Within-Subject Variability and Boosting of T-Cell Interferon-γ Responses after Tuberculin Skin Testing

• Published in: American journal of respiratory and critical care medicine Vol. 180; no. 1; pp. 49 - 58
• Main Authors: van Zyl-Smit, Richard N., Pai, Madhukar, Peprah, Kwaku, Meldau, Richard, Kieck, Jackie, Juritz, June, Badri, Motasim, Zumla, Alimuddin, Sechi, Leonardo A., Bateman, Eric D., Dheda, Keertan
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.07.2009
• Subjects: Adolescent; Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Humans; Intensive care medicine; Interferon-gamma - blood; Interferon-gamma - immunology; Medical sciences; Middle Aged; Mycobacterium bovis - immunology; South Africa; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tuberculin - immunology; Tuberculin Test; Tuberculosis - blood; Tuberculosis - diagnosis; Tuberculosis - immunology; Vaccination; Young Adult; South Africa; Human; Intensive care; boosting; Variability; Cytokine; Latent tuberculosis; Tuberculin; tuberculin skin test; IFN-γ release assay; T-Lymphocyte; Interferon; Resuscitation; Skin test
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.200811-1704OC

The optimal strategy for the diagnosis of latent tuberculosis infection is controversial. Adoption of a two-step strategy (tuberculin skin test [TST] followed by an IFN-gamma release assay [IGRA], compared with an IGRA alone), may be limited by TST-mediated boosting of subsequent IGRA responses. Assessment of within-subject IGRA variability will aid in establishing thresholds for conversions and reversions, and interpretation of serial testing results. To determine short-term IGRA variability and the impact of TST on subsequent IGRA results. Within-subject variability and TST-mediated boosting of IGRA responses were evaluated in 26 South African participants with varying exposure risk. IGRAs (T-SPOT.TB, QuantiFERON-TB Gold In-Tube [QuantiFERON-TB-GIT], PPD, and heparin-binding hemagglutinin) were repeated four times over 21 days pre-TST, and on Days 3, 7, 28, and 84 post-TST administration. All participants showed within-subject IGRA variability. Changes of +/-3 spots (T-SPOT.TB) or +/-80% from the mean IFN-gamma response (QuantiFERON-TB-GIT) over 3 weeks explained 95% of the variability. Spontaneous conversions/reversions occurred in 7 of 26 subjects (27%) (6 for T-SPOT.TB and 1 for QuantiFERON-TB-GIT [P = 0.049]) during the within-patient variability studies (pre-TST). After the TST eight subjects (33%) boosted above the defined baseline variability. By Day 7 post-TST, but not Day 3, 2 (12.5%) initially IGRA-negative test subjects converted. By contrast, boosting of PPD and heparin-binding hemagglutinin occurred by Day 3 post-TST. When using a two-step screening strategy it appears safe to perform a QuantiFERON-TB-GIT or T-SPOT.TB IGRA within 3 days of performing the TST. A 3-spot or 80% IFN-gamma response variation, on either side of baseline values, explains 95% of the short-term variability and may be useful for interpreting conversions and reversions, and values close to the cut-point.