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Published ahead of print on February 2, 2006, doi:10.1164/rccm.200509-1526OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 9, May 2006, 1038-1042

A more recent version of this article appeared on May 1, 2006
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Submitted on September 28, 2005
Accepted on January 27, 2006

Transmission of Mycobacterium Tuberculosis Undetected by Tuberculin Skin Testing

Suzanne T Anderson1*, Amanda J Williams2, Jillian R Brown3, Sandra M Newton3, Marcela Simsova4, Mark P Nicol5, Peter Sebo4, Michael Levin3, Robert J Wilkinson6, and Katalin A Wilkinson7

1 Department of Paediatrics and Wellcome Trust Centre for Research in Clinical Tropical Medicine, Division of Medicine, Imperial College London, Wright Fleming Institute, London, United Kingdom; Tuberculosis Clinic, Northwick Park Hospital, North West London Hospitals NHS Trust, Harrow, Middlesex, United Kingdom, 2 Tuberculosis Clinic, Northwick Park Hospital, North West London Hospitals NHS Trust, Harrow, Middlesex, United Kingdom, 3 Department of Paediatrics and Wellcome Trust Centre for Research in Clinical Tropical Medicine, Division of Medicine, Imperial College London, Wright Fleming Institute, London, United Kingdom, 4 Institute of Microbiology, Czech Academy of Sciences, Prague, Czech Republic, 5 Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 6 Department of Paediatrics and Wellcome Trust Centre for Research in Clinical Tropical Medicine, Division of Medicine, Imperial College London, Wright Fleming Institute, London, United Kingdom; Tuberculosis Clinic, Northwick Park Hospital, North West London Hospitals NHS Trust, Harrow, Middlesex, United Kingdom; Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 7 Department of Paediatrics and Wellcome Trust Centre for Research in Clinical Tropical Medicine, Division of Medicine, Imperial College London, Wright Fleming Institute, London, United Kingdom; Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, Western Cape, South Africa

* To whom correspondence should be addressed. E-mail: s.anderson{at}imperial.ac.uk.

Rationale The development of tuberculin skin test (TST) positivity following infection by Mycobacterium tuberculosis is not invariable and may depend upon bacillary as well as host factors. Objectives Firstly, to compare the diagnostic performance of the TST and a form of in vitro interferon-gamma release assay (IFNGRA) in the circumstances of a contact investigation prompted by unusually severe index case of infectious pulmonary tuberculosis. Secondly to investigate the ability of the strain of M. tuberculosis responsible to induce cytokine secretion from monocytes in vitro. Methods A routine TST based tuberculosis contact screening procedure supplemented by the use of an 'in house' IFNGRA that assays the T cell response to the M. tuberculosis specific antigens ESAT-6, CFP-10 (presented as a fusion protein within the inactivated adenylate cyclase of Bordetella pertussis) and purified protein derivative of M. tuberculosis (PPD). Isolation and genetic typing of the strain of M. tuberculosis responsible, and investigation of its ability to induce cytokine secretion from monocytes in vitro. Measurements and Main Results TST screening suggested a low rate of transmission with just 2/75 unequivocally positive responses. By contrast the IFNGRA suggested an infection rate of 16/75 (22 %). When compared to two reference strains of M. tuberculosis (H37Rv and CDC1551), the outbreak strain induced lower levels of TNF-{alpha}, and IL-12p40 (p < 0.04), cytokines associated with the development of delayed type hypersensitivity. Conclusions These data suggest that infection by M. tuberculosis undetected by TST can occur, and that this may partially relate to strain differences in immunogenicity.
Key words: Mycobacterium tuberculosis, tuberculin, ESAT-6 protein, Adenylate cyclase, Diagnostic tests and procedures




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