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

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.

Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies

“…The estimated granuloma prevalence in PID patients is 1–4% and thus ~4,000 individuals in the US are expected to be affected [15]. RV antigen and RNA have been recently found in association with granulomas at various body sites (skin, liver, kidney, spleen, lung and bone periosteum) in children with a broad spectrum of PIDs [16–19]. RV positive cutaneous granulomas have been reported to develop 2–152 weeks (average 48 weeks) after MMR vaccination typically near the vaccination site, but can also appear at other body sites, e.g., face or legs, and then slowly spread [19].…”

The Safety and Efficacy of Live Viral Vaccines in Patients With Cartilage-Hair Hypoplasia

“…Although there were no reported long-term consequences of live vaccines in our cohort, clinicians and patients should be aware of the risk of delayed development of vaccine-strain rubella virus-associated skin granulomas in patients with CHH (27). In addition, there were no reactivation of vaccine-strain VZV in our patients, possibly reflecting the effective cellular immunity against VZV.…”

Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency

“…The majority of RAG deficient patients with vasculitis were positive for anti-cytokine antibodies, which were demonstrated to aggravate immune dysregulation, hyperinflammation with increased type-1 interferon signature and increased susceptibility to prolonged viral infection (29). As an example, for hyperinflammation in the setting of infections, it has been described for vaccine-derived rubella in cutaneous granuloma formation in RAG deficient patients (38). While we tried to correlate the development of vasculitis with potential infectious trigger, further research needs to be done to identify a causative trigger.…”