RSS Feeds
-
Diagnostic Cohort Studies for Pediatric Tuberculosis: What does the future hold? – authors’ response
Submit responseWe thank Hesseling et al for recognising the importance of our study. Although our estimates of the prognostic power of ELISpot and TST were broadly similar we did not conclude that ELISpot does not predict disease progression significantly better than the tuberculin skin test (TST). The number of incident tuberculosis cases in our cohort was insufficient to determine whether one test was statistically significantly more prognostic than the other; such comparisons require additional larger studies, as explained in our recent response to Hernandez-Garduno (http://www.annals.org/cgi/eletters/0000605-200812020-00248v1 November 7 2008). We complied with STARD guidelines as far as possible given that this was a study of prognostic power not diagnostic utility.
We discussed the paucibacillary nature of childhood tuberculosis and the diagnostic challenge it poses (1). Contrary to Hesseling et al’s assertion, the radiological features of chest radiography (and CT thorax) were presented for all incident cases in Table 2 and its footnotes. We accept the limitations of telephonic system-based screening which is why we explicitly reported the use of this technique in a proportion of children.
We are aware that the risk of tuberculosis infection is a function of proximity and duration of exposure and index case infectivity and we systematically used this principle to validate ELISpot as a marker of latent tuberculosis infection in a series of cross-sectional studies since 2001 (2-4), an approach that has since been widely adopted by others for both types of interferon gamma release assays (IGRA). Levels of tuberculosis exposure within the household of smear positive index cases were considered for the Istanbul Child Tuberculosis Contact Cohort, as described in the first publication on this cohort which was referenced in our paper (4) and we would refer Hesseling et al to that report rather the correspondence they cited. Notwithstanding, it is self-evident that for longitudinal studies aiming to correlate baseline IGRA results with clinical outcomes, cohorts of heavily exposed contacts are entirely appropriate, as recognised by the only other investigators to have conducted such a study to date (5).
Although repeat BCG vaccination is practiced in Turkey we previously reported that repeat vaccination did not provide any incremental protection against tuberculosis infection compared to a single vaccination (4). Hence, the external validity of our findings (1) for populations receiving single vaccination is not limited by this factor.
Use of the 5 mm TST cut-off point as mandated by the Centres for Disease Control and Prevention and the American Thoracic Society was recommended by the reviewers for this analysis of our data. We agree that exploration of higher cut-off values is informative which is why we recently presented data using the local National guidelines of 10 mm and 15 mm induration as TST as cut-off points in unvaccinated and vaccinated children respectively (http://www.annals.org/cgi/eletters/0000605- 200812020-00248v1 November 7 2008). TST-positive children were no more likely to develop disease than TST negative children. Hence, contrary to Hesseling et al’s assertion, the use of a 5 mm cut-off point did not introduce a differential bias favouring ELISpot and, if anything the opposite was the case. The age-dependent provision of IPT based on TST positivity was taken into account in our multivariate analysis and explicitly discussed in our paper (1).
In terms of what the future may hold, we look forward to reading the results of future similar studies when they are published.
1. Bakir M, Millington KA, Soysal A, et al. Prognostic Value of a T Cell Based Interferon-Gamma Biomarker in Child Tuberculosis Contacts. Annals of Internal Medicine. 2008;epub.
2. Lalvani A, Pathan AA, Durkan H, et al. Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Lancet. 2001;357(9273):2017-21.
3. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet. 2003;361(9364):1168-73.
4. Soysal A, Millington KA, Bakir M, et al. Effect of BCG vaccination on risk of Mycobacterium tuberculosis infection in children with household tuberculosis contact: a prospective community-based study. Lancet. 2005;366(9495):1443-51.
5. Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A. Predictive Value of a Whole-blood IFN-{gamma} Assay for the Development of Active TB Disease. Am J Respir Crit Care Med. 2008;177:1164-1170.
Conflict of Interest:
Consultancies
Consultancies: A. Lalvani (Oxford Immunotec Ltd. [nonexecutive director from 2003 to 2007]). Stock ownership or options (other than mutual funds): A. Lalvani (Oxford Immunotec Ltd.), University of Oxford (Oxford Immunotec Ltd.). Patents received: A. Lalvani (T-cell–based diagnosis of tuberculosis infection.) Patents pending: K.A. Millington (T-cell–based diagnosis of tuberculosis infection.), A. Lalvani (T-cell–based diagnosis of tuberculosis infection.
-
DIAGNOSTIC COHORT STUDIES FOR PEDIATRIC TUBERCULOSIS: WHAT DOES THE FUTURE HOLD?
Submit responseDIAGNOSTIC COHORT STUDIES FOR PEDIATRIC TUBERCULOSIS: WHAT DOES THE FUTURE HOLD?
To the Editor
Prospective cohort studies are important to investigate the predictive utility of tuberculosis diagnostic tests in at-risk populations. We commend Bakir and colleagues for their efforts to investigate the predictive value of the ELISPOT-based interferon-gamma release assay (IGRA) for pediatric tuberculosis disease. The authors conclude that although the ELISPOT did not predict disease progression significantly better than the tuberculin skin test (TST) [ELISPOT: 20.5 per 1000 person-years (95% CI, 10.2-36.7) vs. TST: 16.6 per 1000 person- years (95% CI, 8.6-29.0)] (1), the ELISPOT could allow more focused targeting of isoniazied preventive therapy (IPT). A thoughtful review of their methods may guide future study design.
The paucibacillary nature of childhood tuberculosis poses diagnostic challenges. Rigorous tuberculosis case definitions however remain essential for reliable outcome measurement. The low observed yield of culture-positivity amongst cases (3/15; 20%) may be due to limited investigation. Thorough repeated investigations result in considerably higher yields of bacteriological confirmation, correlated with disease severity (2). Radiological features of chest radiography, the mainstay of clinical diagnosis, are not described. Case ascertainment is further limited by telephonic symptom-based screening in 61.6% of children. Limitations of symptom-based approaches in children are well known.
The utility of a diagnostic test is related to the prevalence of disease or infection in the population. Bakir et al provide limited epidemiological data. The risk of tuberculosis infection is a function of the proximity and duration of exposure and index case infectivity, and not a simple dichotomous measure (3). These factors were not considered and only child contacts of smear-positive index cases were enrolled. Repeat BCG vaccination is practiced in the study setting, where BCG has uniquely been shown to protect against tuberculosis infection, (4) further limiting the study’s external validity. The authors’ choice of a 5 mm TST cut-point in a population receiving multiple BCG vaccinations is unusual and may have introduced a differential bias favouring the ELISPOT. Exploration of higher cut-off values would have been informative. Diel et al reported no significant difference between the prognostic value of the ELISA-based IGRA and TST at the 10 mm cut -point despite significance at 5 mm (5). The age-dependent provision of IPT based on TST positivity may also have introduced a bias favouring the ELISPOT. Rigorous identification of non-adherence may improve assessment of the effect of IPT on outcome measures.
More data are required on the predictive utility of IGRAs in settings with varying disease burden. Future studies should include rigorous case definitions, consider local epidemiology including exposure degree and intercurrent exposure, BCG vaccination, age, incorporate serial measures, IPT and adherence. Finally, the use of standard measures for reporting diagnostic studies (6) may improve inter-study comparability.
REFERENCES
1. Bakir M, Millington KA, Soysal A, Deeks JJ, Efee S, Aslan Y, Dosanjh DP, Lalvani A.Prognostic Value of a T-Cell-Based, Interferon-{gamma} Biomarker in Children with Tuberculosis Contact. Ann Intern Med. 2008 Oct 20
2. Marais BJ, Hesseling AC, Gie RP, Schaaf HS, Enarson DA, Beyers N.The bacteriologic yield in children with intrathoracic tuberculosis. Clin Infect Dis. 2006 Apr 15; 42(8):e69-71. Epub 2006 Mar 6.
3. Hesseling AC, Mandalakas AM, Kirchner LH, Chegou NN, Marais BJ, Zhu X, Black GF, Stanley K, Beyers N, Walzl G. Highly Discordant T-Cell Responses In Individuals With Recent Household Tuberculosis Exposure. Thorax. 2008 Aug 5. [Epub ahead of print]
4. Lalvani A, Bakir M, Millington KA, Dosanjh D, Soysal A.BCG and protection against Mycobacterium tuberculosis infection. Lancet. 2006 Feb 4;367(9508):391-2.
5. Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A. 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. 2008; 177:1164-70.
6. STARD Statement Standards for the Reporting of Diagnostic accuracy studies. http://www.stard-statement.org/
Conflict of Interest:
None declared
-
Prognostic Value of a T-Cell–Based, Interferon- Biomarker in Turkish Children – authors’ response
Submit responseIn this study (1) we interpreted TST results in accordance with American Thoracic Society and Centers for Disease Control and Prevention guidelines which deem TST results positive if the induration diameter is ≥ 5 mm (2). However, as Hernández-Garduño rightly noted in his letter, this interpretation does not account for the potential impact of BCG vaccination on the TST response. As suggested by Hernández-Garduño, it might also be of interest to determine the prognostic value of TST for progression to tuberculosis in unvaccinated children. However, because 80% of children in our cohort were BCG-vaccinated, there were insufficient numbers of unvaccinated contacts to determine the prognostic value of TST or ELISpot in this subgroup. In any case, the ELISpot assay utilises M. tuberculosis antigens that are absent from BCG so that test results are not confounded by BCG vaccination status (3). The Turkish Ministry of Health guidelines adjust for BCG vaccination status by recommending to score a TST result as positive if the TST response is ≥ 10 mm induration in unvaccinated children and ≥ 15 mm induration in vaccinated children. When interpreting TST results of the child contacts in our study using these local guidelines, 6 of the 369 contacts that were TST-positive progressed to active tuberculosis within 465 person-years of follow-up (incidence rate 12.9 per 1000 person-years [95% CI 4.7, 28.1]). TST-positive children were no more likely to develop disease than TST-negative children (incidence rate ratio 1.06 (95% CI 0.38, 2.97), P=0.92). The incidence rate of tuberculosis in contacts deemed TST-positive by guidelines that take account of BCG vaccination status was lower than in children deemed TST-positive using US guidelines. This indicates that the increased specificity conferred by using higher thresholds for a positive TST result is achieved at the cost of decreased sensitivity, which is a major inherent limitation of the TST.
In the Gambian study (4) referred to by Hernández-Garduño, neither TST nor ELISpot predicted development of tuberculosis in close contacts, as mentioned in our paper (1). Whilst our data are the first to identify the prognostic value of ELISpot for subsequent development of tuberculosis in recent contacts, the number of incident tuberculosis cases was insufficient to determine whether ELISpot is significantly more prognostic than TST or PPD-ELISpot or SKSD-ELISpot. Such comparisons require additional larger studies that yield more cases of clinical disease and are adequately powered to detect differences between the prognostic power of ELISpot and TST. However, our study showed that a similar number of incident cases were detected by ELISpot as were detected by TST but from significantly fewer contacts with positive test results, probably because many of the 213 TST-positive, ELISpot-negative contacts had false-positive TST results associated with prior BCG vaccination. Thus, targeting preventive treatment to ELISpot-positive children would have required treatment of fewer children than when using TST, while preventing a similar number of TB cases.
References
1. Bakir M, Millington KA, Soysal A, et al. Prognostic Value of a T Cell Based Interferon-Gamma Biomarker in Child Tuberculosis Contacts. Annals of Internal Medicine. 2008;epub.
2. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161(4 Pt 2):S221-S247.
3. Lalvani A. Diagnosing tuberculosis infection in the 21st century: new tools to tackle an old enemy. Chest. 2007;131(6):1898-906.
Hill PC, Jackson-Sillah DJ, Fox A, et al. Incidence of Tuberculosis and the Predictive Value of ELISPOT and Mantoux Tests in Gambian Case Contacts. PLoS ONE. 2008;3(1):e1379.
Conflict of Interest:
Potential Financial Conflicts of Interest: Consultancies: A. Lalvani (Oxford Immunotec Ltd. [nonexecutive director from 2003 to 2007]). Stock ownership or options (other than mutual funds): A. Lalvani (Oxford Immunotec Ltd.), University of Oxford (Oxford Immunotec Ltd.). Patents received: A. Lalvani (T-cell–based diagnosis of tuberculosis infection.) Patents pending: K.A. Millington (T-cell–based diagnosis of tuberculosis infection.), A. Lalvani (T-cell–based diagnosis of tuberculosis infection.)
-
Prognostic Value of a T-Cell–Based, Interferon- Biomarker in Turkish Children
Submit responseThis recent Turkish study on children and adolescents by Dr. Bakir and colleagues reported the predictive value of ELISpot for the development of tuberculosis in close contacts of smear positive cases. The authors concluded that the incidence rate of tuberculosis in children with positive ELISpot results was similar to that in contacts with positive TST but ELISpot detected a similar number of incident cases from fewer contacts with positive test results. The difference was 169 contacts with a positive TST and negative ELISpot. However, 80% of all participants were BCG-vaccinated so it is likely that many of the 169 contacts had a false positive TST. The authors did not estimate the predictive value of both tests in no-BCG-vaccinated children (n=180) which would have given more comparative estimates in tests' performance. Furthermore and surprisingly no difference was found between the predictive values of ELISpot vs. PPD’s (p=0.10), or vs. the nontuberculosis antigen SKSD’s (p=0.21). This indicates that ELISpot does not predict better the development of disease than TST. The study reported 3 out of 15 cases with negative TST, 2 of them were also ELISpot negative at baseline. All cases received preventive therapy before the TB diagnosis but only 6 completed it. All of these also confirm the fact that current tests for LTBI are not 100% sensitive and that preventive therapy is not 100% efficient.
Another recent study in close contacts from Gambia did not show differences in the predicted value of ELISpot and Mantoux tests either(1).
The presence of more than one risk factor for tuberculosis -contact history and malnutrition of instance-in those with LTBI is likely playing an important role in the progression to active disease. Future long term comprehensive IGRA studies accounting for all known conditions and predisposing disorders of tuberculosis will enlighten our knowledge of the true value of IGRA in detecting LTBI and predicting tuberculosis.
1. Hill PC, Jackson-Sillah DJ, Fox A, et al. Incidence of tuberculosis and the predictive value of ELISPOT and Mantoux tests in Gambian case contacts. PLoS ONE. 2008 Jan 2;3(1):e1379.
Conflict of Interest:
None declared