Rubella Virus-Associated Cutaneous Granulomatous Disease: a Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders
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.
KeywordsDNA ligase 4 deficiency ataxia telangiectasia Nijmegen breakage syndrome Artemis deficiency combined immunodeficiency chronic rubella infection resulting in cutaneous granuloma formation
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.
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.
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.
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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