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Diagnosis of Latent Tuberculosis Infection: Too Soon to Pull the Plug on the Tuberculin Skin TestDiagnosis of Latent Tuberculosis Infection

Lauren F. Collins, MD; Carolina Geadas, MD; and Jerrold J. Ellner, MD
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 8 December 2015.

From Duke University Medical Center, Durham, North Carolina, and Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts.

Grant Support: By National Institutes of Health National Institute of Allergy and Infectious Diseases awards 5UO1AI065663 (U.S. Brazil Collaboration on Immunity and Biomarkers in Tuberculosis) and 1U19AI111276 (Biomarkers and Mechanisms of Paucibacillary and Latent Tuberculosis).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1522.

Requests for Single Reprints: Jerrold J. Ellner, MD, Division of Infectious Diseases, Boston Medical Center and Boston University School of Medicine, Crosstown Building, 801 Massachusetts Avenue, Second Floor, Room 20, Boston, MA 02118; e-mail, jerrold.ellner@bmc.org.

Current Author Addresses: Dr. Collins: Medical Education Office, Duke University Medical Center, 2301 Erwin Road, 8th Floor, Room 8254, Durham, NC 27710.

Dr. Geadas: Crosstown Building, 801 Massachusetts Avenue, Second Floor, Room 21, Boston, MA 02118.

Dr. Ellner: Section of Infectious Diseases, Crosstown Building, 801 Massachusetts Avenue, Second Floor, Room 20, Boston, MA 02118.

Author Contributions: Conception and design: L.F. Collins, C. Geadas, J.J. Ellner.

Analysis and interpretation of the data: L.F. Collins, C. Geadas, J.J. Ellner.

Drafting of the article: L.F. Collins, C. Geadas, J.J. Ellner.

Critical revision of the article for important intellectual content: L.F. Collins, C. Geadas, J.J. Ellner.

Final approval of the article: L.F. Collins, J.J. Ellner.

Collection and assembly of data: L.F. Collins, C. Geadas, J.J. Ellner.

Ann Intern Med. 2016;164(2):122-124. doi:10.7326/M15-1522
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Although recommendations for the diagnosis of latent tuberculosis infection include tuberculin skin testing or an interferon-γ release assay, the authors discuss why important differences in these tests need to be considered and why they are not always equivalent.

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Grahic Jump Location

Timeline of TST and IGRA conversion for diagnosis of LTBI.

It is recommended that screening for LTBI be performed within 2 wk after known exposure to a pulmonary TB case. According to the Centers for Disease Control and Prevention guidelines, screening with TST or IGRA is acceptable, and if the initial result is negative, repeated testing with the same method should be performed 8–10 wk later. Upon screening, some exposed contacts will be TST-positive at baseline (A and B), whereas others may convert to TST positivity between testing periods (C and D). After the stated tuberculin window period of 8–10 wk, TST/IGRA concordance increases, as does the correlation of each test with measurements of exposure to the TB index case. We propose that conversion of IGRAs to positivity is delayed compared with that of TST and that less intense exposure to the TB index case may further delay conversion for both tests. IGRA = interferon-γ release assay; LTBI = latent tuberculosis infection; TB = tuberculosis; TST = tuberculin skin testing.

Grahic Jump Location




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Diagnosis of Latent TB Infection
Posted on January 22, 2016
Thomas C. Bailey, MD
Washington University School of Medicine
Conflict of Interest: None Declared
There are a number of problems with the opinion piece by Collins, et al about interferon gamma release assay (IGRA) testing vs tuberculin skin testing (TST) for diagnosing latent tuberculosis infection (LTBI) [1]. First, they define newly infected TB contacts by tuberculin skin test conversion, and compare IGRA performance against this, as though the TST were a gold standard. There is no gold standard for latent TB infection [2]. Second, they dismiss the specificity of IGRA testing for BCG vaccinated individuals on the assertion that it is “of little clinical significance when vaccination is administered before the first year of life.” Because of the booster phenomenon, this assertion goes out the window in the context of household contact investigations that employ baseline and subsequent TSTs, which are routinely done. A BCG vaccinated individual who has a 0 mm skin test at baseline and a 5 mm skin test 10 weeks later (the recommended cut point for determining a positive test among close contacts of recently diagnosed infectious persons with TB), the second test could easily be a boosted response to BCG [3]. Third, it is clear from the figure accompanying this piece that Collins, et al are referring to the QuantiFERON-TB test, with its absolute cutoff at 0.35 IU/mL. The T-spot.TB IGRA employs a “borderline” category of interpretation, whereas the QuantiFERON-TB test does not. In one large study, use of the borderline category resulted in fewer positive results, and fewer reversions than if a borderline category were not employed [4]. The authors also conflate the issues of close contact testing with more general screening. Certainly, in US born populations who are not in high risk groups have a very low pre-test probability of LTBI. In this scenario, no test will perform well but, by simple arithmetic, tests with greater specificity, i.e. IGRAs, will have higher positive predictive values. There is no doubt in persons from high prevalence countries and among close contacts of recently diagnosed infectious cases, the TST will perform better than among lower risk groups but, again, in BCG vaccinated individuals, particularly those that will have two-step testing (as is routinely done in contact investigations), or among BCG vaccinated individuals who will have serial testing, e.g, health care workers, TST results are problematic. The TST is also fraught with myriad problems with regard to proper storage, administration and interpretation. These problems are less of an issue with IGRAs (although proper specimen handling and other preanalytical factors are important, particularly for the QuantiFERON-TB test [5-7]). Yes, it is too soon to abandon the TST, but the basis for recommending the TST over IGRA testing as outlined in this piece is flawed.

1. Ann Intern Med. 2016;164(2):122-124. doi:10.7326/M15-1522
2. MMWR Recommendations and Reports June 25, 2010 / 59(RR05);1-25
3. Clin Infect Dis. (2000) 31 (Supplement 3): S71-S74. doi: 10.1086/314075
4. Am J Respir Crit Care Med Vol 192, Iss 3, pp 367–373, Aug 1, 2015
5. J Clin Microbiol 2010;48:2672–2676
6. J Clin Microbiol 2011;49:3061–3064
7. J Clin Microbiol 2013;51:3521–3526

Posted on February 9, 2016
Colin L. Crawford MRCP
Retired, United Kingdom
Conflict of Interest: None Declared
TO THE EDITOR: The epithelioid cell in tuberculosis is secretory and not a macrophage (1) . The immune response to Mycobacterium tuberculosis antigens is therefore indirect. Collins and colleagues agree (2) that there is an ‘’indirect immunologic footprint’’. Developing a specific diagnostic test using mycobacterial antigens is therefore unlikely.
In an autoimmune model of tuberculoid leprosy,skin tests using a human peripheral nerve antigen,produce secretory epithelioid cells, where the cytoplasm contains rough endoplasmic reticulum filled with an electron dense product,similar to the epithelioid cells in human tuberculosis (3). The antigen is active in doses of 1 µg. In human tuberculoid leprosy, the epithelioid cells stain positively with CD123 indicating that they are plasmacytoid dendritic cells secreting interferon α (4). In other models of granulomatous hypersensitivity the antigen is specific. For example, while skin tests with beryllium in patients with berylliosis elicit granulomas containing epithelioid cells organized into tubercles, tests using zirconium give rise to a foreign body reaction. The antigen is human. Tests in non-human primates have been negative.
The Kveim reagent contains granulomatous tissue from the spleen of sarcoid patients. Skin tests using this reagent produce secretory cells similar to the human disease (5). The test is probably specific. It may be possible to induce a state of granulomatous hypersensitivity in rabbits using this reagent, similar to the experiments using peripheral nerve. A protocol for isolating the active antigen has been published (6). If successful, a Kveim- type reagent could be prepared from human tuberculous infected lymph nodes and injected into rabbits, as the cells in these lymph nodes are CD123 positive and secrete large amounts of interferon α (7), similar to those in human tuberculoid leprosy. The active antigen could then be isolated by ultracentrifugation and used as a diagnostic test.
It will be important to determine if the mature granulomas in the lungs of patients with tuberculosis are also CD123 positive. If confirmed, the granulomas in human tuberculoid leprosy, tuberculosis and probably sarcoidosis are part of the innate immune system involving plasmacytoid dendritic cells and are not delayed type hypersensitivity reactions.
1. Crawford CL. The epithelioid cell in tuberculosis is secretory and not a macrophage. J Infect Dis 2015; 212: 1172-3. [PMID 25801654]
2. Collins LF, Geadas C, Ellner JL. Diagnosis of latent tuberculous infection: too soon to pull the plug. Ann Int Med 2016; 164: 122-4. [ PMID 26642354]
3. Crawford CL, Hardwicke PMD, Evans DHL, Evans EM. Granulomatous hypersensitivity induced by sensory peripheral nerve. Nature 1977; 265: 223-5. [PMID 834298]
4. Andrade PR, Amadeu TP, Nery RO, Pinhero, Sarno EN. CD123, the plasmacytoid cell phenotype marker, is abundant in leprous type 1 reaction. Br J Dermatol 2015; 172: 268-71. [PMID 25256168]
5. Sheffield EA, Mitchell DN, Dewar A, Corrin B. The ultrastructural features of developing Kveim test granulomas. Sarcoidosis 1989; 6 (Suppl): 6-7. [PMID 26233379]
6. Crawford CL, Hardwicke P. An experimental model of sarcoidosis using Kveim tissue. In: Connor MR, Stevens RS, editors. Sarcoidosis: diagnosis, epidemiology and treatment options. New York, NY: Nova Science Publications; 2012: 145-53.
7. Cella M Jarrosay D, Facchetti F, Alebardi O, Nakajima H, Lanzvecchia et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type 1 interferon. Nature Med 1999; 5: 919-23. [PMID 10426316]
Author's Response
Posted on April 11, 2016
Lauren F. Collins, MD, Carolina Geadas, MD, Jerry Ellner, MD
Duke University Center
Conflict of Interest: None Declared
Thank you for referring the letter by Dr. Bailey for comment. We wish to respond to the issues raised:

1. Does TST conversion in household contacts represent new MTB infection? Although increases in TST diameter on repeat testing is a form of boosting, “the epidemiologic scenario of household exposure followed by a large increase in TST reaction most likely represents TST conversion and new infection with M. tuberculosis”1. Further TST conversion in that study was associated with the index case’s AFB smear status and proximity of exposure1.

2. Does the advantage of IGRAs in specificity for BCG-vaccinated persons become more important when household contacts have a baseline and subsequent TST? This theoretical advantage is not borne out by data. In Brazil, prior BCG immunization (presence of BCG scar) of TST converters did not influence concordance or discordance with IGRAs2. We found concordance was more likely in BCG-nonvaccinated than BCG vaccinated (71.4 versus 41.0%), although this was not statistically significant2. BCG vaccination status did not influence TST-IGRA concordance or discordance in other international pediatric3 or adult studies4.

3. The borderline category of the T-spot.TB may decrease reversion in annual screening of health care workers. We agree criteria for “borderline results” is likely to modify the unacceptably high reversion rate on repeated testing. Concurrence between IGRA and TST can be increased by lowering the cut-point for IGRA in household contacts, but this tradeoff was associated with loss of sensitivity2. Even more important would be risk-stratification of the endpoint in IGRAs, as is used in TST interpretation.

4. “Among BCG-vaccinated individuals that will have serial testing, e.g. health care workers, TST results are problematic.” This issue can be mitigated by two-step testing in order to establish a proper baseline post-boosting.

5. “The authors conflate the issue of close contact tracing with more general screening.” Our intent was to offer a hypothesis to explain TST-IGRA discordance based on the intensity and timing of exposure to an index case. We offer guidelines on screening in populations based on a priori likelihood of MTB infection and risk of progression from infection to disease. We disagree that in low prevalence populations IGRAs should be preferred because of higher specificity – the theoretical advantage of specificity in BCG-immunized persons is potentially offset by the instability in values close to the cutpoint.

1. Whalen, C. C. et al. Immune correlates of acute Mycobacterium tuberculosis infection in household contacts in Kampala, Uganda. Am. J. Trop. Med. Hyg. 75, 55–61 (2006).
2. Ribeiro-Rodrigues, R, et al. Discordance of Tuberculin Skin Test and Interferon Gamma Release Assay in Recently Exposed Household Contacts of Pulmonary TB Cases in Brazil. PLoS One (2014).
3. Kampmann, B. et al. Interferon-gamma release assays do not identify more children with active tuberculosis than the tuberculin skin test. Eur. Respir. J. 33, 1374–1382 (2009).
4. Sauzullo, I. et al. Influence of previous tuberculin skin test on serial IFN-γ release assays. Tuberc. Edinb. Scotl. 91, 322–326 (2011).

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