© 2007 American Thoracic Society
Rapid Diagnosis of Smear-negative Tuberculosis by Bronchoalveolar Lavage Enzyme-linked ImmunospotFrom the Authors:We thank Dr. Breen and colleagues for their interest in our recent article (1). It is widely recognized that many patients with active pulmonary tuberculosis (TB) are negative by culture. New diagnostic tests clearly need to have higher sensitivity than culture, and it is important to include patients with culture-negative TB when evaluating new tests. The final diagnosis of TB in our culture-negative patients was made by the attending physicians who were blinded to bronchoalveolar lavage enzyme-linked immunospot assay (BAL-ELISPOT) results. All such patients showed a clear response to anti-TB therapy. All patients diagnosed with latent TB infection (LTBI) on the basis of absence of active TB and a positive blood ELISPOT were offered 9 months of isoniazid chemoprophylaxis. Our observation that six out of seven patients with BAL purified protein derivative (PPD) of tuberculin–specific spot forming cells (SFCs) and no evidence of active pulmonary TB had Mycobacterium tuberculosis (MTB) antigen–specific SFCs in peripheral blood is not in conflict with the study by Silver and colleagues (2). While BAL mononuclear cell (BALMC)–PPD responses did not discriminate well between active TB and previously treated TB or LTBI, this was not the case for pulmonary responses to early secretory antigenic target-6 (ESAT-6) and cultured protein filtrate-10 (CFP-10) in our study. Schwander and coworkers (3) used PPD and Ag 85A/B/C to try to discriminate between local and systemic immune responses in household contacts of patients with TB and community controls. Given that they used different antigens and did not study patients with TB, their results cannot be directly compared with ours. Our promising results have recently been corroborated by an ongoing, prospective, blinded multicenter study by members of the European Tuberculosis Network (TBNET). Interim analysis showed that, out of 22 patients with pulmonary TB, only one was ELISPOT-negative in BAL (C. Jafari and colleagues, unpublished work). Among 70 patients with alternative non-TB diagnoses, 8 were ELISPOT-positive in BAL. Sensitivity and specificity of MTB-specific ELISPOT performed on BALMCs for active TB were thus 95 and 89%, respectively. In contrast, sensitivity and specificity of the MTB-specific nucleic acid amplification were 40 and 96%, respectively (C. Jafari and colleagues, unpublished work). Regarding the possibility of immunodiagnosis of TB in HIV-infected patients, the high diagnostic sensitivity of the Lalvani ELISPOT assay in peripheral blood has been amply demonstrated in both HIV-infected children (4) and adults (5). As stated in our paper, we did not include HIV-infected patients, but we are doing so in our ongoing multicenter study of BAL-ELISPOT responses in patients with suspected active TB in routine practice. In sputum-smear–negative pulmonary TB, the performance of existing routine techniques, such as smear microscopy on BAL, is obviously important in assessing the clinical significance of new, improved tests. In this regard, only 1 of 12 cases in the study of sputum-smear–negative pulmonary TB (the only patient out of 22 patients in the ongoing study) had detectable acid/alcohol-fast bacilli on BAL smear.
Research Center Borstel, Borstel, Germany
Imperial College London, London, United Kingdom FOOTNOTES Conflict of Interest Statement: C.L. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.J. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.L. is a named inventor on several patents related to T-cell diagnosis filed by the University of Oxford; regulatory approval of the Lalvani ELISpot has been undertaken by Oxford Imunnotec, in which he is a shareholder and to which he acts as a scientific advisor. REFERENCES
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