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BCG-Related Inflammatory Syndromes in Severe Combined Immunodeficiency After TCRαβ+/CD19+ Depleted HSCT

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Abstract

Introduction

The live-attenuated BCG vaccine is known to cause disseminated Mycobacterium bovis infection in patients with severe combined immunodeficiency (SCID). However, BCG-related post-hematopoietic stem cell transplantation (HSCT) immune reconstitution inflammatory syndromes, similar to those described in patients with HIV infections, are less-known complications of SCID.

Patients and Methods

We reported on 22 BCG-vaccinated SCID patients who had received conditioned allogeneic HSCT with TCRαβ+/CD19+ graft depletion. All BCG-vaccinated patients received anti-mycobacterial therapy pre- and post-HSCT. Post-transplant immunosuppression consisted of tacrolimus in 10 patients and of 8 mg/kg tocilizumab (d-1, + 14, + 28) and 10 mg/kg abatacept (d-1, + 5, + 14, + 28) in 11 patients.

Results

Twelve patients, five of whom had BCG infection prior to HSCT, developed BCG-related inflammatory syndromes (BCG-IS). Five developed early BCG-IS with the median time of manifestation 11 days after HSCT, corresponding with a dramatic increase of CD3+TCRγδ+ in at least two patients. Early BCG-IS was noted in only one out of 11 patients who received tocilizumab/abatacept and 4 out of 11 patients who did not. Seven patients developed late BCG-IS which corresponded to T cell immune recovery; at the time of manifestation (median 4.2 months after HSCT), the median number of CD3+ cells was 0.42 × 109/ and CD3+CD4+ cells 0.27 × 109/l. In all patients, late BCG-IS was controlled with IL-1 or IL-6 inhibitors.

Conclusion

BCG-vaccinated SCID patients undergoing allogeneic HSCT with TCRαβ+/CD19+ graft depletion are at an increased risk of early and late BCG-IS. Anti-inflammatory therapy with IL-1 and IL-6 blockade is efficient in the prevention of early and treatment of late BCG-IS.

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Acknowledgments

We wish to thank the Immunology and HSCT Units staff and other hospital staff “Podari Zhizn” charitable fund for the continued support of patient’s care.

Author information

Authors and Affiliations

  1. Department of Immunology, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, 1, Samory Mashela str., Moscow, Russia, 117997

    Alexandra Laberko, Daria Yukhacheva, Yulia Rodina & Anna Shcherbina

  2. Department of Pathology, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, 1, Samory Mashela str., Moscow, Russia, 117997

    Dmitriy Abramov & Dmitriy Konovalov

  3. Department of Hematopoietic Stem Cell Transplantation, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, 1, Samory Mashela str., Moscow, Russia, 117997

    Svetlana Radygina, Larisa Shelikhova, Michael Maschan, Alexei Maschan & Dmitry Balashov

  4. Laboratory of Hematopoietic Stem Cell Transplantation and Immunotherapy, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, 1, Samory Mashela str., Moscow, Russia, 117997

    Dmitry Pershin

  5. Phtisiology Consultant, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Olga Kadnikova

Authors
  1. Alexandra Laberko
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  2. Daria Yukhacheva
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  3. Yulia Rodina
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  6. Svetlana Radygina
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  7. Larisa Shelikhova
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  9. Olga Kadnikova
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  10. Michael Maschan
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  11. Alexei Maschan
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  12. Dmitry Balashov
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Contributions

AL collected and interpreted the data and prepared the manuscript. DY, YR, SR, and LS contributed to patients’ care and data collection. DA performed histological examinations. OK assisted with BCG infection treatment. DP coordinated and performed flow cytometry for immune recovery analysis. MM, AM, and DB led the HSCT program and edited the manuscript. AS led SCID patients’ care and designed and coordinated the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Alexandra Laberko.

Ethics declarations

Patients or their legal guardians signed informed consent forms to participate. The protocol and the current study were approved by the institutional ethics committee.

Conflict of Interest

MM received lecturer’s fee from Miltenyi Biotec. The remaining authors declare no conflict of interest.

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Laberko, A., Yukhacheva, D., Rodina, Y. et al. BCG-Related Inflammatory Syndromes in Severe Combined Immunodeficiency After TCRαβ+/CD19+ Depleted HSCT. J Clin Immunol 40, 625–636 (2020). https://doi.org/10.1007/s10875-020-00774-x

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  • DOI: https://doi.org/10.1007/s10875-020-00774-x

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