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Severe BCG-osis Misdiagnosed as Multidrug-Resistant Tuberculosis in an IL-12Rβ1-Deficient Peruvian Girl

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Abstract

Purpose

Mendelian suceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing to severe disease caused by mycobacteria and other intracellular pathogens. Delay in diagnosis can have an impact on the patient’s prognosis.

Methods

We evaluated the IFN-γ circuit by studying IFN-γ production after mycobacterial challenge as well as IL-12Rβ1 expression and STAT4 phosphorylation in response to IL-12p70 stimulation in whole blood of a 6-year-old Peruvian girl with disseminated recurrent mycobacterial infection diagnosed as multidrug-resistant tuberculosis. Genetic studies with Sanger sequencing were used to identify the causative mutation. Microbiological studies based on PCR reactions were used to diagnose the specific mycobacterial species.

Results

We identified a homozygous mutation in the IL12RB1 gene (p. Arg211*) causing abolished expression of IL-12Rβ1 and IL-12 response. MSMD diagnosis led to a microbiological reevaluation of the patient, revealing a BCG vaccine-related infection instead of tuberculosis. Treatment was then adjusted, with good response.

Conclusions

We report the first Peruvian patient with IL-12Rβ1 deficiency. Specific mycobacterial species diagnosis within Mycobacterium tuberculosis complex is still challenging in countries with limited access to PCR-based microbiological diagnostic techniques. Awareness of MSMD warning signs and accurate microbiological diagnosis of mycobacterial infections are of the utmost importance for optimal diagnosis and management of affected patients.

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Acknowledgements

We especially thank the patient and her family, and the physicians taking care of the patient. We would like to thank Dr. Julià Gonzalez for kindly providing the live BCG, Gary Fahle, Jung-Ho Youn, and Christina Henderson (Microbiology Service, NIH Clinical Center), and the National Tuberculosis Laboratory at the CDC. We would also like to thank the health group involved in the patient’s care, Dr. Leonid Lecca and Dr. Silvia Chiang.

Funding

This study was supported by the projects PI12/01990, PI15/01094 and PFIS0200 (AC16/00025) to LA, integrated in the Plan Nacional de I+D+I and cofinanced by the ISCIII – Subdirección General de Evaluación y Formento de la Investigación Sanitaria – and the Fondo Europeo de Desarrollo Regional (FEDER), by “Subvencions per a la Intensificació Facultatius Especialistes” del Departament de Salut de la Generalitat de Catalunya. Programa PERIS 2016-2020 (Referencia: SLT006/17/00199)” and by a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation to LA. This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA. The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institute of Allergy and Infectious Diseases grant number 5R37AI095983, the Rockefeller University, the St. Giles Foundation, INSERM and ANR-GENMSMD (ANR-16-CE17-0005-01).

Author information

Author notes

  1. Wilmer Córdova and Laia Alsina share credit for senior authorship.

Authors and Affiliations

  1. Functional Unit of Clinical Immunology and Primary Immunodeficiencies, Hospital Sant Joan de Déu, University of Barcelona, Pediatric Research Institute Sant Joan de Déu, Barcelona, Spain

    Ana Esteve-Sole, Angela Deyà-Martínez & Laia Alsina

  2. Functional Unit of Clinical Immunology, Hospital Sant Joan de Déu-Hospital Clinic, Barcelona, Spain

    Ana Esteve-Sole, Angela Deyà-Martínez, Manel Juan & Laia Alsina

  3. National reference center Allergy Asthma Immunology, National Institute of Child Health, Lima, Peru

    Suly P. Sánchez-Dávila & Wilmer Cordova

  4. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Alexandra F. Freeman & Steven M. Holland

  5. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    Adrian M. Zelazny, John P. Dekker & Pavel P. Khil

  6. Infectious Diseases and Systemic Inflammatory Response in Pediatrics, Infectious Diseases Unit, Pediatrics Department, Pediatric Research Institute Sant Joan de Déu, Barcelona, Spain

    Antoni Noguera-Julian

  7. Department of Pediatrics, University of Barcelona, Barcelona, Spain

    Antoni Noguera-Julian

  8. CIBER of Epidemiology and Public Health, CIBERESP, Madrid, Spain

    Antoni Noguera-Julian

  9. Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain

    Antoni Noguera-Julian

  10. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Paris, France

    Jacinta Bustamante & Jean-Laurent Casanova

  11. Imagine Institute, Paris Descartes University, Paris, France

    Jacinta Bustamante & Jean-Laurent Casanova

  12. Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France

    Jacinta Bustamante

  13. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New York, NY, USA

    Jacinta Bustamante & Jean-Laurent Casanova

  14. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France

    Jean-Laurent Casanova

  15. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  16. Immunology Department, Biomedical Diagnostics Center, Hospital Clinic-IDIBAPS, Barcelona, Spain

    Manel Juan

Authors
  1. Ana Esteve-Sole
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  2. Suly P. Sánchez-Dávila
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  3. Angela Deyà-Martínez
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  4. Alexandra F. Freeman
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  5. Adrian M. Zelazny
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  6. John P. Dekker
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  7. Pavel P. Khil
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  8. Steven M. Holland
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  9. Antoni Noguera-Julian
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  10. Jacinta Bustamante
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  11. Jean-Laurent Casanova
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  12. Manel Juan
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  13. Wilmer Cordova
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  14. Laia Alsina
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Corresponding author

Correspondence to Laia Alsina.

Ethics declarations

This study was carried out in accordance with the recommendations of the Spanish Ley General de Sanidad (25/4/1986), and parental written informed consent was obtained. The protocol was approved by the local ethics committee (PIC-50-12).

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Esteve-Sole, A., Sánchez-Dávila, S.P., Deyà-Martínez, A. et al. Severe BCG-osis Misdiagnosed as Multidrug-Resistant Tuberculosis in an IL-12Rβ1-Deficient Peruvian Girl. J Clin Immunol 38, 712–716 (2018). https://doi.org/10.1007/s10875-018-0535-6

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  • DOI: https://doi.org/10.1007/s10875-018-0535-6

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