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Early Diagnosis of Subclinical Multidrug-Resistant Tuberculosis

Luca Richeldi, MD, PhD; Katie Ewer, BSc; Monica Losi, BSc; David M. Hansell, MD; Pietro Roversi, MD; Leonardo M. Fabbri, MD; and Ajit Lalvani, MRCP, DM
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From University of Modena and Reggio Emilia and Azienda Ospedaliera Policlinico di Modena, Modena, Italy; University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and Royal Brompton Hospital, London, United Kingdom.

Acknowledgments: The authors thank Patrizia Marchegiano (Azienda Ospedaliera Policlinico di Modena, Modena, Italy) for helping with the organization of the study and Giulio Ferrario and Andrea Gori (University of Milano, Milan, Italy) for restriction fragment length polymorphism typing. The authors also thank Peter Barnes (Center for Pulmonary and Infectious Disease Control, Tyler, Texas), Anna M. Marata (CeVEAS, Modena, Italy), and Giovanni B. Migliori (Tradate, Italy) for their helpful comments.

Grant Support: By the Wellcome Trust (London, United Kingdom) and the Azienda Ospedaliera Policlinico di Modena (Modena, Italy). Ajit Lalvani is a Wellcome Senior Research Fellow in clinical science.

Potential Financial Conflicts of Interest:Consultancies: A. Lalvani (Oxford Immunotec Ltd.); Stock ownership or options (other than mutual funds): A. Lalvani (Oxford Immunotec Ltd.); Patents received, patents pending, and royalties: A. Lalvani (patents filed by the University of Oxford since 1996 relating to T-cell–based diagnosis); Patents pending: K. Ewer (named as inventor on a patent application relating to the application of the RD-1–based ELISPOT assay); Other: The University of Oxford owns stock in Oxford Immunotec Ltd.

Requests for Single Reprints: Ajit Lalvani, MRCP, DM, Nuffield Department of Clinical Medicine, University of Oxford, Level 7, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; e-mail, ajit.lalvani@ndm.ox.ac.uk.

Current Author Addresses: Drs. Richeldi, Roversi, and Fabbri and Ms. Losi: Policlinico di Modena, via del Pozzo 71, 41100 Modena, Italy.

Ms. Ewer and Dr. Lalvani: John Radcliffe Hospital, Level 7, Oxford OX3 9DU, United Kingdom.

Dr. Hansell: Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom.

Author Contributions: Conception and design: L. Richeldi, K. Ewer, A. Lalvani.

Analysis and interpretation of the data: L. Richeldi, K. Ewer, M. Losi, D.M. Hansell, A. Lalvani.

Drafting of the article: L. Richeldi, K. Ewer, A. Lalvani.

Critical revision of the article for important intellectual content: L. Richeldi, K. Ewer, D.M. Hansell, M. Losi, A. Lalvani.

Final approval of the article: L. Richeldi, K. Ewer, M. Losi, D.M. Hansell, P. Roversi, L.M. Fabbri, A. Lalvani.

Provision of study materials or patients: A. Lalvani.

Statistical expertise: K. Ewer.

Obtaining of funding: L.M. Fabbri, A. Lalvani.

Administrative, technical, or logistic support: M. Losi, P. Roversi, L.M. Fabbri, A. Lalvani.

Collection and assembly of data: L. Richeldi, K. Ewer, M. Losi, D.M. Hansell, P. Roversi, A. Lalvani.

Ann Intern Med. 2004;140(9):709-713. doi:10.7326/0003-4819-140-9-200405040-00010
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Background: Tuberculosis control hinges on prompt diagnosis of active cases and screening of contacts by tuberculin skin testing. Rapid blood tests for Mycobacterium tuberculosis infection are a new alternative to the tuberculin skin test, but whether they improve clinical outcomes is unknown.

Objective: To describe how a novel T-cell–based test for M. tuberculosis infection helped diagnose tuberculosis in an asymptomatic, immunosuppressed adult with a negative result on a tuberculin skin test.

Design: Case report.

Setting: Household contact.

Patients: Asymptomatic man receiving maintenance azathioprine therapy for Crohn disease whose wife had multidrug-resistant pulmonary tuberculosis.

Measurements: Enzyme-linked immunospot (ELISPOT) assay, computed tomography, and bronchoalveolar lavage cultures.

Results: The man had a negative tuberculin skin test result and a positive ELISPOT assay result. High-resolution computed tomography of the chest showed consolidation with early cavitation. Bronchoalveolar lavage and culture confirmed multidrug-resistant tuberculosis.

Limitations: This single case report is a proof of concept and is not a formal evaluation of clinical utility.

Conclusions: A positive ELISPOT assay result helped diagnose subclinical active tuberculosis in an immunosuppressed patient with a false-negative tuberculin skin test result. Large prospective studies that compare benefits and costs of this alternative to tuberculin skin testing are needed.


Grahic Jump Location
Figure 1.
Imaging studies of the patients.

A. Chest radiograph of the index patient. Extensive patchy consolidation with areas of cavitation are seen in the mid-zones and upper zones, which is consistent with active tuberculosis. B. High-resolution computed tomography scan through the mid-zones from the index patient. Patchy consolidation and nodules (filled acini) with cavitation are seen in the apical segment of the right lower lobe; the appearances strongly suggest active tuberculosis. C. Chest radiograph of the husband of the index patient. Poorly defined shadowing is seen in the periphery of the right upper zone. The right hilum is dense, possibly reflecting lymphadenopathy. These appearances are nonspecific, but tuberculosis is a differential diagnosis. D. High-resolution computed tomography scan through the lung apices from the husband of the index patient. One of several small foci of consolidation (with early cavitation) is visible. Although nonspecific, this pattern would be consistent with very early active tuberculosis.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Photoµgraphs of enzyme-linked immunosorbent (ELISPOT) assay results from the blood sample of the husband of the index patient.

Each well contains 250 000 peripheral blood mononuclear cells, and each spot represents the “footprint” of an individual Mycobacterium tuberculosis–specific interferon-γ–secreting T cell. The upper 2 wells (A and B ) are duplicate negative controls, and the lower 2 duplicate wells (C and D) show the response to a pool of early secretory antigenic target-6 (ESAT-6)–derived peptides with a mean of 18 spot-forming cells per well, which translates into a frequency of 72 ESAT-6–specific interferon-γ–secreting T cells per million peripheral blood mononuclear cells. Test wells containing ESAT-6–derived peptides are scored as positive if they contain a mean of at least 5 more spot-forming cells than the mean of the negative control wells, and this number is at least twice the mean of the negative control wells. This predefined cutoff translates into a detection threshold of 20 ESAT-6 peptide-specific interferon-γ–secreting T cells per million peripheral blood mononuclear cells. Thus, this ELISPOT assay had a clear-cut positive result and was not borderline. The assay was performed and scored by a scientist using an automated ELISPOT counter with predefined settings for thresholds for spot size and intensity (AutoImmun Diagnostika GmbH, Strassberg, Germany). The scientist was blinded to the patient's tuberculin skin test result, tuberculosis exposure history, and personal identifier.

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Early Diagnosis of Subclinical Multidrug-Resistant Tuberculosis
Posted on June 14, 2004
Nabin K. Shrestha
B. P. Koirala Institute of Health Sciences, Dharan, Nepal
Conflict of Interest: None Declared

TO THE EDITOR: The title of the recent article by Richeldi and colleagues is misleading (1). The assay described undoubtedly helped make an early diagnosis of subclinical tuberculosis. However, its merits must not be overstated. It did not help make an early diagnosis of subclinical multidrug-resistant tuberculosis. The suspicion of multidrug resistance was based on the exposure history, and only confirmed by culture at least 5 weeks later. Early diagnosis of subclinical or clinical multi-drug resistant tuberculosis would be of immense value to those of us who regularly see patients referred because of failure of or relapse after a standard regimen for tuberculosis. The assay described here does not help make that determination.


1. Richeldi L, Ewer K, Losi M, Hansell DM, Roversi P, Fabbri LM, Lalvani A. Early diagnosis of subclinical multidrug-resistant tuberculosis. Ann Intern Med 2004; 140: 709-13.

Conflict of Interest:

None declared

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