Specific effects against tuberculosis do not explain why BCG reduces all-cause mortality
Dr Stensballe reports that BCG-Denmark had no significant effect on all-cause hospitalisation in a randomised trial in Denmark [1]. She does not mention that the paper states, “In a pre-planned secondary analysis of hospital admissions for infection within the present trial, a significant beneficial effect of BCG among children of BCG-vaccinated mothers was observed” [2]. This is consistent with the observation that the beneficial non-targeted effects of live vaccines are enhanced with re-exposure, [3] and when measles vaccine is given in the presence of maternal antibodies [4].
Dr Stensballe suggests that the striking reduction in all-cause mortality associated with BCG may be a specific effect [1]. This is highly unlikely for several reasons.
First, in two randomised trials in low-birth-weight infants in Guinea-Bissau, BCG-Denmark reduced mortality by 48% (95% CI 18%-67%) in the first four weeks of life [5,6]. Given the long incubation period of tuberculosis, fatal disease in the first four weeks of life can only be caused by congenital tuberculosis, which is extremely rare even in highly endemic areas. In addition, only two infants in these trials were exposed to tuberculosis in the first four weeks of life and neither of them died.
Second, in the randomised trials in Guinea-Bissau, most of the neonatal deaths were caused by sepsis, respiratory infection or fever. No aetiological studies were performed in Guinea-Bissau, but in over 500 lung aspirations performed in children with pneumonia in The Gambia, Mycobacterium tuberculosis was detected in only four children, all of whom were malnourished [7,8].
Third, the Global Burden of Disease database attributes only 0.23% of infant deaths to tuberculosis [9].
Therefore, specific protection against tuberculosis can account for only a small proportion of the very large reduction in all-cause mortality associated with the administration of BCG in high-mortality countries.
1 Stensballe L. Bacillus Calmette Guerin (BCG) vaccine. Is the association to childhood mortality a specific effect? The BMJ Published Online First: 20 January 2017.http://www.bmj.com/content/355/bmj.i5170/rr-4 (accessed 20 Jan2017).
2 Stensballe LG, Sørup S, Aaby P, et al. BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial. Arch Dis Child Published Online First: 21 July 2016. doi:10.1136/archdischild-2016-310760
3 Benn CS, Fisker AB, Whittle HC, et al. Revaccination with Live Attenuated Vaccines Confer Additional Beneficial Nonspecific Effects on Overall Survival: A Review. EBioMedicine 2016;10:312–7. doi:10.1016/j.ebiom.2016.07.016
4 Aaby P, Martins CL, Garly M-L, et al. Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival. Clin Infect Dis 2014;59:484–92. doi:10.1093/cid/ciu354
5 Aaby P, Roth A, Ravn H, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204:245–52. doi:10.1093/infdis/jir240
6 Biering-Sorensen S, Aaby P, Napirna B, et al. Small randomized trial among low-birth-weight children of Bacillus Calmette-Guerin vaccination at first health center contact. Pediatr Infect Dis J 2012;31:306–8.
7 Falade AG, Mulholland EK, Adegbola RA, et al. Bacterial isolates from blood and lung aspirate cultures in Gambian children with lobar pneumonia. Ann Trop Paediatr 1997;17:315–9.
8 Ideh RC, Howie SRC, Ebruke B, et al. Transthoracic lung aspiration for the aetiological diagnosis of pneumonia: 25 years of experience from The Gambia. Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis 2011;15:729–35. doi:10.5588/ijtld.10.0468
9 Institute for Health Metrics and Evaluation. GBD Results Tool | GHDx. http://ghdx.healthdata.org/gbd-results-tool (accessed 18 Dec2016).
Rapid Response:
Specific effects against tuberculosis do not explain why BCG reduces all-cause mortality
Dr Stensballe reports that BCG-Denmark had no significant effect on all-cause hospitalisation in a randomised trial in Denmark [1]. She does not mention that the paper states, “In a pre-planned secondary analysis of hospital admissions for infection within the present trial, a significant beneficial effect of BCG among children of BCG-vaccinated mothers was observed” [2]. This is consistent with the observation that the beneficial non-targeted effects of live vaccines are enhanced with re-exposure, [3] and when measles vaccine is given in the presence of maternal antibodies [4].
Dr Stensballe suggests that the striking reduction in all-cause mortality associated with BCG may be a specific effect [1]. This is highly unlikely for several reasons.
First, in two randomised trials in low-birth-weight infants in Guinea-Bissau, BCG-Denmark reduced mortality by 48% (95% CI 18%-67%) in the first four weeks of life [5,6]. Given the long incubation period of tuberculosis, fatal disease in the first four weeks of life can only be caused by congenital tuberculosis, which is extremely rare even in highly endemic areas. In addition, only two infants in these trials were exposed to tuberculosis in the first four weeks of life and neither of them died.
Second, in the randomised trials in Guinea-Bissau, most of the neonatal deaths were caused by sepsis, respiratory infection or fever. No aetiological studies were performed in Guinea-Bissau, but in over 500 lung aspirations performed in children with pneumonia in The Gambia, Mycobacterium tuberculosis was detected in only four children, all of whom were malnourished [7,8].
Third, the Global Burden of Disease database attributes only 0.23% of infant deaths to tuberculosis [9].
Therefore, specific protection against tuberculosis can account for only a small proportion of the very large reduction in all-cause mortality associated with the administration of BCG in high-mortality countries.
1 Stensballe L. Bacillus Calmette Guerin (BCG) vaccine. Is the association to childhood mortality a specific effect? The BMJ Published Online First: 20 January 2017.http://www.bmj.com/content/355/bmj.i5170/rr-4 (accessed 20 Jan2017).
2 Stensballe LG, Sørup S, Aaby P, et al. BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial. Arch Dis Child Published Online First: 21 July 2016. doi:10.1136/archdischild-2016-310760
3 Benn CS, Fisker AB, Whittle HC, et al. Revaccination with Live Attenuated Vaccines Confer Additional Beneficial Nonspecific Effects on Overall Survival: A Review. EBioMedicine 2016;10:312–7. doi:10.1016/j.ebiom.2016.07.016
4 Aaby P, Martins CL, Garly M-L, et al. Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival. Clin Infect Dis 2014;59:484–92. doi:10.1093/cid/ciu354
5 Aaby P, Roth A, Ravn H, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204:245–52. doi:10.1093/infdis/jir240
6 Biering-Sorensen S, Aaby P, Napirna B, et al. Small randomized trial among low-birth-weight children of Bacillus Calmette-Guerin vaccination at first health center contact. Pediatr Infect Dis J 2012;31:306–8.
7 Falade AG, Mulholland EK, Adegbola RA, et al. Bacterial isolates from blood and lung aspirate cultures in Gambian children with lobar pneumonia. Ann Trop Paediatr 1997;17:315–9.
8 Ideh RC, Howie SRC, Ebruke B, et al. Transthoracic lung aspiration for the aetiological diagnosis of pneumonia: 25 years of experience from The Gambia. Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis 2011;15:729–35. doi:10.5588/ijtld.10.0468
9 Institute for Health Metrics and Evaluation. GBD Results Tool | GHDx. http://ghdx.healthdata.org/gbd-results-tool (accessed 18 Dec2016).
Competing interests: No competing interests