The association between Bacillus Calmette-Guérin vaccination (1331 SSI) skin reaction and subsequent scar development in infants

Nina Marie Birk, Thomas Nørrelykke Nissen, Monica Ladekarl, Vera Zingmark, Jesper Kjærgaard, Trine Mølbæk Jensen, Signe Kjeldgaard Jensen, Lisbeth Marianne Thøstesen, Poul-Erik Kofoed, Lone Graff Stensballe, Andreas Andersen, Ole Pryds, Susanne Dam Nielsen, Christine Stabell Benn, Dorthe Lisbeth Jeppesen, Nina Marie Birk, Thomas Nørrelykke Nissen, Monica Ladekarl, Vera Zingmark, Jesper Kjærgaard, Trine Mølbæk Jensen, Signe Kjeldgaard Jensen, Lisbeth Marianne Thøstesen, Poul-Erik Kofoed, Lone Graff Stensballe, Andreas Andersen, Ole Pryds, Susanne Dam Nielsen, Christine Stabell Benn, Dorthe Lisbeth Jeppesen

Abstract

Background: The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis is administered intradermally, and vaccination is often followed by a scar at the injection site. Among BCG-vaccinated individuals, having a scar has been associated with lower mortality. We aimed to examine the impact of vaccination technique for scarring in a high income setting, by assessing the associations between the post injection reaction, the wheal size, and the probability of developing a scar, and scar size.

Methods: This study was nested within a clinical multicenter study randomizing 4262 infants to either BCG vaccination (BCG 1331 SSI) or no intervention. In this substudy, including 492 vaccinated infants, the immediate post BCG vaccination reaction was registered as either wheal (a raised, blanched papule at the injection site), bulge (a palpable element at the injection site), or no reaction. The presence or absence of a BCG scar and the size the scar was measured at 13 months of age.

Results: Of 492 infants included, 87% had a wheal after vaccination, 11% had a bulge, and 2% had no reaction. The mean wheal size was 3.8 mm (95% confidence interval 3.7-3.9). Overall, 95% (442/466, 26 lost to follow-up) of BCG-vaccinated infants had a scar at 13 months of age. In infants with a wheal, the probability of developing a scar was 96%, declining to 87% in the case of a bulge, and to 56% in the case of no reaction (p for same probability = 0.03). Wheal size was positively correlated with the probability of getting a scar and scar size.

Conclusion: Scarring after BCG vaccination has been associated with lower infant mortality. In a high-income setting, we found that correct injection technique is highly important for the development of a BCG scar and that registration of the category of BCG skin reaction (as wheal, bulge, or no reaction) may be used to identify infants at risk of scar failure. Finally, the wheal size was positively associated with both the probability of getting a scar and scar size.

Trial registration: The study was registered at www.ClinicalTrials.gov with trial registration number NCT01694108 .

Conflict of interest statement

Ethics approval and consent to participate

This substudy, as part of the protocol of the main trial, was approved by the Committees on Biomedical Research Ethics (J.no. H-3-2010-087), the Danish Data Protection Board (J.no. 2009–41-4141), and the Danish Medicines Agency (J.no.2612–4356.EudraCT 2010–021979-85. Protocol 2009–323). The study was registered at www.ClinicalTrials.gov with trial registration number NCT01694108. See materials and methods for further information.

Consent for publication

Images included are entirely unidentifiable and there are no details on individuals reported within the manuscript, hence no consent for publication was required.

Competing interests

SDN is an associate editor at BMC Infectious Diseases.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Inclusion into the study on the association between BCG vaccination skin reaction (categorized as wheal, bulge, or no reaction) and the subsequent development of a scar
Fig. 2
Fig. 2
The association between BCG vaccination skin reaction and the subsequent development of a scar. a Measurement of the size of a BCG vaccination wheal at birth. b Subsequent round and flat scar on the infant’s upper left arm at 13 months of age
Fig. 3
Fig. 3
The association between three categories of BCG vaccination skin reaction (wheal, bulge, or no reaction) registered immediately after neonatal BCG vaccination and the probability (%) of developing a scar at 13 months of age. The IRR of getting a scar preceded by a ‘bulge’ (with ´wheal´ as reference), was 0.90; the IRR of getting a scar preceded by ´ no reaction ´ was 0.57, *indicates p = 0.03
Fig. 4
Fig. 4
Violin plot of the association between size of the wheal and size of the scar measured at 13 months in infants vaccinated with BCG at birth. The open circle in the center of the plots depicts the median scar size at a given wheal size, the box depict the interquartile range, and the spikes depict the upper and lower values. The light gray areas reflect the density of the data

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