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Differences in BCG vaccination and tuberculin skin-test positivity
Correspondence
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Phyo AP, Nkhoma S, Stepniewska K, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet 2012; 379: 1960–66. Talundzic E, Okoth SA, Congpuong K, et al. Selection and spread of artemisinin-resistant alleles in Thailand prior to the global artemisinin resistance containment campaign. PLoS Pathog 2015; 11: e1004789. Ariey F, Witkowski B, Amaratunga C, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 2014; 505: 50–55. Huang F, Takala-Harrison S, Jacob CG, et al. A single mutation in K13 predominates in southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment. J Infect Dis 2015; published online April 24. DOI:10.1093/infdis/ jiv249. Carrara VI, Lwin KM, Phyo AP, et al. Malaria burden and artemisinin resistance in the mobile and migrant population on the Thai-Myanmar border, 1999–2011: an observational study. PLoS Med 2013; 10: e1001398.
Differences in BCG vaccination and tuberculin skin-test positivity We read with interest the Article by Lei Gao and colleauges,1 who estimated the prevalence of latent tuberculosis infection in rural populations in China by use of the tuberculin skin test and an interferon-γ release assay (QuantiFERON [QFT]). A key finding from the study was that in two of the four geographical sites (sites A [eastern China, plains] and C [western China, hills]), the prevalence of tuberculin skin test reactions of 10 mm or larger was much higher than QFT positivity, whereas the measurements in both tests were very similar at the other two sites (sites B [central China, plains] and D [western China, basin]). The authors1 attributed this discordance to BCG vaccination and non-tuberculous mycobacteria (NTM) exposure, and suggested that the prevalence of latent tuberculosis infection in China might be overestimated by tuberculin skin tests (28%) compared with QTF (19%), because QTF results correlated better with clinically confirmed or suspected pulmonary tuberculosis. However, we argue that these explanations are unlikely for several reasons.
First, site A had the lowest number of BCG vaccinated participants, yet showed the highest positivity rates with the tuberculin skin test, and lowest QFT rates. Conversely, site B that had the highest number of vaccinated participants showed very similar tuberculin skin test and QFT positivity rates. Second, the authors1 postulate that the high skin-test positivity result at site A might be due to NTM infections. However, available evidence shows that the effect of NTM on tuberculin skin test reactions of more than 10 mm is extremely low.2 Moreover, in 2012 a study on the prevalence of NTM in a coastal province of east China reported very low isolate rates of NTM (1·6%).3 We suggest that regional differences in BCG vaccination programmes, especially age of vaccination or revaccination, could account for the differences between tuberculin skin test reactivity and response to interferon-γ release assays. Consistent evidence shows that with the BCG vaccine administered at birth (or early during infancy) has a minimum effect on tuberculin skin test specificity, especially if the tuberculin skin test is administered 10 years or more after vaccination.2,4 By contrast, if the BCG vaccine is given after infancy or with booster shots, tuberculin skin test specificity is compromised, an effect that can persist for more than 20 years. Therefore, one might speculate that in this study,1 the sites that showed large differences in positivity rates between the tuberculin skin test and QTF included participants vaccinated at an older age (≥20 years). Details about the BCG vaccination programmes for every study site, particularly age distribution of vaccination and revaccinations in addition to agreement between QFT and tuberculin skin test according to tuberculin skin test cutoff values and BCG vaccination status, would be informative. Since both tuberculin skin test and QFT measure cumulative lifetime exposure, analysing the association of positive tests with notification rates of
www.thelancet.com/infection Vol 15 September 2015
tuberculosis over the past 40 years in the four areas would be important. In conclusion, we believe that the study by Gao and colleagues1 provides a unique opportunity to further investigate the effect of BCG vaccination policies and trends in tuberculosis notification rates on tuberculin skin test results. All authors declare no competing interests.
*Anissa Sidibe, Alberto Matteelli, Richard Menzies, Haileyesus Getahun [email protected] Global Tuberculosis Programme, World Health Organization, Geneva 1211, Switzerland © 2015. World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. 1
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Gao L, Lu W, Bai L, et al, for the LATENTTB-NSTM study team. Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study. Lancet Infect Dis 2015; 15: 310–19. Farhat M, Greenaway C, Pai M, Menzies D. Falsepositive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006; 10: 1192–204. Jing H, Wang H, Wang Y, et al. Prevalence of nontuberculous mycobacteria infection, China, 2004–2009. Emerg Infect Dis 2012; 18: 527–28. Menzies D. What does tuberculin reactivity after bacille Calmette-Guerin vaccination tell us? Clin Infect Dis 2000; 31 (suppl 3): S71–S74.
Authors’ reply We are pleased to read the comments from Anissa Sidibe and colleagues, suggesting regional differences in BCG vaccination programmes as a possible explanation for the differences in results of tuberculin skin test and an interferon-γ release assay (QuantiFERON [QFT]) reported in our study.1 Our baseline data clearly shows that unlike QFT, tuberculin skin test results are strikingly variable by geographical location (in China) and age. We agree with their viewpoint that the age at BCG vaccination or revaccination could affect tuberculin skin test reactions and the variability of results might illustrate different BCG vaccination policies and its implementation status at the sites. Although the effect of environmental non-tuberculous mycobacteria (NTM) 1003
2
3
4
5
6
Phyo AP, Nkhoma S, Stepniewska K, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet 2012; 379: 1960–66. Talundzic E, Okoth SA, Congpuong K, et al. Selection and spread of artemisinin-resistant alleles in Thailand prior to the global artemisinin resistance containment campaign. PLoS Pathog 2015; 11: e1004789. Ariey F, Witkowski B, Amaratunga C, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 2014; 505: 50–55. Huang F, Takala-Harrison S, Jacob CG, et al. A single mutation in K13 predominates in southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment. J Infect Dis 2015; published online April 24. DOI:10.1093/infdis/ jiv249. Carrara VI, Lwin KM, Phyo AP, et al. Malaria burden and artemisinin resistance in the mobile and migrant population on the Thai-Myanmar border, 1999–2011: an observational study. PLoS Med 2013; 10: e1001398.
Differences in BCG vaccination and tuberculin skin-test positivity We read with interest the Article by Lei Gao and colleauges,1 who estimated the prevalence of latent tuberculosis infection in rural populations in China by use of the tuberculin skin test and an interferon-γ release assay (QuantiFERON [QFT]). A key finding from the study was that in two of the four geographical sites (sites A [eastern China, plains] and C [western China, hills]), the prevalence of tuberculin skin test reactions of 10 mm or larger was much higher than QFT positivity, whereas the measurements in both tests were very similar at the other two sites (sites B [central China, plains] and D [western China, basin]). The authors1 attributed this discordance to BCG vaccination and non-tuberculous mycobacteria (NTM) exposure, and suggested that the prevalence of latent tuberculosis infection in China might be overestimated by tuberculin skin tests (28%) compared with QTF (19%), because QTF results correlated better with clinically confirmed or suspected pulmonary tuberculosis. However, we argue that these explanations are unlikely for several reasons.
First, site A had the lowest number of BCG vaccinated participants, yet showed the highest positivity rates with the tuberculin skin test, and lowest QFT rates. Conversely, site B that had the highest number of vaccinated participants showed very similar tuberculin skin test and QFT positivity rates. Second, the authors1 postulate that the high skin-test positivity result at site A might be due to NTM infections. However, available evidence shows that the effect of NTM on tuberculin skin test reactions of more than 10 mm is extremely low.2 Moreover, in 2012 a study on the prevalence of NTM in a coastal province of east China reported very low isolate rates of NTM (1·6%).3 We suggest that regional differences in BCG vaccination programmes, especially age of vaccination or revaccination, could account for the differences between tuberculin skin test reactivity and response to interferon-γ release assays. Consistent evidence shows that with the BCG vaccine administered at birth (or early during infancy) has a minimum effect on tuberculin skin test specificity, especially if the tuberculin skin test is administered 10 years or more after vaccination.2,4 By contrast, if the BCG vaccine is given after infancy or with booster shots, tuberculin skin test specificity is compromised, an effect that can persist for more than 20 years. Therefore, one might speculate that in this study,1 the sites that showed large differences in positivity rates between the tuberculin skin test and QTF included participants vaccinated at an older age (≥20 years). Details about the BCG vaccination programmes for every study site, particularly age distribution of vaccination and revaccinations in addition to agreement between QFT and tuberculin skin test according to tuberculin skin test cutoff values and BCG vaccination status, would be informative. Since both tuberculin skin test and QFT measure cumulative lifetime exposure, analysing the association of positive tests with notification rates of
www.thelancet.com/infection Vol 15 September 2015
tuberculosis over the past 40 years in the four areas would be important. In conclusion, we believe that the study by Gao and colleagues1 provides a unique opportunity to further investigate the effect of BCG vaccination policies and trends in tuberculosis notification rates on tuberculin skin test results. All authors declare no competing interests.
*Anissa Sidibe, Alberto Matteelli, Richard Menzies, Haileyesus Getahun [email protected] Global Tuberculosis Programme, World Health Organization, Geneva 1211, Switzerland © 2015. World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. 1
2
3
4
Gao L, Lu W, Bai L, et al, for the LATENTTB-NSTM study team. Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study. Lancet Infect Dis 2015; 15: 310–19. Farhat M, Greenaway C, Pai M, Menzies D. Falsepositive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006; 10: 1192–204. Jing H, Wang H, Wang Y, et al. Prevalence of nontuberculous mycobacteria infection, China, 2004–2009. Emerg Infect Dis 2012; 18: 527–28. Menzies D. What does tuberculin reactivity after bacille Calmette-Guerin vaccination tell us? Clin Infect Dis 2000; 31 (suppl 3): S71–S74.
Authors’ reply We are pleased to read the comments from Anissa Sidibe and colleagues, suggesting regional differences in BCG vaccination programmes as a possible explanation for the differences in results of tuberculin skin test and an interferon-γ release assay (QuantiFERON [QFT]) reported in our study.1 Our baseline data clearly shows that unlike QFT, tuberculin skin test results are strikingly variable by geographical location (in China) and age. We agree with their viewpoint that the age at BCG vaccination or revaccination could affect tuberculin skin test reactions and the variability of results might illustrate different BCG vaccination policies and its implementation status at the sites. Although the effect of environmental non-tuberculous mycobacteria (NTM) 1003