Case report: Persistent shedding of a live vaccine-derived rubella virus in a young man with severe combined immunodeficiency and cutaneous granuloma

Abstract

A young man with X-linked severe combined immunodeficiency developed a persistent vaccine-derived rubella virus (VDRV) infection, with the emergence of cutaneous granulomas more than fifteen years after receipt of two doses of measles-mumps-rubella (MMR) vaccine. Following nasopharyngeal swab (NP) collection, VDRV was detected by real-time polymerase chain reaction (RT-qPCR) and sequencing, and live, replication-competent VDRV was isolated in cell culture. To assess duration and intensity of viral shedding, sequential respiratory samples, one cerebrospinal fluid sample, and two urine samples were collected over 15 months, and VDRV RNA was detected in all samples by RT-qPCR. Live VDRV was cultured from nine of the eleven respiratory specimens and from one urine specimen. To our knowledge, this was the first reported instance of VDRV cultured from respiratory specimens or from urine. To assess potential transmission to close contacts, NP specimens and sera were collected from all household contacts, all of whom were immunocompetent and previously vaccinated with MMR. VDRV RNA was not detected in any NP swabs from the contacts, nor did serologic investigations suggest VDRV transmission to any contacts. This report highlights the need to understand the prevalence and duration of VDRV shedding in granuloma patients and to estimate the risk of VDRV transmission to immune and non-immune contacts.

Keywords: gene therapy; inborn errors of immunity; live virus shedding; skin granuloma; vaccine-derived rubella virus; viral persistence.

Figure 1

Clinical photographs. During dermatology consult, the patient reported that the diffuse hyperpigmented macular appearing lesions had erupted in January 2020 (A), and additional, smaller lesions appeared on the torso by June 2020 (B).

Figure 2

Low power [2.5x objective, (A)] and high power [10x objective, (B)] histologic examination of diffused skin granulomas (hematoxylin-eosin staining). Immunofluorescence staining of the granulomas with RuV anti-capsid antibody (red) in M2-macrophages (green) (C, D). Blue nuclei were the result of counterstaining with 4’,6-diamidino-2-phenylindole (DAPI).

Figure 3

A timeline of viral shedding and treatments. Changes in VDRV RNA load in sequential patient’s samples were determined by RuV RT-qPCR. Samples positive by cell culture were indicated by the red color. Treatments are indicated by the green bars. The anti–VZV treatments included IV acyclovir 750 mg every 8 hours for 10 days followed by oral valacyclovir 1 g every 8 hours for 10 days, then oral acyclovir 800 mg twice daily after this as prophylaxis. Steroid treatments included IV hydrocortisone for 5 days (the first dose 75 mg, and then 50 mg doses), and one dose of IV methylprednisolone 80 mg given with IVIG. Treatments with colony stimulating factor were indicated by the black arrows.

Figure 4

RuV-associated granuloma in bone marrow. Double immunofluorescent IHC staining of sequential tissue sections of bone marrow core biopsy for rubella capsid (RVC, red) and one of the cell type markers (green), CD206 (M2 macrophages), MPO (neutrophils), or CD3 (T cells) shows predominant rubella staining of neutrophils and less frequent rubella staining of M2 macrophages. Numerous RVC^-CD3⁺ T cells were located inside the granuloma outlined with the yellow dashed line. Scale bar: 200 µm.