At least 300,000 people have been diagnosed with primary immunodeficiencies, or inborn errors of immunity, in the United States in 2018 (1). Among children with inborn errors of immunity, emergence of granulomas has been associated with rubella virus (RuV) (2, 3). Although vaccination against rubella is contraindicated for those with inborn errors of immunity, delays in immunodeficiency diagnosis can result in MMR vaccine being administered to these children. Additionally, the prevalence, persistence, and transmissibility of vaccine-derived rubella virus (VDRV) infection have yet to be fully elucidated. In this report, we describe a patient with late-diagnosis X-linked severe combined immunodeficiency (SCID-X1) and VDRV-associated granulomas and an assessment of VDRV shedding and potential transmission to the patient’s close contacts.

A 20-years-old man presented with a new rash to his primary care provider in June 2020. He had been previously diagnosed with SCID-X1 due to hypomorphic interleukin-2 receptor subunit gamma-chain (IL2RG) mutation in 2017, approximately 3 years prior to the onset of his rash. His immunologic evaluation was undertaken due to a history of severe eczema and frequent infections as well as a family history of immunodeficiency. Immunologic work-up was initially notable for hypogammaglobulinemia and he was placed on standard monthly intravenous immunoglobulin (IVIG) infusions. Genetic testing then returned positive for the c.460C>T (p.P154S) mutation in the IL2RG gene. At the time of presentation, the patient reported a six-month history of hyperpigmented, violaceous macules and plaques involving the extremities and torso but sparing the palms, soles, and mucous membranes ( Figure 1 ). His skin lesions began on both feet and spread to the legs, torso, arms, and face over the course of a few months. At the time of initial evaluation, Tinea corporis was confirmed by potassium hydroxide preparation of a skin scraping, and flesh-colored papules with central umbilication clinically resembling those of molluscum contagiosum were also noted. Review of systems was negative for fevers, chills, arthralgias, respiratory, gastrointestinal, or genitourinary symptoms. Laboratory tests obtained eight months after appearance of the skin lesions were notable for a normal serum immunoglobulin G of 798 mg/dL and low CD4⁺ and CD8⁺ T-cell counts at 199 and <45 cells/µL, respectively. Very unusual for a SCID-X1 patient, he had above upper normal range numbers of CD3/CD16⁺56⁺ natural killer cells (1909 cells/µL, normal range 126-729 cells/µL). Prior to SCID-X1 diagnosis, he received routine childhood immunizations, including two doses of MMR vaccine at 1 and 4 years of age and a varicella vaccine. The patient reported two previous episodes of herpes zoster, persistent molluscum contagiosum, bacterial skin and soft-tissue infections, Tinea corporis, onychomycosis, and several episodes of viral and bacterial pneumonia. Prior to the onset of the skin lesions, he had no known exposure to tuberculosis or animal exposures. At the time of presentation, he was enrolled as a university student and lived with two roommates. During university breaks, he lived with his parents and a younger sibling, hereinafter referred to as close contacts.

The patient underwent biopsy of a violaceous macular lesion on his left flank. Dermatopathology revealed superficial and deep dermal infiltrates, predominantly histocytes, aggregating into poorly formed granulomas centered around vessels and adnexal structures. The Gram, Periodic Acid-Schiff, fluorescent rhodamine acid-fast, Fite, and Grocott methenamine silver stains were negative, as were fungal and mycobacterial cultures. Double fluorescent immunohistochemical (IHC) staining of formalin-fixed paraffin-embedded (FFPE) tissue sections of the skin biopsy with mouse monoclonal antibody against RuV capsid and rabbit polyclonal antibody against CD206 (3, 4) revealed the presence of RuV in M2 macrophages in the cores of granulomas located in the upper ( Figures 2A, C ) and deep dermis ( Figures 2B, D ). No staining for RuV capsid was detected in a few myeloperoxidase (MPO)-positive neutrophils near the granulomas (not shown). IHC staining for measles virus and varicella zoster virus (VZV) antigens were negative (not shown).

To our knowledge, this is the first reported detection of shedding of live, replication-competent VDRV into respiratory secretions or urine. Previously, shedding of VDRV RNA into NP secretions has been reported, but no live virus has been recovered in cell culture (7, 11, 12). Granulomatous skin lesions were the only sites from which live VDRVs were isolated previously (7, 12). Moreover, this is the first reported case of continuous shedding of live VDRV for at least 15 months. The patient’s virus is highly divergent from the vaccine virus and replicates more efficiently than the VDRV strains recovered from skin lesions (7), but its teratogenic potential is not possible to estimate at present, given the lack of a suitable animal model for teratogenesis caused by rubella virus.

RuV capsid antigen has been detected in this case and previously in M2 macrophages in multiple rubella-associated M-type granulomas in dermis and hypodermis, and in bone marrow neutrophils and granulomas (3, 4, 13). However, the structure and composition of bone marrow granuloma in this case were different from the previously described granuloma in bone marrow of patient P4 (4). The granulomas in P4 case were poorly formed and consisted mainly of rubella positive macrophages, while the well-formed M-type granulomas in this case contained abundant T cells intermixed with predominantly rubella-negative CD206⁺ macrophages. The presence of T cells in the areas cleared from rubella antigen suggests the restoration of T-cell effector functions after the gene therapy that resulted in regression of the skin lesions. Although skin lesions have been almost resolved after gene therapy treatment, shedding of the live virus continued and pancytopenia persisted. The likely source of the persistently shed virus is VDRV-infected neutrophils still present in the bone marrow 15 months after gene therapy treatment. Pancytopenia may be a result of ongoing inflammation in the bone marrow as VDRV infection and pro-inflammatory cytokines produced by activated M2 macrophages and T cells can interfere with hematopoiesis (14). In addition, the absence of neutrophils in the skin lesions, persistent cytopenia, and the abundance of rubella-positive neutrophils in the bone marrow, taken together, suggest that RuV infection may interfere with maturation and subsequent egress of the infected neutrophils from the bone marrow. This patient also raises some very interesting scientific questions about the role of natural killer cells and neutrophils in rubella- associated chronic inflammation and other aspects of RuV associated granulomatous disease. Since this patient (and other similar patients) are usually undergoing various treatments for the disease, many of these questions need to await accumulation of information to justify more detailed clinical studies.

IgG antibody in the patient’s serum most likely originated from IVIG infusions; thus, his IgG titer was consistent with that of immunocompetent vaccinees as well. High neutralization titer against RA27/3 is a characteristic feature of patients with VDRV persistence (7), including immunocompetent adults (10). Given that the case patient had been vaccinated with MMR more than fifteen years before the granulomas appeared and prior to SCID-X1 diagnosis, it is likely that the case had persistent subclinical VDRV infection, and that the viable VDRV had emerged concurrent to the appearance of VDRV-affected lesions. Encouragingly, despite prolonged close contact with family members, there was no indication of transmission to them, as might be evidenced by the presence of VDRV in NP secretions or elevated RuV antibody titers. It should be noted, however, that the patient did not live at home during the period of documented VDRV shedding and stayed with family only intermittently during short visits and university breaks and that his household contacts were immunocompetent and vaccinated. Unfortunately, it is not possible to determine the onset or duration of VDRV shedding in the patient prior to this study. Limited knowledge of the markers of subclinical rubella infection and rubella re-infection and their unique expression and timing is another limitation of the study, which hampers investigations of VDRV transmission to vaccinated individuals.

This report highlights the strength of a multidisciplinary team approach to diagnosing and treating rubella-associated pathologies. This is a rare case, and only additional investigations can identify whether other immunocompromised individuals persistently shed live VDRV. Therefore, the frequency of live VDRV shedding and potential VDRV transmissibility to immune and especially non-immune individuals should be further investigated in prospective studies to determine the risk, if any, posed to the maintenance of the current rubella and congenital rubella syndrome elimination status in the United States. Though the absence of transmission to close, vaccinated contacts in the current setting is reassuring, we cannot rule out the possibility that VDRV might be transmitted from such a patient to unvaccinated pregnant people, their fetuses, and infants 6–12 months of age, after waning of maternally acquired antibody but prior to receipt of MMR, as reported elsewhere (15). Although exposures are likely rare, the development of a public health strategy for VDRV should be considered to mitigate VDRV transmission to those at elevated risk of infection.

Being diagnosed with a rare condition such as X-SCID can be scary and overwhelming, but it has also given me the opportunity to help the immunology community learn more about my condition. This has been a rewarding silver lining of my diagnosis because the valuable information that the CDC and the NIH are gathering from my case could help to streamline treatments for future patients. This knowledge has helped me to deal with the extra testing and procedures involved with being a participant in these studies, as it is a small sacrifice if it can help improve future treatments for X-SCID.

The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to Danish legislations.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

LP, KB, PC, RL, MS, TL, and ES contributed to conception and design of the study. ES, JL, MS, ED, CL, RL, SD contributed patient’s clinical data. LP, RF, MC, and LH contributed to analysis of patient’s samples and data interpretation. Drafting of the manuscript: KB, RL, LP, and PC. Critical revision of the manuscript: all authors. All authors contributed to the article and approved the submitted version.