Long-term Effect of Bacille Calmette-Guérin Vaccination in Tuberculin Skin Testing
2017; Elsevier BV; Volume: 152; Issue: 2 Linguagem: Inglês
10.1016/j.chest.2017.03.011
ISSN1931-3543
Autores Tópico(s)Immune responses and vaccinations
ResumoFOR RELATED ARTICLE SEE PAGE 282In screening for latent TB infection (LTBI), the predictive value of a positive Mantoux tuberculin skin test (TST) result is the probability that the investigated person is truly infected and may consequently benefit from preventive chemotherapy. One problem in the clinical applicability of the Mantoux TST, however, is its cross-reactivity with antigens present in other mycobacteria, such as Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine strains.2Diel R. Ernst M. Döscher G. et al.Avoiding the effect of BCG vaccination in detecting Mycobacterium tuberculosis infection with a blood test.Eur Respir J. 2006; 28: 16-23Crossref PubMed Scopus (62) Google Scholar Vaccination with BCG was first used in 1921 and has been a part of the World Health Organization Expanded Program on Immunization since 1974. BCG has been intensively used in high-burden countries and remains mandatory in 22 countries.1Zwerling A. Behr M.A. Verma A. Brewer T.F. Menzies D. Pai M. The BCG World Atlas: a database of global BCG vaccination policies and practices.PLoS Med. 2011; 8: e1001012Crossref PubMed Scopus (388) Google Scholar FOR RELATED ARTICLE SEE PAGE 282 The fact that BCG-induced cross-reactivity may lead to false-positive results and decreases the positive predictive value of the TST with respect to the presence or absence of LTBI is well known. However, for decades there has been a running debate in medical circles as to the duration of BCG-induced sensitivity to the TST. Accordingly, practitioners have been uncertain as to when subjects’ TST reactivity can no longer be attributed to their vaccination history. In an early Centers for Disease Control statement,3The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices.MMWR Recomm Rep. 1996 6; 45: 1-18Google Scholar a rule of thumb was created that when vaccination is performed after infancy, TST reactivity is unlikely to persist for longer than 10 years after vaccination. Some years later, Farhat et al4Farhat M. Greenaway C. Pai M. Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria?.Int J Tuberc Lung Dis. 2006; 10: 1192-1204PubMed Google Scholar compared TST indurations among BCG-vaccinated and nonvaccinated subjects, demonstrating in their meta-analysis that the matter is further complicated by the timing of vaccination: 41.8% of the persons vaccinated after infancy had a false-positive TST, which persisted in 21.2% of vaccinees for longer than 10 years. In contrast, persons vaccinated during the first year of life showed false-positive TST results in only 8.5% of cases. Hence, vaccination in this group had only a minor effect on TST reactivity when a 10-mm induration was used as the cutoff for test positivity. In a further meta-analysis, Wang et al5Wang L. Turner M.O. Elwood R.K. Schulzer M. FitzGerald J.M. A meta-analysis of the effect of Bacille Calmette Guerin vaccination on tuberculin skin test measurements.Thorax. 2002; 57: 804-809Crossref PubMed Scopus (438) Google Scholar estimated that compared with nonvaccinated subjects, patients who had received BCG vaccination at infancy had a risk ratio of being TST positive of 2.4 (95% CI, 2.00-2.97) within the first 15 years after vaccination, which fell markedly but remained statistically significant with a risk ratio of 1.2 (95% CI, 1.09-1.22) after 15 years. In this issue of CHEST, researchers from the United States bring forward novel evidence for the ongoing debate. In their study, Mancuso et al6Mancuso J.D. Mody R.M. Olsen C.H. Harrison L.H. Santosham M. Aronson N.E. The long-term effect of Bacille Calmette-Guérin vaccination on tuberculin skin testing: A 55-year follow-up study.Chest. 2017; 152: 282-294Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar investigated annual data on TST reactivity collected from American Native Americans and Alaskan Natives who had participated in a prospective placebo-controlled BCG vaccination trial between 1935 and 1947. Subjects received either intradermal BCG-Phipps or a normal saline placebo injection followed by regular TST, in which an induration of at least 10 mm was defined as positive among the participants aged < 1 year to 20 years. A follow-up study to determine the effectiveness of the BCG vaccine extended the program from 1948 to 1998, that is, for a follow-up of 15 to 55 years after vaccination, and thus enabled an extraordinary evaluation of the long-term effect of BCG vaccination on TST reactivity. No repeated testing was observed during the second period of the study (≥ 15 years after vaccination) among those with a documented positive TST result in their health records. Seizing the opportunity, Mancuso et al6Mancuso J.D. Mody R.M. Olsen C.H. Harrison L.H. Santosham M. Aronson N.E. The long-term effect of Bacille Calmette-Guérin vaccination on tuberculin skin testing: A 55-year follow-up study.Chest. 2017; 152: 282-294Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar used Kaplan-Meier and multivariate Cox regression to compare the BCG and placebo groups with respect to time to TST conversion and reversion. An unexpected novelty of Mancuso et al's6 findings is that the increased risk of TST reactivity in those subjects who were vaccinated after infancy persisted throughout the whole study period (ie, up to 55 years), resulting in an adjusted hazard ratio for the time interval between 15 and 55 years after vaccination of 1.26 (95% CI, 1.11-1.43). This study, therefore, provides first-time evidence that BCG vaccination after infancy clearly influences the TST beyond the conventionally accepted 10- to 15-year period, although the efficacy of BCG itself, that is, the duration of protection after vaccination, is quite short at only 10 to 20 years.7Sterne J.A. Rodrigues L.C. Guedes I.N. Does the efficacy of BCG decline with time since vaccination?.Int J Tuberc Lung Dis. 1998; 2: 200-207PubMed Google Scholar Unfortunately, the authors cannot provide sufficient information on the waning of BCG-induced TST reactivity among vaccinated infants. Initially, only a small sample of 368 infants (180 vaccinated with BCG and 186 infants receiving placebo) was included. Of these, only 71 remained available for long-term follow-up. Thus, no conclusions can be drawn from this study about the effect of BCG on TST reactivity for persons vaccinated in infancy. This is important, as in those countries where BCG vaccination is currently mandatory, it is recommended that BCG be given at birth or at latest before a child’s first birthday.1Zwerling A. Behr M.A. Verma A. Brewer T.F. Menzies D. Pai M. The BCG World Atlas: a database of global BCG vaccination policies and practices.PLoS Med. 2011; 8: e1001012Crossref PubMed Scopus (388) Google Scholar However, 16 countries still recommend multiple BCG vaccinations, that is, at least one additional BCG vaccination 5 to 15 years following the initial application.1Zwerling A. Behr M.A. Verma A. Brewer T.F. Menzies D. Pai M. The BCG World Atlas: a database of global BCG vaccination policies and practices.PLoS Med. 2011; 8: e1001012Crossref PubMed Scopus (388) Google Scholar What we can learn from Mancuso et al's6 study is that the received wisdom on the waning of BCG-induced TST reactivity needs questioning. The accurate diagnosis of LTBI is an important component of any TB control program, and thus uncertainty about the effect of BCG vaccination on tuberculin skin testing may influence individual decisions on acceptance and adherence of LTBI treatment. This is reflected in most recent Centers for Disease Control8Centers for Disease Control and Prevention. Testing for tuberculosis (TB). Available at: https://www.cdc.gov/tb/publications/factsheets/testing/tb_testing.htm.Google Scholar and US Preventive Services Task Force recommendations,9US Preventive Services Task ForceScreening for latent tuberculosis infection in adults. US Preventive Services Task Force recommendation statement.JAMA. 2016; 316: 962-969Crossref PubMed Scopus (134) Google Scholar which call for an interferon gamma release assay (IGRA) to be used in persons who have received BCG9US Preventive Services Task ForceScreening for latent tuberculosis infection in adults. US Preventive Services Task Force recommendation statement.JAMA. 2016; 316: 962-969Crossref PubMed Scopus (134) Google Scholar or when BCG-vaccinated persons come up with a positive TST result,8Centers for Disease Control and Prevention. Testing for tuberculosis (TB). Available at: https://www.cdc.gov/tb/publications/factsheets/testing/tb_testing.htm.Google Scholar regardless of the time elapsed since vaccination. The impressive results of Mancuso et al6Mancuso J.D. Mody R.M. Olsen C.H. Harrison L.H. Santosham M. Aronson N.E. The long-term effect of Bacille Calmette-Guérin vaccination on tuberculin skin testing: A 55-year follow-up study.Chest. 2017; 152: 282-294Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar may result in a warm welcome in the near future for a new alternative to IGRA testing. A TB-specific ESAT-6 and CFP 10-based skin test in which cross-reactivity with BCG is a priori excluded, is currently under development. Named “C-Tb skin test,” the new test has recently been shown to deliver IGRA-like results in a large controlled phase III study.10Ruhwald M, Aggerbeck H, Gallardo RV, et al; TESEC Working Group. Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon γ release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial [published online ahead of print January 31, 2017]. Lancet Respir Med. http://dx.doi.org/10.1016/S2213-2600(16)30436-2.Google Scholar Uninfluenced by BCG vaccination, that test may provide more accurate LTBI results in settings in which the preference is that skin testing be maintained. The Long-term Effect of Bacille Calmette-Guérin Vaccination on Tuberculin Skin Testing: A 55-Year Follow-Up StudyCHESTVol. 152Issue 2PreviewBacille Calmette-Guérin (BCG) vaccination is known to cause false-positive tuberculin skin test (TST) results from cross-reactions with mycobacterial antigens. However, the duration of BCG vaccination influence on the TST is poorly characterized. The objective of this study was to assess the long-term effect of BCG vaccination on TST reactivity. Full-Text PDF
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