295
Higuchi K, Kondo S, Wada M, Hayashi S, Ootsuka G, Sakamoto N, Harada N (2009) Contact investigation in a primary school using a whole blood interferon-gamma assay. J Infect 58:352–357
Connell TG, Ritz N, Paxton GA, Buttery JP, Curtis N, Ranganathan SC (2008) A three-way comparison of tuberculin skin testing, QuantiFERON-TB gold and T-SPOT.TB in children. PLoS One 3:2624
Kampmann B, Whittaker E, Williams A, Walters S, Gordon A, Martinez-Alier N, Williams B, Crook AM, Hutton AM, Anderson ST (2009) Interferon-gamma release assays do not identify more children with active tuberculosis than the tuberculin skin test. Eur Respir J 33:1374–1382
del Corral H, París SC, Marín ND, Marín DM, López L, Henao HM, Martínez T, Villa L, Barrera LF, Ortiz BL, Ramírez ME, Montes CJ, Oquendo MC, Arango LM, Riaño F, Aguirre C, Bustamante A, Belisle JT, Dobos K, Mejía GI, Giraldo MR, Brennan PJ, Robledo J, Arbeláez MP, Rojas CA, García LF (2009) IFNgamma response to Mycobacterium tuberculosis, risk of infection and disease in household contacts of tuberculosis patients in Colombia. PLoS One 4:8257
National Collaborating Centre for Chronic Conditions (2006) Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. Royal College of Physicians, London
Tuberculosis Prevention and Control, Public Health Agency of Canada, and the Canadian Lung Association/Canadian Thoracic Society (2007) Canadian Tuberculosis Standards, 6th edn. Public Health Agency of Canada
Mandalakas AM, Hesseling AC, Chegou NN, Kirchner HL, Zhu X, Marais BJ, Black GF, Beyers N, Walzl G (2008) High level of discordant IGRA results in HIV-infected adults and children. Int J Tuberc Lung Dis 12:417–423
Barry CE 3rd, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, Schnappinger D, Wilkinson RJ, Young D (2009) The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7:845–855
Cruz AT, Geltemeyer AM, Starke JR, Flores JA, Graviss EA, Smith KC (2011) Comparing the tuberculin skin test and T-SPOT.TB blood test in children. Pediatrics 127:e31–e38
Machingaidze S, Wiysonge CS, Gonzalez-Angulo Y, Hatherill M, Moyo S, Hanekom W, Mahomed H (2011) The utility of an interferon gamma release assay for diagnosis of latent tuberculosis infection and disease in children: a systematic review and meta-analysis. Pediatr Infect Dis J 30:694–700
Connell TG, Zar HJ, Nicol MP (2011) Advances in the diagnosis of pulmonary tuberculosis in HIV-infected and HIV-uninfected Children. J Infect Dis 204:1151–1158
Ling DI, Zwerling AA, Steingart KR, Pai M (2011) Immune-based diagnostics for TB in children: what is the evidence? Paediatr Respir Rev 12:9–15
Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J, Fielding K, Wilkinson RJ, Pai M (2011) Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 12(1):45–55
Mandalakas AM, Detjen AK, Hesseling AC, Benedetti A, Menzies D (2011) Interferon-gamma release assays and childhood tuberculosis: systematic review and meta-analysis. Int J Tuberc Lung Dis 15:1018–1032
Connell T, Bar-Zeev N, Curtis N (2006) Early detection of perinatal tuberculosis using a whole blood interferon-gamma release assay. Clin Infect Dis 42:82–85
Bianchi L, Galli L, Moriondo M, Veneruso G, Becciolini L, Azzari C, Chiappini E, de Martino M (2009) Interferon-gamma release assay improves the diagnosis of tuberculosis in children. Pediatr Infect Dis J 28:510–514
Davies MA, Connell T, Johannisen C, Wood K, Pienaar S, Wilkinson KA, Wilkinson RJ, Zar HJ, Eley B, Beatty D, Curtis N, Nicol MP (2009) Detection of tuberculosis in HIV-infected children using an enzyme-linked immunospot assay. AIDS 23:961–969
Stavri H, Ene L, Popa GL, Duiculescu D, Murgoci G, Marica C, Ulea I, Cus G, Popa MI (2009) Comparison of tuberculin skin test with a whole-blood interferon gamma assay and ELISA, in HIV positive children and adolescents with TB. Roum Arch Microbiol Immunol 68:14–19
Warier A, Gunawathi S, Venkatesh JKR, Bose A (2010) T-cell assay as a diagnostic tool for tuberculosis. Indian Pediatr 47:90–92
Ferrara G, Losi M, D'Amico R, Roversi P, Piro R, Meacci M, Meccugni B, Dori IM, Andreani A, Bergamini BM, Mussini C, Rumpianesi F, Fabbri LM, Richeldi L (2006) Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study. Lancet 367:1328–1334
Nakaoka H, Lawson L, Squire SB, Coulter B, Ravn P, Brock I, Hart CA, Cuevas LE (2006) Risk for tuberculosis among children. Emerg Infect Dis 12:1383–1388
Hill PC, Brookes RH, Fox A, Jackson-Sillah D, Lugos MD, Jeffries DJ, Donkor SA, Adegbola RA, McAdam KP (2006) Surprisingly high specificity of the PPD skin test for M. tuberculosis infection from recent exposure in The Gambia. PLoS One 1:68
Hill PC, Brookes RH, Adetifa IM, Fox A, Jackson-Sillah D, Lugos MD, Donkor SA, Marshall RJ, Howie SR, Corrah T, Jeffries DJ, Adegbola RA, McAdam KP (2006) Comparison of enzyme-linked immunospot assay and tuberculin skin test in healthy children exposed to Mycobacterium tuberculosis. Pediatrics 117:1542–1548
Dogra S, Narang P, Mendiratta DK, Chaturvedi P, Reingold AL, Colford JM Jr, Riley LW, Pai M (2007) Comparison of a whole blood interferon-gamma assay with tuberculin skin testing for the detection of tuberculosis infection in hospitalized children in rural India. J Infect 54:267–276
Bergamini BM, Losi M, Vaienti F, D'Amico R, Meccugni B, Meacci M, De Giovanni D, Rumpianesi F, Fabbri LM, Balli F, Richeldi L (2009) Performance of commercial blood tests for the diagnosis of latent tuberculosis infection in children and adolescents. Pediatrics 123:419–424
Lighter J, Rigaud M, Eduardo R, Peng CH, Pollack H (2009) Latent tuberculosis diagnosis in children by using the QuantiFERON-TB Gold In-Tube test. Pediatrics 123:30–37
Domínguez J, Ruiz-Manzano J, De Souza-Galvão M, Latorre I, Milà C, Blanco S, Jiménez MA, Prat C, Lacoma A, Altet N, Ausina V (2008) Comparison of two commercially available gamma interferon blood tests for immunodiagnosis of tuberculosis. Clin Vaccine Immunol 15:168–171
Hesseling AC, Mandalakas AM, Kirchner HL, Chegou NN, Marais BJ, Stanley K, Zhu X, Black G, Beyers N, Walzl G (2009) Highly discordant T cell responses in individuals with recent exposure to household tuberculosis. Thorax 64:840–846
Hansted E, Andriuskeviciene A, Sakalauskas R, Kevalas R, Sitkauskiene B (2009) T-cell-based diagnosis of tuberculosis infection in children in Lithuania: a country of high incidence despite a high coverage with bacille Calmette-Guerin vaccination. BMC Pulm Med 9:41
Adetifa IM, Ota MO, Jeffries DJ, Hammond A, Lugos MD, Donkor S, Patrick O, Adegbola RA, Hill PC (2010) Commercial interferon gamma release assays compared to the tuberculin skin test for diagnosis of latent Mycobacterium tuberculosis infection in childhood contacts in the Gambia. Pediatr Infect Dis J 29:439–443
Lucas M, Nicol P, McKinnon E, Whidborne R, Lucas A, Thambiran A, Burgner D, Waring J, French M (2010) A prospective large-scale study of methods for the detection of latent Mycobacterium tuberculosis infection in refugee children. Thorax 65:442–448
Altet-Gómez N, De Souza-Galvao M, Latorre I, Milà C, Jiménez MA, Solsona J, Cantos A, Zamora JJ, Ruiz-Manzano J, Ausina V, Domínguez J (2011) Diagnosing TB infection in children: analysis of discordances using in vitro tests and tuberculin skin test. Eur Respir J 37:1166–1174
Statement of interest
The authors are members of the European Society of Pediatric Infectious Diseases (ESPID). V. Amanatidou is a researcher funded by the 2010 ESPID Fellowship Award.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Amanatidou, V., Syridou, G., Mavrikou, M. et al. Latent tuberculosis infection in children: diagnostic approaches. Eur J Clin Microbiol Infect Dis 31, 1285–1294 (2012). https://doi.org/10.1007/s10096-011-1524-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10096-011-1524-3