Abstract
BackgroundTuberculin skin testing is simple and relatively inexpensive, but the specificity of PPD is affected by BCG vaccination.ObjectiveDetermine optimal dose and specificity of recombinant ESAT-6 and CFP-10 (C-Tb) produced in Lactococcus lactis for diagnosis of M. tuberculosis infection.MethodsIn a dose finding phase I trial 0.01 or 0.1 µg preserved and unpreserved C-Tb was injected by Mantoux technique in 38 patients with active tuberculosis and induration responses measured. In a phase II specificity trial in 151 uninfected, BCG vaccinated participants 0.1 µg C-Tb was compared to 2 TU PPD.Results0.1 µg C-Tb gave a median induration of 15 mm after 2 days. Phenol preservation did not affect the response. The specificity of C-Tb was 99.3% (95% CI 96–100%) regarding indurations ≥5 mm as a positive outcome. This was higher than the specificity of PPD (63% using a cut-off of 5 mm or 92% using a cut-off of 15 mm to adjust for non-specific BCG responses). Local adverse reactions following C-Tb injection included transient itching and discomfort as expected components of the immune response.ConclusionC-Tb offers a simple and convenient skin test to diagnose M. tuberculosis infection using a single, universal cut-off unaffected by BCG vaccination.Trial RegistrationClinicalTrials.gov NCT01033929 and NCT01241188.
Highlights
Tuberculosis (TB) constitutes an enormous global burden with 8.7 million new cases and an estimated 1.4 million deaths in 2011 [1]
We report here (i) a phase I trial to determine an optimal dose of C-Tb and to compare unpreserved and phenol preserved C-Tb when testing patients with active tuberculosis, and (ii) a phase II trial to investigate the specificity of C-Tb in uninfected, BCG vaccinated participants which represent two key populations in which a TST must operate for clinical diagnosis of active or latent TB
One patient retrospectively failed the inclusion criteria as sputum culture revealed M. kansasii instead of M. tuberculosis infection. This patient showed no response to 0.01 mg C-Tb
Summary
Tuberculosis (TB) constitutes an enormous global burden with 8.7 million new cases and an estimated 1.4 million deaths in 2011 [1]. In low prevalence countries a predominant goal is to detect and treat latent TB in order to achieve the stage of TB elimination. This includes testing high risk groups such as close contacts of an active TB case, HIV-infected, and children below 5 years of age [6,7]. Many guidelines include Tuberculin Purified Protein Derivative (PPD) and the interferon-c release assays (IGRAs) QuantiFERONH-TB Gold In Tube (QFT-IT, Cellestis, Carnegie, Australia) and T-SPOTH.TB (Oxford Immunotec, Abingdon, UK) for the detection of latent TB, either alone or in combination [4,8,9]. Tuberculin skin testing is simple and relatively inexpensive, but the specificity of PPD is affected by BCG vaccination
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