Rubella virus-associated chronic inflammation in primary immunodeficiency diseases

Abstract

Purpose of the review: The aim of this article is to summarize recent data on rubella virus (RuV) vaccine in chronic inflammation focusing on granulomas in individuals with primary immunodeficiencies (PIDs).

Recent findings: The live attenuated RuV vaccine has been recently associated with cutaneous and visceral granulomas in children with various PIDs. RuV vaccine strain can persist for decades subclinically in currently unknown body site(s) before emerging in granulomas. Histologically, RuV is predominately localized in M2 macrophages in the granuloma centers. Multiple mutations accumulate during persistence resulting in emergence of immunodeficiency-related vaccine-derived rubella viruses (iVDRVs) with altered immunological, replication, and persistence properties. Viral RNA was detected in granuloma biopsies and nasopharyngeal secretions and infectious virus were isolated from the granuloma lesions. The risk of iVDRV transmissibility to contacts needs to be evaluated. Several broad-spectrum antiviral drugs have been tested recently but did not provide significant clinical improvement. Hematopoietic stem cell transplantation remains the only reliable option for curing chronic RuV-associated granulomas in PIDs.

Summary: Persistence of vaccine-derived RuVs appears to be a crucial factor in a significant proportion of granulomatous disease in PIDs. RuV testing of granulomas in PID individuals might help with case management.

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FIGURE 1

Cutaneous granulomas in PID patients. (a) Hematoxylin and eosin staining of a cutaneous granuloma from case 1. A well-formed granuloma is centrally located. (b, c) Cutaneous skin lesions from case 3. Acute and chronic ulcers are observed. (d–f) Distribution of infected cells in skin samples of PID patients. Histological immunofluorescent staining showing focal (d, case 1) or widespread (e, case 2) distribution of RuV capsid in granulomas and focal capsid localization in the epidermis (f, case 5). Activation status of macrophages in granulomas (g–i, case 6). Double immunofluorescent staining of granulomas with RuV capsid antibody (red) and M2 macrophage specific antibodies, CD206 (g, green) or CD163 (h, green). (i) RuV antigen expression in the suprabasal cell layer of skin epidermis (case 1). Double immunofluorescent staining with RuV capsid antibody (red) and keratinocyte specific antibody (cytokeratin, green). Nuclei were counterstained with DAPI, 4′,6-diamidino-2-phenylindole. Previously published in Ref. [8].

FIGURE 2

Phylogenetic tree of iVDRV. The genetic relationships between the consensus genome sequences from each original granuloma sample and the whole genomes of the WHO reference viruses were inferred using the maximum likelihood method in molecular evolutionary genetics analysis 7. All taxa are labeled with WHO names with iVDRV sequences marked with red dots. The genetic distances were computed using the maximum composite likelihood method. The scale bar indicates the number of base substitutions per site. RA27/3 and iVDRVs represent a separate branch on the tree with RA27/3 being basal. Previously published in Ref. [15^▪].