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Editorial |

Improving the Diagnosis of Latent TB Infection: Tools for TB Elimination? FREE TO VIEW

Neil W. Schluger, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, New York, NY

CORRESPONDENCE TO: Neil W. Schluger, MD, FCCP, Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, PH-8, Room 101, 622 W 168th St, New York, NY 10032


Copyright 2017, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(6):1207-1208. doi:10.1016/j.chest.2017.04.161
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Published online

Treatment of latent TB infection (LTBI) is increasingly seen as an important component of TB control and elimination programs, particularly in low-prevalence countries such as the United States and in western Europe.,, However, the burden of latent infection in the world is enormous, estimated at some 1.7 billion persons. Even in the United States, a country with a very low prevalence of TB, it is estimated that there are roughly 11 million persons with LTBI. It will be difficult or impossible to treat all these persons under any circumstances. However, if treatment of LTBI was targeted at those most likely to experience active disease, the challenge might become more manageable. How are such persons best identified?

The tuberculin skin test (TST), developed originally by Charles Mantoux in 1908 and refined in 1934 by Florence Siebert, is one of the oldest and most widely used diagnostic tests in medicine. Its major role has been to identify persons with TB infection who can then be treated to reduce the risk of active disease. The limitations of the TST have been well known for a long time. Operational issues include using the proper technique both for administering and interpreting the test as well as requiring patients to return 48 to 72 hours after administration for that interpretation. Biological issues primarily involve confounding of TST results by prior vaccination with Bacille Calmette-Guérin (BCG). This arises because some of the antigens in purified protein derivative (PPD) used in the TST are also produced by mycobacterial strains used in the BCG vaccine. Because of this, the specificity of the TST in persons previously vaccinated with BCG is low.

The development of the interferon gamma release assay (IGRA) addressed many of the limitations of the TST. The IGRA assesses essentially the same immunologic phenomenon as the TST but requires only a simple blood draw and no return visit by the patient. Significantly improved specificity over TST is conferred by using only two or three antigens to stimulate the immune response, rather than the 100 or so that are found in PPD. The antigens used in the IGRA are not produced by the mycobacterial strains that compose BCG, so there is little confounding by prior vaccination. Because of this advantage, the IGRA is preferred over the TST by the US Centers for Disease Control and Prevention, the American Thoracic Society, and the Infectious Disease Society of America when testing persons who have previously received BCG vaccination. The IGRA has been taken up widely in the United States and elsewhere. Still, on a per-test basis, the IGRA is more costly than the TST, and decisions about the most cost-effective strategy for screening are complex.

Ever since TB-specific antigens were identified and used in the IGRA, there has been interest in also using them to replace PPD for use in skin testing. In the current issue of The Lancet Respiratory Medicine, Ruhwald et al report results from a high-quality trial that does just that. Results from the QuantiFERON-TB Gold In-Tube (QFT-G) assay were compared in several patient groups with both a traditional TST and a novel C-Tb skin test developed at the Statens Serum Institute in Denmark: Negative control subjects, close TB contacts, occasional TB contacts, and patients with active pulmonary TB were examined. All study participants were older than 5 years of age. The C-Tb test is operationally similar to a traditional TST, with PPD replaced by the same two antigens, ESAT-6 and CFP10, that are used in the QFT-G. Results showed that the C-Tb and QFT-G results were quite similar, and they correlated closely with an epidemiologic likelihood of LTBI, regardless of BCG vaccination status. Conversely, TST results correlated poorly with an epidemiologic risk of LTBI in persons with a history of BCG vaccination. The trial clearly shows that C-Tb is a significant improvement over the standard TST. In settings in which the use of the IGRA is limited because of cost and infrastructure issues, the C-Tb could be an excellent alternative for identifying persons with LTBI.

Although the IGRA and the newer C-Tb skin test identify persons with LTBI much more accurately overall than does the traditional TST, their positive predictive value in identifying persons who will go on to acquire active TB disease is poor. Only 5% to 10% of persons with LTBI, as defined by a positive TST result, will ever experience active TB disease. Improving the predictive ability of tests for LTBI would significantly conserve resources and reduce unnecessary administration of medication.

A second study in this month’s The Lancet Respiratory Medicine by Andrews et al evaluated quantitative QFT-G results in very young children tested several months after they had been administered a novel TB vaccine candidate. (The novel MVA85A vaccine candidate was shown to provide no protection.) The authors found that children with QFT-G conversions at interferon values from 0.35 International Unit/mL (the manufacturer’s cutoff for a positive result) up to 4.0 International Unit/mL did not experience active TB more often than children who never had conversion to a positive QFT-G result. However, for children with QFT-G conversion results at interferon levels > 4.0 International Unit/mL, the risk of active TB developing was substantially higher than it was in nonconverters (incident rate ratio, 42.5; 95% CI, 17.2-99.7) and was also higher than in converters at lower interferon levels (incident rate ratio, 11.4; 95% CI, 2.4-107.2). A significant caveat, however, is that active TB in these children was diagnosed very soon after the QFT-G results were noted (on average, about 44 days later), suggesting that they might already have had active TB at the time the IGRA was done.

At present, IGRA results are generally interpreted as positive or negative according to cutoff values determined by the manufacturers. Andrews et al’s study suggests revisiting this issue and paying more attention to quantitative results. If validated and confirmed in future studies, these findings could greatly refine our efforts at prevention of TB by treatment of latent infection, or perhaps by identifying very young children who have already progressed to active disease. Whether these findings also apply in populations other than very young children is also an important question not addressed by this study.

It seems clear that treating LTBI will play an important role in eliminating TB. The two papers in the current The Lancet Respiratory Medicine represent important advances in our ability to identify LTBI in an efficient and effective manner. Still, our ability to predict the development of active TB in latently infected persons remains far less than ideal.

References

Reid A. .Grant A.D. .White R.G. .et al Accelerating progress towards tuberculosis elimination: the need for combination treatment and prevention. Int J Tuberc Lung Dis. 2015;19:5-9 [PubMed]journal. [CrossRef] [PubMed]
 
Dye C. .Glaziou P. .Floyd K. .et al Prospects for tuberculosis elimination. Annu Rev Public Health. 2013;34:271-286 [PubMed]journal. [CrossRef] [PubMed]
 
World Health Organization Towards tuberculosis elimination: an action framework for low-incidence countries.  2014;:- [PubMed] World Health Organization Genevajournal
 
Houben R.M. .Dodd P.J. . The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 2016;13:e1002152- [PubMed]journal. [CrossRef] [PubMed]
 
Bennett D.E. .Courval J.M. .Onorato I. .et al Prevalence of tuberculosis infection in the United States population: the national health and nutrition examination survey, 1999-2000. Am J Respir Crit Care Med. 2008;177:348-355 [PubMed]journal. [CrossRef] [PubMed]
 
Lewinsohn D.M. .Leonard M.K. .LoBue P.A. .et al Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64:111-115 [PubMed]journal. [CrossRef] [PubMed]
 
Crossa A. .Kessler J. .Harris T.G. . Enhanced tuberculosis infection treatment outcomes after implementation of QuantiFERON(R)-Gold testing. PLoS One. 2015;10:e0138349- [PubMed]journal. [CrossRef] [PubMed]
 
Nienhaus A. .Schablon A. .Costa J.T. .et al Systematic review of cost and cost-effectiveness of different TB-screening strategies. BMC Health Serv Res. 2011;11:247- [PubMed]journal. [CrossRef] [PubMed]
 
Ruhwald M. .Aggerbeck H. .Gallardo R.V. .et al Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon gamma release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial. Lancet Respir Med. 2017;5:259-268 [PubMed]journal. [CrossRef] [PubMed]
 
Shea K.M. .Kammerer J.S. .Winston C.A. .et al Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup. Am J Epidemiol. 2014;179:216-225 [PubMed]journal. [CrossRef] [PubMed]
 
Andrews J.R. .Nemes E. .Tameris M. .et al Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study. Lancet Respir Med. 2017;5:282-290 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Reid A. .Grant A.D. .White R.G. .et al Accelerating progress towards tuberculosis elimination: the need for combination treatment and prevention. Int J Tuberc Lung Dis. 2015;19:5-9 [PubMed]journal. [CrossRef] [PubMed]
 
Dye C. .Glaziou P. .Floyd K. .et al Prospects for tuberculosis elimination. Annu Rev Public Health. 2013;34:271-286 [PubMed]journal. [CrossRef] [PubMed]
 
World Health Organization Towards tuberculosis elimination: an action framework for low-incidence countries.  2014;:- [PubMed] World Health Organization Genevajournal
 
Houben R.M. .Dodd P.J. . The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 2016;13:e1002152- [PubMed]journal. [CrossRef] [PubMed]
 
Bennett D.E. .Courval J.M. .Onorato I. .et al Prevalence of tuberculosis infection in the United States population: the national health and nutrition examination survey, 1999-2000. Am J Respir Crit Care Med. 2008;177:348-355 [PubMed]journal. [CrossRef] [PubMed]
 
Lewinsohn D.M. .Leonard M.K. .LoBue P.A. .et al Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64:111-115 [PubMed]journal. [CrossRef] [PubMed]
 
Crossa A. .Kessler J. .Harris T.G. . Enhanced tuberculosis infection treatment outcomes after implementation of QuantiFERON(R)-Gold testing. PLoS One. 2015;10:e0138349- [PubMed]journal. [CrossRef] [PubMed]
 
Nienhaus A. .Schablon A. .Costa J.T. .et al Systematic review of cost and cost-effectiveness of different TB-screening strategies. BMC Health Serv Res. 2011;11:247- [PubMed]journal. [CrossRef] [PubMed]
 
Ruhwald M. .Aggerbeck H. .Gallardo R.V. .et al Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon gamma release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial. Lancet Respir Med. 2017;5:259-268 [PubMed]journal. [CrossRef] [PubMed]
 
Shea K.M. .Kammerer J.S. .Winston C.A. .et al Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup. Am J Epidemiol. 2014;179:216-225 [PubMed]journal. [CrossRef] [PubMed]
 
Andrews J.R. .Nemes E. .Tameris M. .et al Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study. Lancet Respir Med. 2017;5:282-290 [PubMed]journal. [CrossRef] [PubMed]
 
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