Skip to main content

Advertisement

SpringerLink
Log in

Inborn Errors of Immunity in Patients with Adverse Events Following BCG Vaccination in Brazil

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Objective

The Bacille Calmette-Guérin (BCG) vaccine is routinely applied in Brazil. Adverse events (AE) may occur in patients with inborn or acquired immunodeficiencies, varying between local (BCGitis) or disseminated (BCGosis) reactions. We evaluated 53 individuals with local or disseminated adverse events to BCG vaccination to assess if they had inborn errors of immunity (IEI).

Methods

Patients diagnosed with an adverse event following BCG vaccination between 2014 and 2017 were included in the study. We collected clinical data, immunophenotyped T and B lymphocytes, and natural killer cells (NK), assessed oxidative function of neutrophils through dihydrorhodamine (DHR) 123 testing, and genotyped 361 genes related to IEI through targeted (panel) sequencing.

Results

The median age of the 53 individuals was four months (IQ 1.5–12), and 52.8% were male. Forty-eight (90.6%) individuals presented only locoregional AE and five (9.4%) presented both locoregional and disseminated AE. Nine (16.9%) patients were diagnosed with an IEI. Four of them presented BCGitis and five presented BCGosis after BCG vaccination. Clinically, four presented chronic granulomatous disease (CGD), three Mendelian susceptibility to mycobacterial disease (MSMD), and two severe combined immunodeficiency (SCID). Patients with IEI had a higher frequency of systemic symptomatology (p = 0.002), history of other infections (p < 0.001), parental consanguinity (p = 0.01), familial history of sick siblings (p < 0.001), or early deaths in the family (p < 0.01).

Conclusion

There is a high frequency of IEI in patients with locoregional and disseminated adverse events to BCG vaccination, revealing the need for the investigation of IEI accompanied by clinical and familial inquiry.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Data Availability

The data generated for this study can be found within the article or its supplementary materials.

References

  1. World Health Organization. BCG vaccine: WHO position paper, February 2018 – Recommendations. Vaccine. 2018;36(24):3408–10.

    Article  CAS  PubMed  Google Scholar 

  2. World Health Organisation. (2018). Global tuberculosis report 2018. World Health Organisation. Available at: https://apps.who.int/iris/handle/10665/274453. Accessed 12 February 2020

  3. World Health Organisation. (2015). WHO | WHO End TB Strategy. World Health Organisation, 1-18. Available at: https://apps.who.int/iris/handle/10665/274453. Accessed 15 January 2020.

  4. Boman G. The ongoing story of the Bacille Calmette-Guérin (BCG) vaccination. Acta Paediatr. 2016;105(12):1417–20.

    Article  PubMed  Google Scholar 

  5. Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M. The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med. 2011 Mar;8(3):e1001012.

  6. Brasil. Ministério da Saúde Secretaria de Atenção à Saúde. Departamento de Ações Progrmáticas Estratégicas, B. (2019).Manual de para o Controle da Tuberculose. Ministério da Saúde (p.364). Ministério da Saúde. Available at https://www.aids.gov.br/pt-br/pub/2019/manual-de-recomendacoes-para-o-controle-da-tuberculose-no-brasil. Accessed 8 March 2020.

  7. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doenças Transmissíveis.(2014).Manual de Vigilância Epidemiológica de Eventos Adversos Pós-Vacinação. Ministério da Saúde (p.250). Available at: https://bvsms.saude.gov.br/bvs/publicacoes/manual_vigilancia_epidemiologica_eventos_adversos_pos_vacinacao.pdf. Accessed 17 September 2019.

  8. das NevasFraga Moreira T, de Moraes-Pinto MI, Costa-Carvalho BT, Grumach AS, Weckx LY. Clinical management of localized bcg adverse events in children. Rev Inst Med Trop Sao Paulo. 2016;58(1):84.

    PubMed  Google Scholar 

  9. Alrabiaah AA, Alsubaie SS, Bukhari EI, Gad A, Alzamel FA. Outbreak of Bacille Calmette-Guérin-related lymphadenitis in Saudi children at a university hospital after a change in the strain of vaccine. Ann Saudi Med. 2012;32(1):4–8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bukhari E, Alzahrani M, Alsubaie S, Alrabiaah A, Alzamil F. Bacillus Calmette-Guerin lymphadenitis: a 6-year experience in two Saudi hospitals. Indian J Pathol Microbiol. 2012;55(2):202–5.

    Article  CAS  PubMed  Google Scholar 

  11. Western Cape Department of Health. Intradermal BCG immunization: information for health workers about the use of intradermal BCG (bacille Calmette-Guerin) vaccine against tuberculosis in the Expanded Programme on Immunization in South Africa. Available at: https://bvsms.saude.gov.br/bvs/publicacoes/manual_vigilancia_epidemiologica_eventos_adversos_pos_vacinacao.pdf. Accessed 5 July 2016.

  12. Lotte A, Wasz-Hockert OPN, et al. Second IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc. 1988;63:47–59.

    CAS  Google Scholar 

  13. Hesseling AC, Rabie H, Marais BJ, Manders M, Lips M, Schaaf HS, et al. Bacille Calmette-Guérin vaccine – induced disease In HIV-infected and HIV-uninfected children. Clin Infect Dis. 2006 Feb 15;42(4):548–58.

  14. Jacob CMA, Pastorino AC, Azevedo AM, Marques HHS, Sato HK, Ferrazole L, et al. Mycobacterium bovis dissemination (BCG strain) among immunodeficient Brazilian infants. J Investig Allergol Clin Immunol. 1996;6(3):202–6.

    CAS  PubMed  Google Scholar 

  15. Marciano BE, Huang CY, Joshi G, Rezaei N, Carvalho BC, Allwood Z, et al. BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies. J Allergy Clin Immunol. 2014;133(4):1134–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mazzucchelli JTL, Bonfim C, Castro GG, Condino-Neto AA, Costa NMX, Cunha L, et al. Severe combined immunodeficiency in Brazil: management, prognosis, and BCG-associated complications. J Investig Allergol Clin Immunol. 2014;24(3):184–91.

    CAS  PubMed  Google Scholar 

  17. Conti F, Lugo-Reyes SO, Blancas Galicia L, He J, Aksu G, Borges de Oliveira E, et al. Mycobacterial disease in patients with chronic granulomatous disease: a retrospective analysis of 71 cases. J Allergy Clin Immunol. 2016;138(1):241-248.e3.

    Article  PubMed  Google Scholar 

  18. Bustamante J, Aksu G, Vogt G, de Beaucoudrey L, Genel F, Chapgier A, et al. BCG-osis and tuberculosis in a child with chronic granulomatous disease. J Allergy Clin Immunol. 2007;120(1):32–8.

    Article  PubMed  Google Scholar 

  19. de Oliveira-Junior EB, Zurro NB, Prando C, Cabral-Marques O, Pereira PVS, Schimke L-F, et al. Clinical and genotypic spectrum of chronic granulomatous disease in 71 Latin American patients: first report from the LASID Registry. Pediatr Blood Cancer. 2015;62(12):2101–7.

    Article  PubMed  Google Scholar 

  20. Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science (80- ). 1998;280(5368):1432–5.

  21. Dorman SE, Holland SM. Mutation in the signal-transducing chain of the interferon-γ receptor and susceptibility to mycobacterial infection. J Clin Invest. 1998;101(11):2364–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med. 2006;203(7):1745–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile J-F, Newport M, et al. Interferon-γ –receptor deficiency in an infant with fatal Bacille Calmette-Guérin infection. N Engl J Med. 1996;335(26):1956–62.

    Article  CAS  PubMed  Google Scholar 

  24. Casanova JL, Jouanguy E, Lamhamedi S, Blanche S, Fischer A. Immunological conditions of children with BCG disseminated infection. Lancet (London, England). 1995;346(8974):581.

    Article  CAS  PubMed  Google Scholar 

  25. Talbot EA, Perkins MD, Silva SFM, Frothingham R. Disseminated Bacille Calmette-Guerin disease after vaccination: case report and review. Clin Infect Dis. 1997;24(6):1139–46.

    Article  CAS  PubMed  Google Scholar 

  26. de Moraes-Vasconcelos D, Grumach AS, Yamaguti A, Andrade MEB, Fieschi C, de Beaucoudrey L, et al. Paracoccidioides brasiliensis disseminated disease in a patient with inherited deficiency in the 1 subunit of the interleukin (IL)-12/IL-23 receptor. Clin Infect Dis. 2005;41(4):31–7.

    Article  Google Scholar 

  27. Sicherer SH. Severe Mycobacterial and Salmonella infections in interleukin-12receptor-deficient patients. Pediatrics. 1999;104(2):397–8.

    Article  Google Scholar 

  28. Carneiro-Sampaio M, Jacob CMA, Leone CR. A proposal of warning signs for primary immunodeficiencies in the first year of life. Pediatr Allergy Immunol. 2011;22(3):345–6.

    Article  PubMed  Google Scholar 

  29. de Beaucoudrey L, Samarina A, Bustamante J, Abel L, Sanal O, Casanova J-L, et al. Revisiting humal IL-12Rbeta1 deficiency: a survey of 141 patients from 30 countries. Production. 2011;89(5):381–402.

    Google Scholar 

  30. Bukhari E, Alaklobi F, Bakheet H, Alrabiaah A, Alotibi F, Aljobair F, et al. Disseminated bacille Calmette-Guérin disease in Saudi children: clinical profile, microbiology, immunology evaluation and outcome. Eur Rev Med Pharmacol Sci. 2016;20(17):3696–702.

    CAS  PubMed  Google Scholar 

  31. Al-Hammadi S, Alsuwaidi AR, Alshamsi ET, Ghatasheh GA, Souid AK. Disseminated Bacillus Calmette-Guérin (BCG) infections in infants with immunodeficiency. BMC Res Notes. 2017;10(1):1–5.

    Article  Google Scholar 

  32. Sarrafzadeh SA, Nourizadeh M, Mahloojirad M, Fazlollahi MR, ShokouhiShoormasti R, Badalzadeh M, et al. Molecular, immunological, and clinical features of 16 Iranian Patients with Mendelian susceptibility to Mycobacterial Disease. J Clin Immunol. 2019;39(3):287–97.

    Article  CAS  PubMed  Google Scholar 

  33. de Moraes-Pinto, MI; Ono, E. ; Antunes, E. ; Miyamoto, M. ; Dinelli, MIS. ; Santos-Valente, EC ; Almeida, LC. ; Costa-Carvalho, BT. ; Santos, AMN. ; Salomão, R. . Lymphocyte subsets from birth through adulthood: values in a healthy Brazilian population and in patients under investigation for primary immunodeficiencies. In: Autoimmunity in Primary Immunodeficiencies. XII LAGID Meeting / I BRAGID Meeting, 2007, São Paulo. Clinics. São Paulo, 2007. v. 62. p. S54-S54.

  34. Dourado I, Rios MH, Pereira SMM, Cunha SS, Ichihara MY, Goes JCL, et al. Rates of adverse reactions to first and second doses of BCG vaccination: results of a large community trial in Brazilian schoolchildren. Int J Tuberc Lung Dis. 2003;7(4):399–402.

    CAS  PubMed  Google Scholar 

  35. Muzy de Souza GR, Couto Sant’Anna C, Lapa e Silva J, Biasotto Mano D, ManhãesBethlem N. Intradermal BCG vaccination complications— analysis of 51 cases. Tubercle. 1983;64(1):23–7.

    Article  CAS  PubMed  Google Scholar 

  36. Averbuch D, Chapgier A, Boisson-Dupuis S, Casanova J-L, Engelhard D. The clinical spectrum of patients with deficiency of signal transducer and activator of transcription-1. Pediatr Infect Dis J. 2011;30(4):352–5.

    Article  PubMed  Google Scholar 

  37. Boisson-Dupuis S, Kong X-F, Okada S, Cypowyj S, Puel A, Abel L, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol. 2012;24(4):364–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, et al. Inherited IL-12p40 deficiency. Medicine (Baltimore). 2013;92(2):109–22.

    Article  CAS  PubMed  Google Scholar 

  39. Rosain J, Oleaga-Quintas C, Deswarte C, Verdin H, Marot S, Syridou G, et al. A variety of alu-mediated copy number variations can underlie IL-12Rβ1 deficiency. J Clin Immunol. 2018;38(5):617–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Louvain de Souza T, de Souza Campos Fernandes RC, Azevedo da Silva J, Gomes Alves Júnior V, Gomes Coelho A, Souza Faria AC, et al. Microbial disease spectrum linked to a novel IL-12Rβ1 N-Terminal signal peptide stop-gain homozygous mutation with paradoxical receptor cell-surface expression. Front Microbiol. 2017;8:616.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Esteve-Solé A, Sologuren I, Martínez-Saavedra MT, Deyà-Martínez À, Oleaga-Quintas C, Martinez-Barricarte R, et al. Laboratory evaluation of the IFN-γ circuit for the molecular diagnosis of Mendelian susceptibility to mycobacterial disease. Crit Rev Clin Lab Sci. 2018 Apr 3;55(3):184–204.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Movahedi Z, Norouzi S, Mamishi S, Rezaei N. BCGiosis as a presenting feature of a child with chronic granulomatous disease. Brazilian J Infect Dis. 2011;15(1):83–6.

    Google Scholar 

  43. Zhou Q, Hui X, Ying W, Hou J, Wang W, Liu D, et al. A cohort of 169 Chronic granulomatous disease patients exposed to BCG vaccination: a retrospective Study from a single center in Shanghai, China (2004–2017). J Clin Immunol. 2018;38(3):260–72.

    Article  CAS  PubMed  Google Scholar 

  44. Sadeghi-Shanbestari M, Ansarin K, Maljaei SH, Rafeey M, Pezeshki Z, Kousha A, et al. Immunologic aspects of patients with disseminated bacille Calmette-Guerin disease in north-west of Iran. Ital J Pediatr. 2009;35:42.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bolursaz MR, Lotfian F, Velayati AA. Bacillus Calmette-Guérin vaccine complications in Iranian children at a University Hospital. Allergol Immunopathol (Madr). 2017;45(4):356–61.

    Article  CAS  PubMed  Google Scholar 

  46. Ying W, Sun J, Liu D, Hui X, Yu Y, Wang J, et al. Clinical characteristics and immunogenetics of BCGosis/BCGitis in Chinese children: a 6 year follow-up study. PLoS ONE. 2014;9(4):1–6.

    Article  Google Scholar 

  47. For Immunodeficiency BG. Os 10 sinais de alerta para imunodeficiênica primária na criança adaptados [Internet]. [cited 2020 Feb 28]. Available from: www.imunopediatria.org.br

  48. Aelami MH, Alborzi A, Pouladfar G, Geramizadeh B, Pourabbas B, Mardaneh J. Post-vaccination disseminated bacillus calmette guerin infection among children in southern Iran. Jundishapur J Microbiol. 2015;8(11):1–7.

    Article  Google Scholar 

  49. Paiman SA, Siadati A, Mamishi S, Tabatabaie P, Khotaee G. Disseminated Mycobacterium bovis infection after BCG vaccination. Iran J Allergy Asthma Immunol. 2006;5(3):133–7.

    Google Scholar 

  50. Sharifi Asadi P, Aghamohammadi A, Mahmoudi S, Pourakbari B, Saboui F, Mamishi S. Clinical, laboratory and imaging findings of the patients with disseminated bacilli Calmette-Guerin disease. Allergol Immunopathol (Madr). 2015;43(3):254–8.

    Article  CAS  PubMed  Google Scholar 

  51. Amanati A, Pouladfar G, Kadivar MR, SanaeiDashti A, Jafarpour Z, Haghpanah S, et al. A 25-year surveillance of disseminated Bacillus Calmette-Guérin disease treatment in children in Southern Iran. Med (United States). 2017;96(52):1–5.

    Google Scholar 

  52. Sellami K, Amouri M, Kmiha S, Bahloul E, Aloulou H, Sfaihi L, et al. Adverse Reactions Due to the Bacillus Calmette-Guerin Vaccine: Twenty Tunisian Cases. Indian J Dermatol. 2018;63(1):62–5.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Luk ADW, Lee PP, Mao H, Chan K-W, Chen XY, Chen T-X, et al. Family history of early infant death correlates with earlier age at diagnosis but not shorter time to diagnosis for severe combined immunodeficiency. Front Immunol. 2017;12:8.

    Google Scholar 

  54. McWilliams LM, Dell Railey M, Buckley RH. Positive family history, infection, low absolute lymphocyte count (ALC), and absent thymic shadow: diagnostic clues for all molecular forms of severe combined immunodeficiency (SCID). J Allergy Clin Immunol Pract. 2015;3(4):585–91.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Roxo-Junior P, Silva J, Andrea M, Oliveira L, Ramalho F, Bezerra T, et al. A family history of serious complications due to BCG vaccination is a tool for the early diagnosis of severe primary immunodeficiency. Ital J Pediatr. 2013;39(1):2–5.

    Article  Google Scholar 

  56. Rosain J, Kong XF, Martinez-Barricarte R, Oleaga-Quintas C, Ramirez-Alejo N, Markle J, et al. Mendelian susceptibility to mycobacterial disease: 2014–2018 update. Immunol Cell Biol. 2019;97(4):360–7.

    Article  PubMed  Google Scholar 

  57. Bustamante J, Boisson-Dupuis S, Abel L, Casanova J-L. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin Immunol. 2014;26(6):454–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fekrvand S, Yazdani R, Olbrich P, Gennery A. Primary immunodeficiency diseases and Bacillus Calmette-Guérin ( BCG ) -vaccine e derived complications : a systematic review. J Allergy Clin Immunol Pract. 2020;8(4):1371–86.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the patients and guardians that gave permission for the research; doctors who referred patients, in particular Dra. Sálua Soares Mafra e Dra. Maria Cristina Gonçalves Magalhães; staff of the Laboratório de Pesquisa Translacional do IMIP (Translational Research Laboratory of IMIP), particularly Alexandra Karla Santos Barreto and Francisco Sales de Albuquerque; Departamento de doenças Infecto-Parasitárias Infantil do HUOC (Department of Child Infectious-Parasitic Diseases at HUOC), especially Dra. Regina Coeli Ferreira Ramos; and Prof. Dr. José Natal Figueiroa–statistical analysis.

Funding

This study was funded by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – Processo no 486308/2013–8).

Author information

Authors and Affiliations

  1. Department of Clinical Immunology, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Pernambuco, Brazil

    Paula T. Lyra, Edvaldo Souza, Ana Carla A. Moura & Luiz Arraes

  2. Children’s Department of Infectious Disease, Oswaldo Cruz University Hospital (HUOC), Universidade de Pernambuco (UPE), Recife, PA, Brazil

    Paula T. Lyra, Ana Carla A. Moura & Maria Ângela W. Rocha

  3. Faculdade Pernambucana de Saúde (FPS), Recife, PA, Brazil

    Edvaldo Souza

  4. Translational Research Laboratory Prof. C. A. Hart, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, PE, Brazil

    Marina C. Matta & Leuridan C. Torres

  5. Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

    Antonio Victor Campos Coelho & João Bosco Oliveira

  6. Universidade Federal de Pernambuco (UFPE), Recife, PA, Brazil

    Luiz Arraes

Authors
  1. Paula T. Lyra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edvaldo Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Carla A. Moura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marina C. Matta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leuridan C. Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Victor Campos Coelho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria Ângela W. Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luiz Arraes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. João Bosco Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PTL – data collection, literature review and article writing; JBO – lymphocyte immunophenotyping, genetic sequencing, article review; ACAMF and MAWR – data collection; MCM and LCT – DHR test execution and analysis; ESS, LA, AVCC – article review and editorial changes.

Corresponding author

Correspondence to Paula T. Lyra.

Ethics declarations

Ethics Approval

The study adheres to the Declaration of Helsinki principles for research in human beings and was approved by the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)’s Committee of Ethics in Research (ethics approval number: CAAE 11841312.0.0000.5201).

Consent to Participate

Written informed consent was obtained from all patients and/or their parents or legal guardians.

Consent for Publication

Written informed consent for publication of clinical details were obtained from all patients and/or their parents or legal guardians.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 66 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lyra, P.T., Souza, E., Moura, A.C.A. et al. Inborn Errors of Immunity in Patients with Adverse Events Following BCG Vaccination in Brazil. J Clin Immunol 42, 1708–1720 (2022). https://doi.org/10.1007/s10875-022-01302-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-022-01302-9

Keywords

Search

Navigation