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1. Can IFN Gamma Release Assays Differentiate Between Active Tuberculosis and Sarcoidosis ?

   • Ivan Landires, MD
   • and Roland Brosch PhD

   Institut Pasteur, UP Pathogénomique Mycobacterienne Integrée, Paris, France

   Dear Editor,

   We have read with great interest the recent article by Dosanjh and colleagues (1) who found that the ELISpotPLUS assay was a clinically useful diagnostic test for evaluation of patients with suspected tuberculosis. This assay uses an additional region of difference 1–encoded antigen, Rv3879c, alongside early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10, which are all part of the recently identified, novel ESX-1 secretion system of Mycobacterium tuberculosis (2).

   As mentioned in the editorial (3), the use of these tests for the diagnosis of active tuberculosis is based on the logic that one must have tuberculous infection in order to have tuberculosis disease. But, is the ELISpotPLUS assay able to establish a differential diagnosis between active tuberculosis and sarcoidosis? M. tuberculosis has been proposed as a candidate trigger for the development of sarcoidosis and several mycobacterial antigens have been recovered from sarcoidal tissue (4). Recent studies have detected Th-1 immune responses to M. tuberculosis ESAT -6 using the ELISpot assay in sarcoidosis patients (5). A diagnosis of sarcoidosis is firm when chest radiographic evidence is accompanied by compatible biopsy and characteristic clinical features, with all other causes of granulomas ruled out (4). For that reason it will be important to evaluate ELISpotPLUS responses to ESX-1 peptides in sarcoidosis patients and compare these findings with ELIspotPLUS results from patients with active tuberculosis. Overall, we suggest that this issue merits further investigation.

   References.

   1. Dosanjh DP, Hinks TS, Innes JA, Deeks JJ, Pasvol G, Hackforth S, et al. Improved diagnostic evaluation of suspected tuberculosis. Ann Intern Med. 2008; 148: 325-36.

   2. Brodin P, Rosenkrands I, Andersen P, Cole ST, and Brosch R. ESAT-6 proteins: protective antigens and virulence factors? Trends Microbiol. 2004; 12:500-508.

   3. Menzies D. Using tests for latent tuberculous infection to diagnose active tuberculosis: can we eat our cake and have it too? Ann Intern Med. 2008; 148: 325-36.

   4. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007; 357: 2153-65.

   5. Drake WP, Dhason MS, Nadaf M, Shepherd BE, Vadivelu S, Hajizadeh R, et al. Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis. Infect Immun. 2007; 75: 527-30.

   Conflict of Interest:

   None declared

   Submit response
   Published April 2, 2008
2. Assume Nothing About Tb and HIV

   • David M. Brett-Major, M.D.

   Division of Infectious Diseases, National Naval Medical Center, Bethesda MD

   Assume Nothing About Tb and HIV.

    

   Dear Editor,

    

   I am grateful that Dosanjh and colleagues and others continue to troll the murky waters of tuberculosis diagnosis.¹  As the editorial asserts, how this emerging field of in vitro immunoassay diagnostics for both active and latent infection by Mycobacterium tuberculosis should be navigated is an open question.²  While I read the results of the study with interest, that they had not screened for HIV infection in all of their subjects surprised me.¹  They cite a 1998 survey of tuberculosis in England and Wales for this decision, which in fairness was published shortly before initiating enrollment in 2002.³  The overall HIV co-infection rate was 3.3 per cent, 5.8 per cent in London.  Even with sporadic testing (actual testing rates not provided) for HIV, Dosanjh and colleagues observed HIV-Tb co-infection rates of 5.2 per cent among culture-confirmed, and 10.3 per cent among clinically indeterminate tuberculosis patients. 

    

   According to WHO Europe Region data (http://www.euro.who.int/InformationSources/Data/20050117_3 acc. 12 March 2008), the UK may have an increasing incidence of tuberculosis, with a more dramatically increasing reported HIV incidence (table).  In the same year that the CDC published a universal opt-out recommendation for HIV testing, UK guidelines continued to focus almost completely on STD clinics.⁴  Although, mention of tuberculosis and other conditions suspicious for HIV was made.  A recent small sampling of primary and secondary care centers in the UK revealed poor penetrance of HIV testing even for African patients recently immigrated from highly HIV endemic areas.⁵ 

    

   We have our own significant challenges in achieving goals for HIV screening, and the UK represents a unique health care setting.  Also, I am unfamiliar with the intricacies of UK reporting to WHO Europe.  However, readers should remain concerned and investigators mindful of the global associations between tuberculosis and HIV patient populations.

    

    

   WHO Reported Incidence for Tuberculosis and HIV, UK

   	1996	1997	1998	1999	2000	2001	2002	2003	2004	2005	2006
   Tb	12	12	12	12	12	12	12	13	13	14	---
   HIV	5	5	5	5	6	7	10	12	12	14	15
   AIDS	3	2	1	1	1	1	1	1	1	1	1

   Estimated incidences per 100,000 rounded to whole case.  Data abstracted from WHO Europe HFA-DB.

    

   1.         Dosanjh DP, Hinks TS, Innes JA, et al. Improved diagnostic evaluation of suspected tuberculosis. Annals of Internal Medicine 2008;148(5):325-36.

   2.         Menzies D. Using tests for latent tuberculous infection to diagnose active tuberculosis: can we eat our cake and have it too? Annals of Internal Medicine 2008;148(5):398-9.

   3.         Rose AM, Watson JM, Graham C, et al. Tuberculosis at the end of the 20th century in England and Wales: results of a national survey in 1998. Thorax 2001;56(3):173-9.

   4.         Rogstad K, Palfreeman A, Rooney G, et al. UK National Guidelines on HIV Testing 2006. International Journal of STD & AIDS 2006;17(10):668-76.

   5.         Burns FM, Johnson AM, Nazroo J, et al. Missed opportunities for earlier HIV diagnosis within primary and secondary healthcare settings in the UK. AIDS (London, England) 2008;22(1):115-22.

    

   David M. Brett-Major, M.D.

    

   Division of Infectious Diseases, Department of Internal Medicine, National Naval Medical Center, Bethesda MD; and,

   Division of Tropical Public Health, Departments of Preventive Medicine and Biometrics, and Medicine, Uniformed Services University, Bethesda MD

    

   The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Uniformed Services University, Department of Defense, nor the U.S. Government.

   Conflict of Interest:

   None declared

   Submit response
   Published March 18, 2008
3. The application strategy of tuberculin skin testing, ELISpotPLUS and ELISpot

   • Liu Hong, PhD
   • Kaichun Wu, Daiming Fan

   Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University

   To the editor:

   We read with interest the article by Dosanjh and colleagues (1). They clearly show that ELISpotPLUS is a sensitive and clinically useful diagnostic test for evaluation of patients with suspected tuberculosis. However, they don¡¯t show the cost effectiveness of ELISpotPLUS versus tuberculin skin testing and ELISpot. Clinicians will need to know which assay is recommended for wide clinical application. Could the authors comment on the application strategy of the three assays, including separate application and combined application?

   This study is based on the participants predominantly in South Asian and black ethnicity, so the results may not be applicable for all patients with suspected tuberculosis. Will incorporation of Rv3879c improve sensitivity over standard ELISpot for all patients? Could the authors comment on the potential effect of epigenetic inheritance on the roles of Rv3879c, which is regulated by a special molecular network? So it is indispensable to ask whether the molecular network involve other important antigens for the clinical diagnostic evaluation of suspected tuberculosis.

   References:

   1. Dosanjh DP, Hinks TS, Innes JA, et al. Improved Diagnostic Evaluation of Suspected Tuberculosis. Ann Intern Med. 2008 Mar 4;148(5):325-36.

   Conflict of Interest:

   None declared

   Submit response
   Published March 17, 2008