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COMPARISON OF TSPOT.TB AND TUBERCULIN SKIN TEST IN CHILDREN EXPOSED TO PATIENTS WITH TUBERCULOSIS

COMPARISON OF TSPOT.TB AND TUBERCULIN SKIN TEST IN CHILDREN EXPOSED TO PATIENTS WITH TUBERCULOSIS. *Ümit S. Çelik , * Emine Kocabaş, ** İlker Ünal, *** Mustafa Yılmaz, **** Kurthan Mert, ***** Levent Etiz * Çukurova University, Pediatric Infectious Department

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COMPARISON OF TSPOT.TB AND TUBERCULIN SKIN TEST IN CHILDREN EXPOSED TO PATIENTS WITH TUBERCULOSIS

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  1. COMPARISON OF TSPOT.TB AND TUBERCULIN SKIN TEST IN CHILDREN EXPOSED TO PATIENTS WITH TUBERCULOSIS *Ümit S. Çelik, *Emine Kocabaş, **İlker Ünal, ***Mustafa Yılmaz, ****Kurthan Mert, *****Levent Etiz * Çukurova University, Pediatric Infectious Department ** Çukurova University, Biostatistics Department *** Çukurova University, Pediatric Immunolgy Department **** Çukurova University, Pediatrics **** Çukurova University, Pediatric Haematology Department

  2. Two main routes for traditional diagnosis of infection; • Direct detection of pathogen (microscopy, culture, PCR) • Detect to immune response to the pathogen (ELISA)

  3. Immune response = antibodies + T cells • T cells control intracellular pathogens • Many diseases where antibodies don’t work. • T cells are key in these diseases( HIV, Autoimmune disease, HPV, Hepatitis, mycobacterial infection)

  4. The Biological Basics of IFN- and Tuberkulin Skin Test

  5. TST • Measures cell-mediated immune response • Uses PPD: a antigenic mixture • Limitations of TST: • fairly high proportion of false positives and false negatives • technical problems in administration and interpretation • difficulty in separating true infection from the effects of BCG and non-tuberculous mycobacteria (NTM)

  6. İnterferon gamma release assay (IGRA) T-SPOT.TB® [Oxford Immunotec, UK] Pai M et al. Lancet Infect Dis 2004;4:761-76 QuantiFERON-TB Gold® [Cellestis Ltd, Australia]

  7. Early diagnosis of infectious cases and treatment of individuals latently infected with Mycobacterium tuberculosis are the key strategies for reducing the incidence of TB. • In children up to 50% of untreated infants and 15% of older children with latent TB infection develop disease within two years of being infected. • In many years, TST is commonly used to aid diagnosis of latent TB in children. • However, the TST is not sufficiently spesific and sensitive.

  8. Areas of uncertainty • Discordance between the TST and IGRAs results • Discordance within IGRAs • Correlation between bacterial burden and T cell responses; effect of TB treatment on T cell responses • Test performance in high-risk populations such as HIV+, children, immunocompromised • Performance in serial testing and variability of IFN-g over time Celik Ü, Kocabas E. Tuberk Toraks 2007;55(1):108-117 Pai M et al. Exp Rev Mol Diagn 2006;6(3):413-422

  9. Objective • The compare the results of tuberculin skin test (TST) and a T-cell-based test (T-SPOT.TB) for tuberculosis infection in children exposed to a case of smear-positive and/or culture proven pulmonary tuberculosis

  10. Material-Method • One-hundred and ninety-one children who had close or far contact with smear-positive and/or culture proven 51 PTB cases were prospectively enrolled into the study, which take place from September 2005 to January 2007. • All individuals agreed to participate in the study by written consent. • Ethical approval for the study was granted by the ethics commision of the Cukurova University Faculty of Medicine. • Each family was interviewed using a standardized questionnaire. • Information was obtained on: the contact’s birth date, age, sex, and father’s education, BCG vaccination status (documented or verbally from parents), and the presence or absence of a typical BCG scar in the deltoid region,results of tuberculin skin testing, and the chest radiographic findings. • All adults diagnosed pulmonary tuberculosis (sputum smear positive and culture positive) at three goverment funded tuberculosis clinic and Cukurova University Faculty of Medicine in Adana during one year from September 2005, patients had one or more child household or far contact.

  11. Definitions • Close contacts were defined as household (they slept in the same bedroom) and intimate contacts. • Far contacts were defined as living at different home and either only once at week nor spending less time then an hour at same room. • Index case numbers were digitized as the basic of all children contact with pulmonary tuberculosis patient.

  12. Definitions II • In the absence of a recognised gold standart and in agreement with published studies latent TB infection was defined as an asymptomatic child with a positive TST as defined above and a normal chest radiograph. • Uninfected was defined as an asymptomatic child with a negative TST.

  13. 191 child contact were enrolled the study. • All children underwent a Mantoux test and chest radiography and 4-10 ml venous blood sample taken for TSPOT.TB test each children.

  14. Tuberculin skin test • The TST applied was the intradermal TST (Mantoux technique) with 0,1 ml 5 TU PPD and interpreted by trained health care workers and pediatricians. • The test were done and read after 72 hours by the study pediatricians who were blinded T SPOT-TB. • A positive TST was defined as Turkish Ministry Health guideline : induration of >15 mm in individuals with evidence of prior BCG vaccination, >10 mm with no history of BCG vaccination.

  15. TSPOT.TB • The T SPOT-TB test was performed according to the manufacturer’s instructions included in the assay kit (T SPOT-TB, Oxford Immunotec). • Test wells were scored as positive if they contained at least five spot-forming cells more than the negative control well and this number was at least twice the number of the negative control well. • Patients were considered positive if there was a positive response to one or both of the antigen panels (ESAT 6and/or CFP-10).

  16. Technical performance of the T SPOT-TB test • Evaluable results were obtained with the T SPOT-TB test for 167 of 191 children. • The cells of four patient did not sufficiently respond to the positive control stimulation with phytohaemagglutinin, and these patient was therefore disregarded from the data analysis. • In twenty patients were not being able to obtain sufficient lymphocytes so they we excluded the study. • Excluding this twenty four cases, a good response to the positive control stimulation with phytohaemagglutinin was observed in all patients.

  17. Statistical Methods • Analyses were performed using SPSS verion 15.0 (SPSS Inc. Chicago USA) • Concordance between test results from the TSTand TSPOT TB was assessed using kappa κ coefficients. • κ > 0,75 excellent agreement; κ=0,4-0,75 good agreement; κ<0,4 poor agreement.

  18. Statistical Methods • Categorical data were compared by the ki-squared test • Logistical regression was used to estimate odds ratios (ORs) of positive responses to each test for each of the variables measured. • All p values reported are based on two-tailed comparisons, with statistical significance set at p < 0.05. • Percent and count were used to summaries of discrete variables • t test was used to compare the current measurement of positive or negative test results of individuals at independent groups.

  19. The overall agreement was 68% between TST and TSPOT.TB (concordance, (kappa:0.372) (p=0.057)

  20. 52 children were TCT negative TSPOT.TB positive.

  21. When the children were grouped according to TST diameters, concordance between TSPOT.TB and TST assesed to within four group. • 44 children’s TCT diameters were between 0 and 4 mm 49 children were between 5 and 9 mm 41 children were between 10 and 14 mm 33 children were 15 mm and higher.

  22. Tests results according to TCT diameter

  23. Tests results according to contact status

  24. Between the TST and TSPOT. TB was more likely to be concordance (kappa=0.423, p<0.001) in close contact group than the other group. • In far contact group, accordance was poorer (kappa=0.044, p=0.49).

  25. Tests results according to BCG scar status

  26. According to the number of BCG scar; • These tests was excellent harmony in no BCG scar group. (kappa=0.719, p<0.001) • Kappa was 0.252 in one BCG scar group, • 0.424 in two BCG scar group.

  27. TSPOT.TB spesifity was 60.9%

  28. When number of the index case was excess than one, TSPOT.TB OR=4.28 (%95 CI 1.312-13.989) • In the other hand, in this situation PPD OR=6.452 (%95 CI 2.303-18.074)

  29. The suitability of both two tests found similiar with the literature in our study (55-90%). • TSPOT.TB assay was unaffected by BCG vaccination status. • Some studies showed that the degree of exposure of contacts to the source case is usually more closely correlated with a positive result in a whole blood IFN gamma assay.). Kang YA et al. JAMA 2005. Brock I. et al. AJRCCM 2006. • This is true for our study to. • Although a decline at exposure positive case can get TSPOT.TB either. • Maybe , this is especially important for childhood.

  30. The guideline of UK for IGRA tests usage, emphasizes the use of these tests at TCT positive patients. • Can we make a mistake 1/3 patients if we don’t perform these tests at TCT negative patients respect to our study? • Today, we discuss this issue.

  31. In the past, when exposed contacts had a negative TST this was taken as evidence that they had avoided primary infection. Menzies D et al. The tuberculin skin test. In: Reichman Tuberculosis2000 Arend reported that IGRA+/TST- discordance was associated with indicators of recent exposure. Arend SM. AJRCCM 2007. The sensitivity of IFN gamma had reported more at HIV+ or negative drug users. Some individuals at the study (9/24), showed TCT negativity although known positivity previously. Converse et al. J Infect Dis 1997)

  32. One of the new study and letters aimed to discuss this subject. Ewer K, et al. AJRCCM 2006;174 Girardi E et al. AJRCCM 2007,15;175(2):198-199. • Should individuals who are TCT-/IGRA+ preventive therapy?

  33. There are lesser contacts than literature who were TST+ TSPOT.TB- • This is true infection!!.

  34. Respect to these results, this study prolonged and both TCT and TSPOT.TB tests of this groups patients (TST-/IGRA+) started to repeat. • In conlusion, as IFN gamma assays can determine the approachs to this hard considerable group of patients; will be an important data.

  35. Areas of uncertainty • Discordance between the TST and IGRAs results • Discordance within IGRAs • Correlation between bacterial burden and T cell responses; effect of TB treatment on T cell responses • Test performance in high-risk populations such as HIV+, children, immunocompromised • Performance in serial testing and variability of IFN-g over time Celik Ü, Kocabas E. Tuberk Toraks 2007;55(1):108-117 Pai M et al. Exp Rev Mol Diagn 2006;6(3):413-422

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