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Rubella Virus-Associated Cutaneous Granulomatous Disease: a Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders

  • David Buchbinder
  • Fabian Hauck
  • Michael H. Albert
  • Anita Rack
  • Shahrzad Bakhtiar
  • Anna Shcherbina
  • Elena Deripapa
  • Kathleen E. Sullivan
  • Ludmila Perelygina
  • Marc Eloit
  • Bénédicte Neven
  • Philippe Pérot
  • Despina Moshous
  • Félipe Suarez
  • Christine Bodemer
  • Francisco A. Bonilla
  • Louise E. Vaz
  • Alfons L. Krol
  • Christoph Klein
  • Mikko Seppanen
  • Diane J. Nugent
  • Jasjit Singh
  • Hans D. Ochs
Original Article

Abstract

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3–18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2–152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.

Keywords

DNA ligase 4 deficiency ataxia telangiectasia Nijmegen breakage syndrome Artemis deficiency combined immunodeficiency chronic rubella infection resulting in cutaneous granuloma formation 

Notes

Acknowledgements

We thank the patients and their families for participating in our research studies. We would also like to acknowledge the support of the U.S. Centers for Disease Control and Prevention in Atlanta, GA. Patient blood samples and biopsy material were obtained after provision of informed consent.

Authorship Contributions

All the authors helped draft and approved the submitted manuscript. HDO, DB, and FH coordinated the collection of the data and creation of the manuscript. All the authors diagnosed and treated the various immune disorders. HDO, DB, and FH reviewed the literature and illustrated the manuscript. LP provided laboratory support for the diagnosis of rubella virus and associated analyses. HDO, DB, and FH made possible this multi-institutional investigation.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, US Department of Health and Human Services.

Ethics Statements

1. CDC, VVPDB personnel were not involved in any clinical decisions regarding these patients. All decisions were made by physicians treating these cases. Patient blood samples and biopsy material were obtained by physicians after provision of informed consent. CDC’s direct role involving the patients was only laboratory testing of specimens.

2. Archived FFPE specimens from patients with granuloma were tested with non-disclosure of patient information, which was determined to be ethically acceptable by the Internal Review Board at the CDC. This work was determined to be non-applicable for human subject regulations (ID number 2014 6417).

3. In addition, RV RT-PCR detection and sequencing analysis in the biopsy material for possible rubella virus in these tissue specimens was done for the purpose of possible public health response as a part of ongoing CDC surveillance for rubella virus. Note that rubella virus-positive granulomas have been shown to shed divergent infectious rubella virus, which is the public health concern. In addition, CDC, VVPDB, rubella team personnel have international public health responsibilities as part of the CDC Global Specialized Laboratory in the WHO Measles and Rubella Laboratory Network.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • David Buchbinder
    • 1
    • 2
  • Fabian Hauck
    • 3
  • Michael H. Albert
    • 3
  • Anita Rack
    • 3
  • Shahrzad Bakhtiar
    • 4
  • Anna Shcherbina
    • 5
  • Elena Deripapa
    • 5
  • Kathleen E. Sullivan
    • 6
  • Ludmila Perelygina
    • 7
  • Marc Eloit
    • 8
  • Bénédicte Neven
    • 9
    • 10
  • Philippe Pérot
    • 8
    • 11
  • Despina Moshous
    • 9
    • 10
  • Félipe Suarez
    • 12
  • Christine Bodemer
    • 13
  • Francisco A. Bonilla
    • 14
  • Louise E. Vaz
    • 15
  • Alfons L. Krol
    • 16
  • Christoph Klein
    • 3
  • Mikko Seppanen
    • 17
  • Diane J. Nugent
    • 1
    • 2
  • Jasjit Singh
    • 2
    • 18
  • Hans D. Ochs
    • 19
  1. 1.Department of Pediatric HematologyChildren’s Hospital of Orange CountyOrangeUSA
  2. 2.Department of PediatricsUniversity of California at IrvineOrangeUSA
  3. 3.Department of Pediatrics, Dr. von Hauner Children’s Hospital, University HospitalLMUMunichGermany
  4. 4.Division for Pediatric Stem Cell Transplantation and ImmunologyUniversity Hospital FrankfurtFrankfurt/MainGermany
  5. 5.Department of ImmunologyDmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and ImmunologyMoscowRussia
  6. 6.Division of Allergy ImmunologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  7. 7.Division of Viral DiseasesCenters for Disease Control and PreventionAtlantaUSA
  8. 8.Biology of Infection Unit, Pathogen Discovery LaboratoryInstitut PasteurParisFrance
  9. 9.Unité d’Immunologie-Hématologie et Rhumatologie PédiatriquesHôpital Necker-Enfants-Malades, AP-HPParisFrance
  10. 10.INSERM U116 and Institut ImagineUniversité Paris-DescartesParisFrance
  11. 11.Centre d’innovation et de Recherche Technologique (Citech)Institut PasteurParisFrance
  12. 12.Unité d’hématologie adulte, Hopital Necker-Enfants-Malades, AP-HP, INSERM U116 & Institut ImagineUniversité Paris-DescartesParisFrance
  13. 13.Service de dermatologie pédiatrique, Hopital Necker-Enfants-Malades, AP-HP, INSERM U116 & Institut ImagineUniversité Paris-DescartesParisFrance
  14. 14.Boston Children’s HospitalBostonUSA
  15. 15.Department of Infectious Disease, Doernbecher Children’s HospitalOregon Health Sciences UniversityPortlandUSA
  16. 16.Department of Dermatology, Doernbecher Children’s HospitalOregon Health Sciences UniversityPortlandUSA
  17. 17.Rare Disease Center, Children’s HospitalHelsinki University Central HospitalHelsinkiFinland
  18. 18.Department of Infectious DiseaseChildren’s Hospital of Orange CountyOrangeUSA
  19. 19.Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Department of PediatricsUniversity of WashingtonSeattleUSA

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