Outcomes for Nitazoxanide Treatment in a Case Series of Patients with Primary Immunodeficiencies and Rubella Virus-Associated Granuloma

Perelygina, Ludmila; Buchbinder, David; Dorsey, Morna J.; Éloit, Marc; Hauck, Fabian; Hautala, Timo; Moshous, Despina; Uriarte, Ignacio; Deripapa, Elena; Icenogle, Joseph P.; Sullivan, Kathleen E.

doi:10.1007/s10875-019-0589-0

Cited by 24 publications

(33 citation statements)

References 9 publications

(5 reference statements)

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“…The most common treatments were oral and topical steroids which were moderately effective in some patients in all case series. Consistent with other reports ( 18 , 37 ), a broad-spectrum antiviral drug nitazoxanide provided only mild improvement. There have been responses in this case series to TNF-α and IL-1R inhibitors, both are known suppressors of myeloid-driven inflammation, suggesting that they offer some ability to resolve lesions in patients with granulomatous inflammation dominated by chronic neutrophil infiltration.…”

Section: Discussionsupporting

confidence: 90%

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Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

et al. 2021

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Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

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Section: Discussionsupporting

confidence: 90%

“…This report is one of the few to describe therapeutic efforts to treat granulomas in IEI patients, which have not been standardized and were limited to small case series ( 18 , 21 , 23 , 37 ). Unfortunately, the lack of an animal model for RuV persistent infections is impeding thorough investigations of antiviral strategies.…”

Section: Discussionmentioning

confidence: 99%

Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

et al. 2021

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“…Detailed case descriptions have been published separately [69, 70]. Briefly, all four patients received MMR vaccination at about one year of age and one patient received the second dose at age 5 (the OR case).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10−3 subs/site/year and 8.9 x 10−4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.

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“…More recently, many of these granulomas have been found to contain vaccine-strain rubella antigen (11). Treatment generally consists of corticosteroids, tumor necrosis factor (TNF) inhibition, or nitazoxanide with responses reported in the literature variable at best (8, 9, 12).…”

Section: Introductionmentioning

confidence: 99%

Vasculitis in a Child With the Hyper-IgM Variant of Ataxia-Telangiectasia

et al. 2019

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A subset of patients with Ataxia-Telangiectasia (A-T) have dramatically reduced levels of IgG, IgA, and IgE with retained or elevated IgM levels. Several reports suggest that these A-T patients with a “hyper-IgM phenotype” (HIgM) suffer more clinical immunologic consequences than other A-T patients. The immunopathologic mechanism driving this phenomenon is unknown, making it difficult to predict response to immunomodulatory therapy. We describe an A-T patient with HIgM who underwent tumor necrosis factor (TNF) receptor blockade for cutaneous granuloma and after several months of successful therapy developed non-malignant lymphoproliferation, cytopenia, and increased serum immunoglobulin levels. This process was subsequently followed by an immune-complex-mediated intrarenal small vessel vasculitis that led to renal failure. The vasculitis was successfully treated with rituximab and corticosteroids. This case underscores the importance of HIgM as an unfavorable prognostic indicator in A-T and highlights the complexity of immunomodulatory treatment in this population, and the potential for a successful approach tailored to the immune defect.

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Outcomes for Nitazoxanide Treatment in a Case Series of Patients with Primary Immunodeficiencies and Rubella Virus-Associated Granuloma

Cited by 24 publications

References 9 publications

Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

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

Vasculitis in a Child With the Hyper-IgM Variant of Ataxia-Telangiectasia

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