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The Predictive Value of the ELISpot-Based Interferon-[ggr ]–Release Assay for Tuberculosis Disease
- Ajit Lalvani, DM; and
- Kerry A. Millington, DPhil
IN RESPONSE:
We thank Dr. Hesseling and colleagues for recognizing 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 TST. The number of incident tuberculosis cases in our cohort was insufficient to determine whether 1 test was statistically significantly more prognostic than the other; such comparisons require additional larger studies. We complied with STARD (Standards for the Reporting of Diagnostic accuracy studies) guidelines as far as possible, given that this was a study of prognostic power and not diagnostic utility.
We discussed the paucibacillary nature of childhood tuberculosis and the diagnostic challenge it poses. Contrary to Dr. Hesseling and colleagues' assertion, Table 2 of our article presented the radiologic features of chest radiography (and computed tomography of the thorax) for all incident cases. 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 for tuberculosis infection is a function of proximity and duration of exposure and index-case infectivity. We systematically used this principle to validate ELISpot as a marker of latent tuberculosis infection in a series of cross-sectional studies since 2001 (1–3), an approach that has been widely adopted by others for both types of IGRAs. Levels of tuberculosis exposure within the household of smear-positive index case patients were considered for the Istanbul Child Tuberculosis Contact Cohort, as described in the first publication on this cohort (3), which was referenced in our article. We would refer Dr. Hesseling and colleagues to that report rather than the correspondence they cited. Notwithstanding, for longitudinal studies aiming to correlate baseline IGRA results with clinical outcomes, cohorts of heavily exposed contacts are entirely appropriate, as recognized by the only other investigators to have conducted such a study to date (4).
Although repeated BCG vaccination is practiced in Turkey, we previously reported that repeated vaccination did not provide any incremental protection against tuberculosis infection compared with a single vaccination (3). Therefore, the external validity of our findings for populations receiving single vaccination is not limited by this factor.
Use of the 5-mm TST cutoff point as mandated by the Centers for Disease Control and Prevention and the American Thoracic Society was recommended by the reviewers for this analysis of our data. However, we also analyzed 10-mm and 15-mm induration TST as cutoff points in unvaccinated and vaccinated children, respectively, in accordance with local national guidelines. Tuberculin skin test was not prognostic when using these higher stratified cutoff thresholds but was almost prognostic on multivariate analysis (P = 0.080) when using the 5-mm threshold. Therefore, contrary to the assertion of Dr. Hesseling and colleagues, the use of a 5-mm cutoff point did not introduce a differential bias favoring ELISpot and, if anything, the opposite was the case. The age-dependent provision of isoniazid preventive therapy based on TST positivity was taken into account in our multivariate analysis and explicitly discussed in our article.
We look forward to reading the results of future similar studies when they are published.
Ajit Lalvani, DM
Kerry A. Millington, DPhil
Imperial College London
London W2 1PG, United Kingdom
Article and Author Information
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Potential Financial Conflicts of Interest: Consultancies: A. Lalvani (Oxford Immunotec [nonexecutive director from 2003 to 2007]). Stock ownership or options (other than mutual funds): A. Lalvani (Oxford Immunotec), University of Oxford (Oxford Immunotec). 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).
