This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200811-1704OCv1 200811-1704OCv2 180/1/49    most recent Alert me when this article is cited Alert me if a correction is posted Services Related articles in AJRCCM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Zyl-Smit, R. N. Articles by Dheda, K. Search for Related Content PubMed PubMed Citation Articles by van Zyl-Smit, R. N. Articles by Dheda, K.

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

¹ Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute Department of Medicine, University of Cape Town, Cape Town, South Africa; ² Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada; ³ Department of Radiology, University of Cape Town and Groote Schuur Hospital, and ⁴ Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa; ⁵ Centre for Infectious Diseases and International Health, Royal Free and University College Medical School, London, United Kingdom; ⁶ Dipartimento di Scienze Biomediche, University of Sardinia, Sassari, Italy; and ⁷ Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

Correspondence and requests for reprints should be addressed to Keertan Dheda, M.D., Ph.D., Lung Infection and Immunity Unit, Department of Medicine, J Floor, Old Main Building, Groote Schuur Hospital, Cape Town 7935, South Africa. E-mail: Keertan.dheda{at}uct.ac.za

Rationale: 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- 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.

Objectives: To determine short-term IGRA variability and the impact of TST on subsequent IGRA results.

Methods: 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.

Measurements and Main Results: All participants showed within-subject IGRA variability. Changes of ±3 spots (T-SPOT.TB) or ±80% from the mean IFN- 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.

Conclusions: 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- 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.

Key Words: latent tuberculosis • IFN- release assay • tuberculin skin test • variability • boosting

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The optimal strategy for the diagnosis of latent tuberculosis infection is unclear. The two-step strategy (tuberculin skin test [TST] followed by an IFN- release assay [IGRA]), as recommended by some guidelines, may be confounded by within-subject variability and TST-mediated boosting of subsequent IGRA responses. What This Study Adds to the Field The TST potentially boosts IGRA responses, predominantly in IGRA-positive subjects, but occurs after Day 3 and may thus confound the interpretation of subsequent T-cell responses. IGRAs should ideally be performed at no more than 3 days after a TST. On the basis of results of within-subject variability, cut-points for conversions and reversions are proposed, but require validation before widespread application in low tuberculosis risk environments.

 

Related articles in AJRCCM:

Diagnosing Latent Tuberculosis Infection: Guess Who's Coming to Dinner?

Luca Richeldi
AJRCCM 2009 180: 1-2. [Full Text]  

This article has been cited by other articles:

				IGRA Variability and the Effect of TST Journal Watch Infectious Diseases, July 22, 2009; 2009(722): 6 - 6. [Full Text]

				L. Richeldi Diagnosing Latent Tuberculosis Infection: Guess Who's Coming to Dinner? Am. J. Respir. Crit. Care Med., July 1, 2009; 180(1): 1 - 2. [Full Text] [PDF]