Cutaneous granulomas associated with rubella virus: A clinical review

Abstract

Since the initial identification of vaccine-derived rubella virus (RuV) in the cutaneous granulomas of pediatric patients with inborn errors of immunity in 2014, more than 80 cases of RuV granulomas have been reported implicating both vaccine-derived and wild type RuV. Previously thought to arise exclusively in patients with significant immunocompromise, the identification of RuV granulomas in clinically immunocompetent patients adds nuance to our understanding of the interplay between host environment, immune dysregulation, and RuV granuloma formation.

This review summarizes the literature on RuV granulomas including clinical and histopathologic features, proposed pathomechanisms supporting granuloma development, and potential therapeutic options. There is no standardized algorithm to guide the workup and diagnosis of suspected RuV granulomas. We highlight the importance of contributing RuV granuloma cases to ongoing Centers for Disease Control and Prevention surveillance efforts to monitor wild type and vaccine-derived RuV transmission. Studies advancing our understanding of RuV granulomas may provide insights into the role of viral infectious agents in granulomatous disease pathogenesis and guide the development of improved therapeutic options.

BACKGROUND

Granulomas represent an inflammatory response characterized by aggregates of macrophages and other immune cells. Granulomatous disorders can be conceptually divided into infectious and noninfectious etiologies. In practice, there can be overlap in the clinical and histopathologic findings across granuloma subtypes. Recent advancements in molecular analytic technology have improved the identification of potential underlying infectious triggers of granulomatous dermatoses.^1,2

Rubella virus (RuV) is an enveloped, positive-sense RNA virus primarily transmitted through contact with respiratory secretions. Nearly 50% of rubella infections are asymptomatic.³ Symptomatic infection may begin with 1 to 5 days of prodromal symptoms such as low-grade fever, headache, malaise, coryza, lymphadenopathy, and conjunctivitis; and lead to a mild, maculopapular exanthem that spreads in a cephalocaudal pattern.⁴ Arthralgias or arthritis may also occur.⁵ Maternal infection with RuV during gestation can lead to vertical transmission to the fetus, with potentially devastating consequences such as miscarriage, stillbirth, or congenital rubella syndrome.^4,6–8 Widespread vaccination with the live attenuated rubella vaccine has drastically reduced rubella and congenital rubella syndrome cases worldwide, with elimination declared in the United States in 2004 and in the Americas in 2015.^4,9

In 2014, persistence of vaccine-derived RuV (Wistar RA 27/3 strain) was first identified in skin biopsies of granulomas using next-generation sequencing in pediatric patients with inborn errors of immunity (IEI).¹⁰ Sequencing of 2 patients’ biopsy samples revealed vaccine-derived RuV while no other viral read was found.¹⁰ Cases of vaccine-derived and wild type RuV have since been reported in granulomatous lesions of clinically immunocompromised and immunocompetent adult patients.^11,12 We use the term ‘RuV granulomas’ to describe lesions in which RuV has been identified via reverse-transcription polymerase chain reaction (RT-PCR) or immunohistochemical (IHC) staining within granulomas. We summarize the existing literature on RuV granulomas including clinical and histopathologic features, proposed pathomechanisms supporting granuloma development, and potential therapeutic options.^10–23

INCIDENCE AND EPIDEMIOLOGY

The incidence and prevalence of RuV granulomas are unknown due to its recent recognition. Since the initial discovery of the live attenuated RuV component of the measles, mumps, rubella (MMR) vaccine within the cutaneous granulomas of pediatric patients with IEI,¹⁰ nearly 60% of idiopathic cutaneous granulomas in patients with IEI have been associated with RuV.^23–27 In patients with IEI, the prevalence of idiopathic granulomas has been recently estimated to be 1% to 4%.²⁶ Therefore, the estimated prevalence of RuV granulomas in patients with IEI is 0.6% to 2.4%. The majority of patients with RuV granulomas exhibited an underlying immunodeficiency.^{10,11,15,16,20,21,24,26} The development of extensive idiopathic cutaneous granulomas is associated with IEI syndromes in children and adults, with cutaneous granulomas being the presenting symptom of IEI in 30% of 50 collated cases.²⁴ Most patients with RuV granulomas exhibit significant T-cell deficiency or dysfunction.^18,28 The spectrum of IEI in patients with RuV granulomas includes but is not limited to ataxia telangiectasia, Nijmegen breakage syndrome, common variable immunodeficiency, activated phosphoinositide 3-kinase syndrome, and DiGeorge syndrome (Supplementary Table 1, available via Mendeley at https://data.mendeley.com/datasets/jdxs9w75kf).^{11,14–16,18,22,28} Ataxia telangiectasia was the most common IEI diagnosis among pediatric patients. Buchbinder et al suggests that adequate RuV-specific T-cell responses may be vital to controlling RuV and preventing RuV granulomas development; another study hypothesizes that mutations in RuV epitopes recognized by virus-specific cytotoxic CD8⁺ T-cells allow for the persistence of attenuated RuV in tissues.^20,24 This hypothesis is supported by the abundance of T-cell abnormalities seen amongst patients with RuV granulomas and, conversely, the prevalence of RuV granulomas in patients with primary T-cell deficiencies.^16,20,24 Deficits in antibody number or function have also been identified in patients with RuV granulomas.^22,29 Suspicion for RuV granulomas should be greatly increased among patients with IEI with idiopathic cutaneous granulomas.

The ability of RuV to persist within the host and lead to granulomatous lesions is not limited to vaccine-derived RuV. In 2021, Shields et al described wild type RuV in the granulomatous lesions of an adult with common variable immunodeficiency.¹¹ The patient presented with extensive violaceous plaques and crusted hyperkeratotic nodules that clinically mimicked cutaneous sarcoidosis and histopathologically mimicked CD8⁺ cutaneous T-cell lymphoma.¹¹ RuV RNA was detected in affected skin biopsies and nasopharyngeal swabs by RT-PCR, with the full viral genome sequenced from the patient’s skin biopsies. Isolation of RuV in cell culture from the patient’s skin and nasopharyngeal samples was unsuccessful. IHC for RuV capsid protein detected rubella antigen in 4 distinct biopsies collected from different body sites.¹¹

In 2022, Wanat et al reported RuV granulomas in 4 clinically immunocompetent adults previously diagnosed with idiopathic cutaneous granulomas.¹² All patients were without history of recurrent or serious systemic infections. RuV granulomas were diagnosed via RT-PCR in affected tissues. Live wild type RuV was recovered via cell culture from the skin biopsy of 1 patient. This was the first reported case of live wild type RuV cultured from cutaneous granulomas in a clinically immunocompetent adult. Disease onset occurred in the 5th decade of life or later in all patients. Laboratory workup demonstrated isolated immunologic abnormalities of unknown clinical significance including low CD8⁺ T-cell counts, low T-cell mitogen responses, and/or low immunoglobulin (IgG, IgA, IgM) levels. Disease onset in late adulthood suggests that immunosenescence or acquired immune dysfunction may contribute to the multifactorial pathogenesis of RuV granulomas.¹² The hypothesized potential role of acquired immune dysfunction in RuV granuloma development is supported by a reported case of RuV granulomas developing in a pediatric patient (without diagnosed IEI) with acquired lymphopenia presumed to be secondary to severe malnutrition.²²

CLINICAL PRESENTATION AND DIAGNOSIS

There is no standard algorithm to guide the diagnosis and evaluation of idiopathic granulomas, including RuV granulomas. The unpredictable time course between exposure and cutaneous disease onset creates a diagnostic challenge. Cutaneous granulomas may develop from 3 weeks to decades following presumed exposure to wild type or vaccine-derived RuV.^18,20,27,28 Buchbinder et al found the period between MMR vaccination to cutaneous granuloma onset was shorter in patients with DNA repair disorders (median 48 months, range 2–152 months) compared to patients with other IEI (median 102 months, range 13–135 months) amongst 21 patients with RuV granulomas.²⁰ The median time from vaccine exposure to RuV granuloma onset was 19 months (range 3 weeks-216 months) for 66 collated cases (Supplementary Table 1).

Primary lesions may present as pink erythematous to violaceous papules and plaques that may be asymptomatic, pruritic, or tender (Table I). Lesions commonly appear at the extremity site of prior MMR vaccination and/or other extremities.^{12,16,17,30,34} In immunodeficient patients, RuV granulomas frequently progress to involve multiple sites and form confluent, locally destructive plaques. Involvement of the face, buttocks, back, and trunk has been reported. Lesions involving mucosal surfaces and genitals have not been described.^{10,14,15,21,27} Extracutaneous RuV granulomas have been identified in the liver, gastrointestinal tract, brain, spleen, lung, pancreas, lymph nodes, and bone marrow (Supplementary Table 1).^16,22

Table I.

Clinical characteristics of cutaneous rubella virus granulomas

Case*	Country	Onset age	Sex	RuV type	Immunodeficiency	Morphology	Anatomic sites
113	UK	11 y	M	WT	AT	Purple, ill-defined lesion with subsequent ulceration	Right leg
214	US	6y	M	Vaccine	CVID	Large, red, telangiectatic, sclerotic, stellate plaques with scattered hemorrhagic crusts, scale, and erosions	Face, extremities
315,29	US	10 y	M	Vaccine	NBS	Erythematous papules coalescing into plaques
415	US	1y	F	Vaccine	None†	Red papules, erythematous to violaceous papulonodules progressing to erythematous to violaceous, confluent, plaques with scale and scarring	Extremities
510	France	18 mo	F	Vaccine	AT	Nodules	Face, extremities, buttocks, trunk
610	France	11 y	M	Vaccine	APDS	Erythematous, infiltrated plaque	Face, extremities, buttocks, trunk
710	France	33 mo	F	Vaccine	AT	Erythematous, annular papules with hyperkeratotic atrophic centers and well-limited infiltrated borders	Extremities, buttocks
812	US	45 y	F	Vaccine	None	Papules coalescing into plaque	Left arm
912	US	45 y	F	Vaccine	None	Papules progressing to pink to violaceous plaque	Left arm
1012	US	55 y	F	Vaccine	None	Papules and nodules coalescing into plaque with focal pustules	Left arm
1112	US	56 y	M	WT	None	Papules and nodules coalescing into indurated plaques with pustules	Left arm
1211	US	60 y	M	WT	CVID	Diffuse violaceous plaques and nodules, hyperkeratotic nodules with crust	Surgical scars, back, hands
1416	France	30 mo	M	Vaccine	CID	Purplish, confluent, subcutaneous nodules with ulceration	Right arm, right leg
1917,30	Canada	2 y	M	Vaccine	AT	Erythematous nodule with a slightly rolled, firm border, and central crusting	Right arm, left leg
4421	Germany	7.5 y	M		Artemis deficiency	Progressive and disfiguring destruction	Right nostril
4521,22	Germany	3y	F	Vaccine	AT	progressive granulomatous lesion	Left arm
4623	Japan	13 mo	F	Vaccine	LIG4S	Erythematous papules, erythematous maculopapular flat-topped symmetric eruption	Entire body
4728	Germany	22 mo			GS2	Papulopustular, granulomatous exanthema	Face, extremities
4828,31	Lithuania	17 mo			GS2	Macules evolving into papules	Face, extremities
4928,32	France	36 mo			GS2	Inflammatory papules, some ulcerating	Face, extremities, buttocks
5028	Germany	22 mo		Vaccine	GS2	Pustules and hyperkeratotic papules	Extremities
5128	Lithuania	92 mo			GS2	Extensive skin lesions	Trunk, buttocks
5228	Germany	13 mo			GS2	Erythematous papules
5328	Germany				GS2	Red papules	Legs
5528	France	28–40 mo		Vaccine	FHL2	Erythematous, hyperkeratotic papules	Face, arms
5628	Germany	24 mo			FHL3	Small granuloma, enlarging over time	Right thigh
5728	Australia	16 mo			FHL3	Purplish papules with overlying scale	Face, extremities
5828	Australia	30 mo			FHL3	Small maculopapular lesions	Extremities
8222	US	1.25 y			CID	Firm brown-red papules	Extremities
8933	US	20 y	M	Vaccine	SCID	Hyperpigmented, violaceous macules and plaques	Extremities, torso, face

APDS, Activated phosphoinositide 3-kinase syndrome; AT, ataxia telangiectasia; CID, combined immunodeficiency; CVID, common variable immunodeficiency; F, female; FHL2, familial hemophagocytic lymphohistiocytosis type 2, FHL3, familial hemophagocytic lymphohistiocytosis type 3; GS2, Griscelli syndrome type 2; LIG4S, DNA ligase 4 deficiency; M, male; NOD2, nucleotide-binding oligomerization domain-containing protein 2; NBS, Nijmegen breakage syndrome; RuV, rubella virus; SCID, severe combinded immunodeficiency; WT, wildtype; y, years.

^*Cases numbered according to Supplementary Table 1.

^†NOD2 mutation found.

Many RuV granulomas were previously diagnosed as chronic ‘idiopathic’ granulomatous lesions (often concerning for infection), cutaneous sarcoidosis, or CD8⁺ granulomatous cutaneous T-cell lymphoma.^11,12 The presence of chronic granulomas refractory to treatment and without easily identifiable infectious cause should raise suspicion for a RuV driver. Meticulous history and evaluation are warranted to rule out other infectious and noninfectious etiologies of granulomas. Attention should be paid to immune status, vaccination status, travel and potential exposures, and past infections.

Currently, diagnosis of RuV granulomas requires molecular testing of skin biopsy. In the United States, only the Centers for Disease Control and Prevention (CDC) performs RT-PCR for RuV and/or IHC for RuV capsid antigen for the detection of RuV in granulomas. These tests are not routinely available in dermatology practice settings, presenting a barrier to diagnosis. The CDC provides support for serologic and molecular testing for RuV infection as part of the reference and surveillance responsibility of the CDC Rubella Laboratory.³⁵ Presumed RuV granuloma specimens can be sent for RT-PCR of lesional tissue, while concurrent testing for rubella immunity (serologic) and RuV shedding (RT-PCR of nasopharyngeal and oropharyngeal swabs and urine) is recommended. Rubella capsid IHC, virus isolation, and viral sequencing are currently performed for research and surveillance for possible public health response given concern for potential viral transmission from RuV granuloma.

Discovery of RuV granuloma(s) in a clinically immunocompetent patient warrants thorough workup for any predisposing immune-related dysfunction. Laboratory workup should include comprehensive metabolic panel and complete blood count with differential. Humoral and cellular immunity should be evaluated by measuring serum immunoglobulin levels, flow cytometry of lymphocytes, and T-cell responses to mitogens.¹² Patients should be up to date on routine malignancy screenings.

HISTOPATHOLOGY AND SPATIAL ORGANIZATION

Histopathologic features of cutaneous RuV granulomas have been described in 42 patients (Supplementary Table 2, available via Mendeley at https://data.mendeley.com/datasets/jdxs9w75kf). Palisaded granulomas comprised of histiocytes, lymphocytes, and giant cells are most frequently described.^{10–21,23,30} The majority of reported RuV cutaneous granulomas exhibit well-formed epithelioid granulomas with necrotizing and nonnecrotizing features.²² Traditional stains and cultures for microbes (Gram stain, Periodic acid–Schiff, Ziehl-Neelsen, methenamine silver, mycobacterial and mycological cultures) should be performed to exclude other infectious causes.

RuV antigens and RuV infected cells are distributed in specific patterns within granulomas. Using fluorescent IHC staining of RuV granuloma biopsies, Perelygina et al classified RuV granulomas into 4 patterns of inflammation based upon the location of RuV within specific cell-types (macrophages, neutrophils), outlined in Table II.²² Cutaneous granulomas were classified as nonnecrotizing macrophage-predominant (M-type), necrotizing macrophage-predominant (M[n]-type), or necrotizing neutrophil-predominant (N-type) granulomas.²²

Table II.

Cell composition and spatial organization of rubella virus granulomas²²

Type	Summary	Description
M-type cutaneous granulomas	Nonnecrotizing, macrophage predominant granulomas	• Central core of interconnected RVC + CD206+ M2 macrophages of epithelioid morphology • RVC diffusely distributed in cytoplasm of macrophages • Periphery ofCD163+ M2 macrophages and CD14+ monocytes (some RVC+) • Few neutrophils (mostly RVC−) and CD3+ T cells (all RVC−) throughout granuloma
M(n)-type cutaneous granulomas	Necrotizing, macrophage predominant granulomas	• Central necrotic core surround by ring of RVC 1 CD206+ M2 macrophages of epithelioid morphology • Cell debris in necrotic centers stained strongly positive for MPO and CD3 and weakly positive for RVC and CD206* • Periphery ofCD163+ M2 macrophages and CD14+ monocytes (some RVC+)
N-type cutaneous granulomas	Necrotizing, neutrophil predominant granulomas	• Central core of tightly packed MPO+ and RVC 1 neutrophils and areas of necrosis • Clusters of CD206+ M2 macrophages (few RVC+) adjacent to granuloma cores • Abundant CD163+ M2 macrophages and T cells distributed around granuloma core
DNI-type noncutaneous granulomas	Diffuse neutrophil inflammation intermixed with macrophages and T cells	• Disorganized aggregates of abundant RVC 1 neutrophils intermixed with macrophages (some RVC+) and T cells (RVC−) • CD206+ RVC 1 macrophages of DNI-type granulomas were not interconnected and were rounded with shorter cell processes • RVC likely located in phagosomes of macrophages

DNI, Diffuse neutrophil inflammation; MPO, myeloperoxidase; MPO⁺, myeloperoxidase positive; RVC, rubella virus capsid antigen.

^*Suggests that neutrophils and T cells migrated into the granulomas to destroy rubella virus infected macrophages resulting in cellular necrosis.

PROPOSED PATHOMECHANISM OF VIRAL PERSISTENCE AND GRANULOMA FORMATION

The pathogenesis of RuV persistence and granuloma formation is unclear. Other RNA viruses establish persistence in immune privileged sites (eg, central nervous system, placenta, fetus) via low-level replication rather than latency.³⁶

Molecular and histopathologic examinations of RuV granulomas in a cohort of patients with IEI demonstrated RuV-positive cells were myeloperoxidase positive (neutrophil marker), CD14⁺ and CD68⁺ (monocyte/macrophage markers), CD206⁺ and CD163⁺ (M2 macrophage markers), and inducible nitric oxide synthase (iNOS) (M1 macrophage marker) negative.¹⁹ Other cell types (endothelial cells, T cells, B cells, dermal Langerhans, and dendritic cells) were negative for RuV antigen on IHC staining.^19,27 For 1 patient, the RuV immunostaining patterns remained unchanged across 3 skin biopsies over 7 years.¹⁹ These findings indicate that M2 macrophages and neutrophils were the main cell types harboring RuV and supporting RuV long-term persistence within the cutaneous and visceral granulomas. Perelygina et al hypothesized that immune deficiency allows RuV to persist while infection of M2 macrophages and neutrophils further compromises viral clearance.^37,38 The cell reservoir and maintenance mechanisms of asymptomatic RuV persistence prior to granuloma formation remain unknown.

Viral evolution is a known defense mechanism against eradication within infected organisms and populations.^39–42 Vaccine-derived RuVs have been found to persist in cutaneous granulomas of patients with IEI as genetically distinct quasispecies populations,^29,38 which are collections of closely related viral genomes in the setting of error-prone replication of RNA viruses and environmental selective pressure.³⁹ Discovery of distinct RuV lineages in separate anatomic locations (nasopharynx vs skin, left vs right arm²⁹) raises the possibility that RuV may persist and evolve independently at different body sites.^29,40 As high quasispecies complexity allows viruses to adapt quickly to selective pressures, distinct quasispecies in granulomas suggests contiguous viral evolution within a host may contribute to RuV persistence.^29,39 The degree of divergence of the genomic sequences of vaccine-derived RuV from the RA27/3 vaccine strain genome had a positive, linear correlation with the duration of persistence within the patient; this suggests intrahost viral evolution occurs on a continuous basis.²⁹

Mounting evidence suggests it is unlikely that RuV exists as a bystander in the development of granulomas. Dhossche et al proposes the idea of locus minoris resistentia in RuV granuloma pathogenesis, suggesting that specific host locations may be more vulnerable to RuV persistence and granuloma formation.¹⁵ Cases of RuV granulomas appearing at sites of prior MMR vaccination and one report of RuV granuloma affecting the site of a prior surgical scar suggest the possibility of implantation or subsequent koebnerization.^11,12

POTENTIAL THERAPEUTIC OPTIONS

RuV granulomas were often treatment resistant despite the variety of medical and procedural interventions attempted (Tables III and IV).^21,22 Resolution of RuV granulomas was infrequently described and often occurred with scarring and tissue destruction.^20,48 In pediatric cases, cutaneous RuV granulomas progressed unremittingly unless resolution of immunodeficiency was attained via hematopoietic stem cell transplantation (HSCT).^18,21 Patients achieved significant improvement in cutaneous granulomas upon initiation of conditioning prior to HSCT.²¹ Patients with Nijmegen breakage syndrome experienced clinically significant improvement of cutaneous RuV granulomas with intensive chemotherapy for lymphoma,¹⁸ suggesting depletion of RuV-infected immune cells (neutrophils, macrophages, etc.) may contribute to clinical response.²¹ While HSCT may be effective for the treatment of RuV granulomas among patients with IEI, its potential benefits must be carefully weighed against its significant mortality risk.⁴⁹ HSCT and intensive chemotherapy carry risks of immunosuppression, malignancy, and severe infection. Further research is required to elucidate therapeutic targets in RuV granulomas.

Table III.

Clinical features and diagnosis of rubella virus granulomas for the clinical dermatologist

	Description
Clinical appearance	• Affecting extremity site of prior MMR vaccination(s) • Pink erythematous to violaceous papules and plaques • Progressive, confluent, locally destructive plaques
Relevant history	• Chronic ‘idiopathic’ granulomatous lesions without easily identifiable infectious etiology • Known or likely vaccination with live attenuated RuV • Known immunodeficiency or IEI • Refractory to multiple treatment modalities
Histopathologic features	• Palisaded granulomas comprised of histiocytes, lymphocytes, and giant cells • Well-formed epithelioid granulomas with necrotizing and nonnecrotizing features • Negative stains and cultures for non-RuV microbes, including but not limited to:  ○ Gram stain  ○ Periodic acid—Schiff (PAS)  ○ Ziehl-Neelsen  ○ Methenamine silver O Mycobacterial and mycological cultures
Diagnosis	• Skin biopsy with RT-PCR for RuV • Recommended concurrent testing:  ○ Serologic test for rubella immunity  ○ RT-PCR of nasopharyngeal and oropharyngeal swabs and urine • Experimental:  ○ IHC for RuV capsid antigen  ○ RuV isolation and sequencing

IEI, Inborn errors of immunity; IHC, immunohistochemical; MMR, measles, mumps, rubella; RT-PCR, reverse-transcription polymerase chain reaction; RuV, rubella virus.

Table IV.

Therapeutic options for rubella virus granulomas

Treatment	Description	Treatment outcome
Interferons (IFNs)	Family of cytokines important in innate immunity following the recognition of virus	Minimal effect on RuV granulomas in vivo20 IFN has been shown to worsen cutaneous granulomatous dermatitis and sarcoidosis43,44
Ribavirin	Guanosine analog and direct antiviral that blocks viral replication	Efficacious against hepatitis C but limited efficacy against RuV when used alone and carries significant toxicity risk11,45 May be effective in improving RuV granuloma11
Nitazoxanide	Antimicrobial approved for the treatment of parasites, protozoa, and anaerobic bacteria and broad-spectrum antiviral. Carries a favorable adverse event profile.	Significant inhibition of RuV replication in cell cultures in vitro46 No appreciable clinical improvement of cutaneous lesions in patients treated with oral nitazoxanide38,46 Biopsies collected prior to and following nitazoxanide therapy were positive for RuV by RT-PCT and cell culture, confirming failure to clear the RuV infection38
Rapamycin	Mammalian target of rapamycin (mTOR) inhibitor.	Previously used in the treatment of immunodeficiency-related cutaneous granulomas with anecdotal evidence of granuloma improvement24 Concerns that mTOR inhibitors may facilitate specific viral infections, such as influenzae A47
Intravenous Immunoglobulin (IVIG)	Blood product composed of pooled antibodies typically administered to patients with antibody deficiencies	Formulation-dependent neutralizing activity against RuV and low-titer RuV antibody has been detected following injection of IVIG in patients without prior rubella antibody33 Not highly effective in elimination of persisting RuV in granulomas May help prevent viremia and extracellular spread in tissue48

RT-PCR, Reverse-transcription polymerase chain reaction; RuV, rubella virus.

REMAINING CHALLENGES

The variable time to onset, clinical presentation, and histopathological features of RuV granulomas present diagnostic challenges that may lead to misdiagnosis as cutaneous sarcoidosis, CD8⁺ granulomatous cutaneous T-cell lymphoma, and other cutaneous granulomatous diseases. Application of deep sequencing technologies may help clarify the pathomechanisms underlying formation of cutaneous granulomas. Increased awareness of RuV granulomas may improve diagnosis, advance our understanding of the disease course and prognosis, and provide potential therapeutic targets.

Though evidence continues to emerge underscoring the likely role of RuV driving granulomas, research to elucidate disease pathogenesis is needed. Previously thought to arise exclusively in the context of significant immunosuppression, its discovery in clinically immunocompetent patients adds nuance to our understanding of the interplay between host environment, immune dysregulation, and RuV granuloma formation. While live-attenuated vaccines are contraindicated in patients with IEI, the first dose of the MMR vaccine is often administered (12–15 months of age) prior to IEI diagnosis.⁵⁰ Although avoidance of the live attenuated MMR vaccine can eliminate vaccine-strain RuV exposure, patients with IEI are at increased risk of developing RuV infection and/or granulomas following exposure to nonattenuated, wild type RuV.¹⁰ Benefits of MMR vaccinations greatly outweigh the risk of vaccine-strain RuV granuloma development. Patients without known contraindications should be advised to follow the standard MMR vaccination schedule.^4,26 Given our inability to predict which patients will form granulomas, challenging questions remain regarding vaccination strategies among patients with IEI.

RuV RNA and/or antigen has rarely been isolated from nasopharyngeal swabs of patients with RuV granulomas, though no cases of transmission to susceptible individuals have been reported.^29,51 One reported case found continuous shedding of live, replication-competent vaccine-derived RuV in respiratory secretions and urine of a patient with RuV granulomas for 1.5 years; however, surveillance testing of close contacts did not show signs of RuV transmission.³³ As risk of RuV transmission from patients with RuV granulomas remains possible, patients found to shed replication-competent RuV should be counseled to avoid pregnant and/or immunocompromised contacts. It is important to contribute any cases of RuV granulomas to ongoing CDC surveillance efforts to monitor for wild type RuV transmission and the possibility of vaccine-derived RuV transmission.

The discovery of RuV granulomas complicates our understanding of the role of viruses in granuloma formation. Other case reports have implicated the role of herpes simplex, varicella zoster, hepatitis C, Epstein Barr, and human T-cell lymphoma virus-1 in cutaneous granulomatous conditions.^52–59 However, confirmation of viral antigens has only been consistently demonstrated within RuV granulomas.

CONCLUSION

This review provides our current understanding of RuV granulomas, including guidelines and resources for diagnosis and treatment. Despite elimination of RuV and congenital rubella syndrome in the United States and Americas, further research is needed to estimate the prevalence of persistent rubella infections, understand the role of persistent RuV in granuloma formation, and its continued impact on public health. Current studies on RuV granulomas include a multicenter retrospective cohort study examining idiopathic granulomas across the United States to determine the role of RuV in granuloma formation and monitoring for potential shedding of RuV. Continued collaborative efforts with the CDC are needed to improve care for patients impacted by RuV granulomas. Studies advancing our understanding of RuV granulomas may provide general insight into the role of viral infectious agents in the formation of granulomatous disease and guide the development of improved therapeutic options.

CAPSULE SUMMARY.

• Rubella virus granulomas should be suspected in patients with chronic cutaneous granulomas refractory to treatment and without easily identifiable infectious causes.

• Continued multidisciplinary collaborative efforts are needed to understand the prevalence, pathomechanisms, and consequences of rubella virus persistence and granuloma formation, including potential for rubella virus transmission.

Abbreviations used:

APDS

activated phosphoinositide 3-kinase syndrome

AT

ataxia telangiectasia

CDC

Centers for Disease Control and Prevention

CID

combined immunodeficiency

CVID

common variable immunodeficiency

FHL2

familial hemophagocytic lymphohistiocytosis type 2

FHL3

familial hemophagocytic lymphohistiocytosis type 3

GS2

Griscelli syndrome type 2

HSCT

hematopoietic stem cell transplantation

IEI

inborn errors of immunity

IFN

interferon

IgA

immunoglobulin A

IgM

immunoglobulin M

IgG

immunoglobulin G

IHC

immunohistochemical

IVIG

intravenous immunoglobulin

LIG4s

DNA ligase 4 deficiency

MMR

measles, mumps, rubella

MPO

myeloperoxidase

NBS

Nijmegen breakage syndrome

RT-PCR

reverse-transcription polymerase chain reaction

RuV

rubella virus

RVC

rubella virus capsid antigen

WT

wildtype