Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-29 (of 29 Records) |
Query Trace: Perelygina L [original query] |
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Neutralization of rubella vaccine virus and immunodeficiency-related vaccine-derived rubella viruses by intravenous immunoglobulins
Chen MH , Perelygina L , Hao L , Beard RS , Lackner C , Farcet MR , Karbiener M , Icenogle J , Kreil TR . J Infect Dis 2024 The association between granulomas and vaccine-derived rubella virus (VDRV) in people with primary immune deficiencies (PID) has raised concerns about the ability of immunoglobulin (IG) preparations to neutralize VDRVs. We investigated the capacity of IG to neutralize rubella vaccine virus and four VDRV strains. As expected, the rubella vaccine virus itself was potently neutralized by IG preparations; however, the VDRV isolates from patients after intra-host evolution, 2-6 times less so. Diagnosis of immune deficiencies before possible live-virus vaccination is thus of critical importance, while IG replacement therapy can be expected to provide protection from rubella virus infection. | The occurrence of granulomas associated with vaccine derived rubella viruses (VDRV) in people with primary immune deficiencies (PID) challenges immunoglobulin (IG) preparations regarding their rubella neutralizing ability. This study confirmed potent rubella virus neutralization capacity of IG preparations and thus suggests protection of IG-treated PID patients against rubella. The study also highlights the importance of early diagnosis and timely given IG to prevent possible systemic spread of VDRV persisting locally in granulomas. | eng |
Surveillance for rubella virus in samples obtained from non-immunodeficient individuals
Patel S , Russo P , M HR , Maurer K , Hao L , Beard RS , Perelygina L , Sullivan KE . Pediatr Allergy Immunol 2024 35 (1) e14082 |
Rubella virus chronic inflammatory disease and other unusual viral phenotypes in inborn errors of immunity
Kilich G , Perelygina L , Sullivan KE . Immunol Rev 2023 Infectious susceptibility is a component of many inborn errors of immunity. Nevertheless, antibiotic use is often used as a surrogate in history taking for infectious susceptibility, thereby disadvantaging patients who present with viral infections as their phenotype. Further complicating clinical evaluations are unusual manifestations of viral infections which may be less familiar that the typical respiratory viral infections. This review covers several unusual viral phenotypes arising in patients with inborn errors of immunity and other settings of immune compromise. In some cases, chronic infections lead to oncogenesis or tumor-like growths and the conditions and mechanisms of viral-induced oncogenesis will be described. This review covers enterovirus, rubella, measles, papillomavirus, and parvovirus B19. It does not cover EBV and hemophagocytic lymphohistiocytosis nor lymphomagenesis related to EBV. EBV susceptibility has been recently reviewed. Our goal is to increase awareness of the unusual manifestations of viral infections in patients with IEI and to describe treatment modalities utilized in this setting. Coincidentally, each of the discussed viral infections can have a cutaneous component and figures will serve as a reminder of the physical features of these viruses. Given the high morbidity and mortality, early recognition can only improve outcomes. |
Nucleoside analogs NM107 and AT-527 are antiviral against rubella virus
Dittmar M , Whig K , Miller J , Kamalia B , Suppiah S , Perelygina L , Sullivan KE , Schultz DC , Cherry S . PNAS Nexus 2023 2 (9) pgad256 Rubella is a highly contagious viral infection that usually causes a mild disease in children and adults. However, infection during pregnancy can result in a fetal or newborn death or congenital rubella syndrome (CRS), a constellation of permanent birth defects including cataracts, heart defects, and sensorineural deafness. The live-attenuated rubella vaccine has been highly effective, with the Americas declared free of endemic rubella transmission in 2015. However, rubella remains a significant problem worldwide and the leading cause of vaccine-preventable birth defects globally. Thus, elimination of rubella and CRS is a goal of the World Health Organization. No specific therapeutics are approved for the rubella virus. Therefore, we set out to identify whether existing small molecules may be repurposed for use against rubella virus infection. Thus, we performed a high-throughput screen for small molecules active against rubella virus in human respiratory cells and identified two nucleoside analogs, NM107 and AT-527, with potent antiviral activity. Furthermore, we found that combining these nucleoside analogs with inhibitors of host nucleoside biosynthesis had synergistic antiviral activity. These studies open the door to new potential approaches to treat rubella infections. |
Rubella virus-associated necrotizing neutrophilic granuloma in a patient with common variable immunodeficiency
Pei S , Khazaeli M , Hao L , Chen MH , Perelygina L , Kuraitis D . J Cutan Pathol 2023 50 (11) 971-976 Patients with inborn errors of immunity (IEI) may develop granulomas in multiple organ systems including the skin. Vaccine strain rubella virus (RuV), part of the live attenuated measles, mumps, and rubella (MMR) vaccine, has been identified within these granulomas. RuV is typically found in macrophages; however, recently neutrophils have been identified as a novel cell type infected. Here, we present a case of RuV-associated cutaneous granuloma with RuV localized to neutrophils. A 46-year-old female with common variable immunodeficiency presented with verrucous papules and crusted plaques from the right knee to the distal shin of 20 years duration, associated with prior physical trauma. Biopsy specimen showed palisaded granulomas surrounding central necrosis with scattered aggregates of neutrophils. Vaccine-derived RuV was detected by molecular sequencing in lesional skin. Fluorescent immunohistochemistry with CD206, myeloperoxidase (MPO), and RV capsid (RVC) antibodies demonstrated that RuV localized to neutrophils but not macrophages. The clinical presentation, cutaneous findings, and likely presence of RVC-positive granulocytes in bone marrow provide potential support to the evolving hypothesis of persistent RuV within neutrophils contributing to chronic granulomatous inflammation in a milieu of immune dysregulation. |
Cutaneous granulomas associated with rubella virus: A clinical review
Zhang D , Wanat KA , Perelygina L , Rosenbach M , Haun PL , Drolet BA , Shields BE . J Am Acad Dermatol 2023 90 (1) 111-121 Since the initial identification of vaccine-derived rubella virus (RuV) in the cutaneous granulomas of pediatric patients with inborn errors of immunity (IEI) 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 CDC 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. |
Rubella virus-associated necrotizing granulomatous inflammation with extensive eyelid, ocular, and orbital involvement
Pimentel MA , Kim DH , Walker LW , Noelck MB , Perelygina L , Kripps KA , Cartwright VW , Funk T , Green S , Kuo A , Ng J , Ophaug SL , Passo R , Redd T , Small A . Pediatr Dermatol 2023 40 (6) 1107-1111 We present a case of cutaneous granulomatous disease associated with rubella virus in a 4-year-old girl without an identifiable immunodeficiency. In this case, a combination of anti-inflammatory, anti-viral, and anti-neutrophil therapies successfully treated vision-threatening eyelid, conjunctival, scleral, and orbital inflammation. |
Refractory, fatal autoimmune hemolytic anemia due to ineffective thymic-derived T-cell reconstitution following allogeneic hematopoietic cell transplantation for hypomorphic RAG1 deficiency
Yonkof JR , Basu A , Redmond MT , Dobbs AK , Perelygina L , Notarangelo LD , Abraham RS , Rangarajan HG . Pediatr Blood Cancer 2022 70 (5) e30183 Pathogenic recombination-activating gene 1 (RAG1) variants cause a phenotypic spectrum ranging from severe combined immunodeficiency (SCID) to combined immunodeficiency with granulomas and autoimmunity (CID-G/A), depending on residual recombinase activity.1-4 Our patient, a 12-year-old African American female with hypogammaglobulinemia and T-, B-cell lymphopenia, was diagnosed with CID at 5 years of age, with a history of recurrent herpes simplex virus (HSV) gingivostomatitis, bacterial pneumonia, and cutaneous abscess. She tolerated two doses of live measles–mumps–rubella (MMR) vaccine. She was referred to our facility for steroid-refractory sterile non-caseating cutaneous granulomas (Figure S1) affecting posterior thigh and midface, appearing at 9 years and with progressive lymphopenia (Figure 1A) concerning for a CID. Next-generation sequencing identified compound heterozygous pathogenic RAG1 variants, c.1187G>A, p.Arg396His and c.1566G>T, p.Trp522Cys (NM_000448.2). Residual recombinase activity is estimated at 40%–50% for RAG1-Trp522Cys and less than 5%–30% for RAG1-Arg396His.2, 5, 6 |
Case report: Persistent shedding of a live vaccine-derived rubella virus in a young man with severe combined immunodeficiency and cutaneous granuloma.
Bonner KE , Sukerman E , Liko J , Lanzieri TM , Sutton M , DeBess E , Leesman C , Icenogle J , Hao L , Chen MH , Faisthalab R , Leman RF , Cieslak PR , DeRavin SS , Perelygina L . Front Immunol 2022 13 1075351 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. |
Case Report: Rubella Virus-Induced Cutaneous Granulomas in Two Pediatric Patients With DNA Double Strand Breakage Repair Disorders - Outcome After Hematopoietic Stem Cell Transplantation.
Baumann U , Schulte JH , Gro JP , Beier R , Ludwig M , Wahn V , Hofmann J , Maecker-Kolhoff B , Sauer M , Kaiser-Labusch P , Karimian N , Blume-Peytavi U , Ghoreschi F , Ott H , Perelygina L , Klemann C , Blankenstein O , vonBernuth H , Krger R . Front Immunol 2022 13 886540 We report two patients with DNA repair disorders (Artemis deficiency, Ataxia telangiectasia) with destructive skin granulomas, presumably triggered by live-attenuated rubella vaccinations. Both patients showed reduced nave T cells. Rapid resolution of skin lesions was observed following hematopoietic stem cell transplantation. However, the patient with AT died due to complications of severe hepatic veno-occlusive disease 6 month after HSCT. Dried blood spots obtained after birth were available from this patient and showed absent T-cell receptor excision circles (TRECs). Therefore, newborn screening may help to prevent patients with moderate T-cell deficiency from receiving live-attenuated rubella vaccine potentially causing granulomas. |
Improved diagnostic and multiplex RT-qPCR for detecting rubella viral RNA.
Chen MH , Abernathy E , Icenogle JP , Perelygina LM . J Virol Methods 2022 306 114555 An examination of the nucleic acid sequence alignment of 48 full-length rubella virus genomes revealed that the 5' terminus of the genome is more conserved than the commonly used detection windows for rubella virus RNA located in the E1 protein coding region, suggesting that the 5' terminus could be a target for improving detection of all rubella virus genotypes. Two candidate primer sets were tested and the window between nucleotides (nts) 98 and 251 was found to have the greatest analytical sensitivity for detection of different genotypes. The new method had a limit of detection of four copies of rubella RNA per reaction with high specificity. The average coefficient variation of Ct was 2.2%. Concordance between the new method and currently used method, based on testing 251 clinical specimens collected from a rubella outbreak, was 99.4%. The assay was further improved upon by the incorporation of detection of both rubella virus RNA and mRNA from a cellular reference gene in a multiplex format. The multiplex format did not reduce the sensitivity or the reproducibility of rubella RNA detection and, of 60 specimens tested, the concordance between the single target and multiplex assays was 85.0%. To assess the utility of the multiplex assay for molecular surveillance, 62 rubella IgM positive serum samples from a rubella outbreak were tested, and eleven tested positive using the multiplex method while none were positive using the method targeting E1. These results show that the assay based on the new detection window near the 5' terminus of the genome can improve the detection of rubella virus for the purpose of molecular surveillance and case confirmation, with the added benefit of improved efficiency due to multiplexing. |
Association of Persistent Rubella Virus With Idiopathic Skin Granulomas in Clinically Immunocompetent Adults.
Wanat KA , Perelygina L , Chen MH , Hao L , Abernathy E , Bender NR , Shields BE , Wilson BD , Crosby D , Routes J , Samimi SS , Haun PL , Sokumbi O , Icenogle JP , Sullivan KE , Rosenbach M , Drolet BA . JAMA Dermatol 2022 158 (6) 626-633 IMPORTANCE: Vaccine-derived and wild-type rubella virus (RuV) has been identified within granulomas in patients with inborn errors of immunity, but has not been described in granulomas of healthy adults. OBJECTIVE: To determine the association between RuV and atypical granulomatous inflammation in immune-competent adults. DESIGN, SETTING, AND PARTICIPANTS: This case series, conducted in US academic dermatology clinics from January 2019 to January 2021, investigated the presence of RuV in skin specimens using RuV immunofluorescent staining of paraffin-embedded tissue sections, real-time reverse-transcription polymerase chain reaction, whole-genome sequencing with phylogenetic analyses, and cell culture by the US Centers for Disease Control and Prevention. Rubella immunoglobulin G, immunoglobulin M enzyme-linked immunoassay, and viral neutralization assays were performed for the sera of immunocompetent individuals with treatment refractory cutaneous granulomas and histopathology demonstrating atypical palisaded and necrotizing granulomas. Clinical immune evaluation was performed. MAIN OUTCOMES AND MEASURES: Identification, genotyping, and culture of vaccine-derived and wild-type RuV within granulomatous dermatitis of otherwise clinically immune competent adults. RESULTS: Of the 4 total immunocompetent participants, 3 (75%) were women, and the mean (range) age was 61.5 (49.0-73.0) years. The RuV capsid protein was detected by immunohistochemistry in cutaneous granulomas. The presence of RuV RNA was confirmed by real-time reverse-transcription polymerase chain reaction in fresh-frozen skin biopsies and whole-genome sequencing. Phylogenetic analysis of the RuV sequences showed vaccine-derived RuV in 3 cases and wild-type RuV in 1. Live RuV was recovered from the affected skin in 2 participants. Immunology workup results demonstrated no primary immune deficiencies. CONCLUSIONS AND RELEVANCE: The case series study results suggest that RuV (vaccine derived and wild type) can persist for years in cutaneous granulomas in clinically immunocompetent adults and is associated with atypical (palisaded and necrotizing type) chronic cutaneous granulomas. These findings represent a potential paradigm shift in the evaluation, workup, and management of atypical granulomatous dermatitis and raises questions regarding the potential transmissibility of persistent live RuV. |
Drug Sensitivity of Vaccine-Derived Rubella Viruses and Quasispecies Evolution in Granulomatous Lesions of Two Ataxia-Telangiectasia Patients Treated with Nitazoxanide.
Faisthalab R , Suppiah S , Dorsey M , Sullivan KE , Icenogle J , Perelygina L . Pathogens 2022 11 (3) A strong association between rubella virus (RuV) and chronic granulomas, in individuals with inborn errors of immunity, has been recently established. Both the RA27/3 vaccine and wild-type RuV strains were highly sensitive to a broad-spectrum antiviral drug, nitazoxanide (NTZ), in vitro. However, NTZ treatment, used as a salvage therapy, resulted in little or no improvements of RuV-associated cutaneous granulomas in patients. Here, we report investigations of possible causes of treatment failures in two ataxia-telangiectasia patients. Although a reduction in RuV RNA in skin lesions was detected by real-time RT-PCR, live immunodeficiency-related vaccine-derived rubella viruses (iVDRV) were recovered from granulomas, before and after the treatments. Tizoxanide, an active NTZ metabolite, inhibited replications of all iVDRVs in cultured A549 cells, but the 50% and 90% inhibitory concentrations were 10-40 times higher than those for the RA27/3 strain. There were no substantial differences in iVDRV sensitivities, neither before nor after treatments. Analysis of quasispecies in the E1 gene, a suspected NTZ target, showed no effect of NTZ treatments on quasispecies' complexity in lesions. Thus, failures of NTZ therapies were likely due to low sensitivities of iVDRVs to the drug, and not related to the emergence of resistance, following long-term NTZ treatments. |
Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity.
Perelygina L , Faisthalab R , Abernathy E , Chen MH , Hao L , Bercovitch L , Bayer DK , Noroski LM , Lam MT , Cicalese MP , Al-Herz W , Nanda A , Hajjar J , Vanden Driessche K , Schroven S , Leysen J , Rosenbach M , Peters P , Raedler J , Albert MH , Abraham RS , Rangarjan HG , Buchbinder D , Kobrynski L , Pham-Huy A , Dhossche J , Cunningham Rundles C , Meyer AK , Theos A , Atkinson TP , Musiek A , Adeli M , Derichs U , Walz C , Krüger R , von Bernuth H , Klein C , Icenogle J , Hauck F , Sullivan KE . Front Immunol 2021 12 796065 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. |
Granulomatous Dermatitis Associated With Rubella Virus Infection in an Adult With Immunodeficiency.
Shields BE , Perelygina L , Samimi S , Haun P , Leung T , Abernathy E , Chen MH , Hao L , Icenogle J , Drolet B , Wilson B , Bryer JS , England R , Blumberg E , Wanat KA , Sullivan K , Rosenbach M . JAMA Dermatol 2021 157 (7) 842-847 IMPORTANCE: Immunodeficiency-related, vaccine-derived rubella virus (RuV) as an antigenic trigger of cutaneous and visceral granulomas is a rare, recently described phenomenon in children and young adults treated with immunosuppressant agents. OBJECTIVE: To perform a comprehensive clinical, histologic, immunologic, molecular, and genomic evaluation to elucidate the potential cause of an adult patient's atypical cutaneous granulomas. DESIGN, SETTING, AND PARTICIPANTS: A prospective evaluation of skin biopsies, nasopharyngeal swabs, and serum samples submitted to the Centers for Disease Control and Prevention was conducted to assess for RuV using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and viral genomic sequencing. The samples were obtained from a man in his 70s with extensive cutaneous granulomas mimicking both cutaneous sarcoidosis (clinically) and CD8+ granulomatous cutaneous T-cell lymphoma (histopathologically). The study was conducted from September 2019 to February 2021. MAIN OUTCOMES AND MEASURES: Identification and genotyping of a novel immunodeficiency-related RuV-associated granulomatous dermatitis. RESULTS: Immunohistochemistry for RuV capsid protein and RT-PCR testing for RuV RNA revealed RuV in 4 discrete skin biopsies from different body sites. In addition, RuV RNA was detected in the patient's nasopharyngeal swabs by RT-PCR. The full viral genome was sequenced from the patient's skin biopsy (RVs/Philadelphia.PA.USA/46.19/GR, GenBank Accession #MT249313). The patient was ultimately diagnosed with a novel RuV-associated granulomatous dermatitis. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that clinicians and pathologists may consider RuV-associated granulomatous dermatitis during evaluation of a patient because it might have implications for the diagnosis of cutaneous sarcoidosis, with RuV serving as a potential antigenic trigger, and for the diagnosis of granulomatous cutaneous T-cell lymphoma, with histopathologic features that may prompt an evaluation for immunodeficiency and/or RuV. |
Rubella virus-associated chronic inflammation in primary immunodeficiency diseases.
Perelygina L , Icenogle J , Sullivan KE . Curr Opin Allergy Clin Immunol 2020 20 (6) 574-581 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. |
Notes from the field: Monkey bite in a public park and possible exposure to herpes B virus - Thailand, 2018
Wu AC , Rekant SI , Baca ER , Jenkins RM , Perelygina LM , Hilliard JK , Schmid DS , Leman RF . MMWR Morb Mortal Wkly Rep 2020 69 (9) 247-248 On January 7, 2019, the Oregon Public Health Division (OPHD) was contacted by a local health department regarding an Oregon teen who, on December 24, 2018, was bitten by a macaque monkey (Figure) in a public park in Phuket, Thailand. The bleeding wound was immediately rinsed with bottled water without soap. Subsequently, hotel staff members applied a topical pain reliever. The following day, the teen went to a local clinic in Thailand and received the first dose of rabies postexposure prophylaxis vaccine; rabies immune globulin was not administered. She received 2 additional doses of rabies vaccine while in Thailand. | | On January 5, 2019, the patient left Thailand and was evaluated by a physician in Oregon on January 7. The physician contacted the local health department, seeking guidance about when to administer the final dose of rabies vaccine. Upon learning about the macaque bite, the local health department contacted OPHD, where staff members expressed concern about possible exposure to Macacine herpesvirus 1 (B virus). This virus, commonly found in macaques,* can, in rare cases, cause severe encephalitic infection in humans if not treated promptly (1). The case fatality rate of untreated B virus infection approaches 80% (2). OPHD contacted CDC, and the National B Virus Resource Center (NBVRC) in Atlanta, Georgia, to discuss testing.† |
Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies.
Perelygina L , Chen MH , Suppiah S , Adebayo A , Abernathy E , Dorsey M , Bercovitch L , Paris K , White KP , Krol A , Dhossche J , Torshin IY , Saini N , Klimczak LJ , Gordenin DA , Zharkikh A , Plotkin S , Sullivan KE , Icenogle J . PLoS Pathog 2019 15 (10) e1008080 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. |
Cutaneous granulomatous disease with presence of rubella virus in lesions
Dhossche J , Johnson L , White K , Funk T , Leitenberger S , Perelygina L , Krol A . JAMA Dermatol 2019 155 (7) 859-861 Granulomatous disease prompts a search for antigenic triggers, given our understanding of granuloma formation as a defense mechanism against persistent antigen in tissue. Cutaneous granulomas in patients with primary immunodeficiency have been attributed to immune dysregulation because no infectious trigger has been identified in these patients.1 However, recent reports have emerged of skin biopsies in at least 9 children with primary immunodeficiency confirming the presence of vaccine-derived rubella virus (VDRV) related to the RA27/3 vaccine strain in granulomas and its absence in normal skin.2-4 Immune deficiency may allow for the persistence of vaccine-strain virus, which could accrue mutations.3 We report herein the cases of 2 children with cutaneous granulomas harboring VDRV, one with primary immunodeficiency, and the other with undefined immunodeficiency. |
Outcomes for nitazoxanide treatment in a case series of patients with primary immunodeficiencies and rubella virus-associated granuloma
Perelygina L , Buchbinder D , Dorsey MJ , Eloit M , Hauck F , Hautala T , Moshous D , Uriarte I , Deripapa E , Icenogle J , Sullivan KE . J Clin Immunol 2019 39 (1) 112-117 PURPOSE: Nitazoxanide was recently reported as having in vitro effectiveness against the rubella virus. Immunodeficiency-related vaccine-derived rubella occurs in some patients who have an inherited immunodeficiency and who received the MMR vaccine. This study investigated the in vivo effectiveness of nitazoxanide therapy. METHODS: This is a retrospective analysis of seven patients treated with nitazoxanide as salvage therapy for immunodeficiency-related vaccine-derived rubella infection. The patients were recruited from an ongoing rubella detection surveillance project. RESULTS: Seven patients with persistent rubella were treated with nitazoxanide and one demonstrated significant clinical improvement. Two additional patients exhibited diminished viral capsid production with one patient having transient slowing of progression. The cohort overall generally had low T cell counts and had a high burden of comorbidities. There were three deaths. Two deaths were from PML and one was related to hematopoietic stem cell transplantation. CONCLUSIONS: Nitazoxanide has limited in vivo anti-viral effects for immunodeficiency-related vaccine-derived rubella. Most patients did not exhibit clinical improvement. |
Rubella Virus-Associated Cutaneous Granulomatous Disease: a Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders.
Buchbinder D , Hauck F , Albert MH , Rack A , Bakhtiar S , Shcherbina A , Deripapa E , Sullivan KE , Perelygina L , Eloit M , Neven B , Perot P , Moshous D , Suarez F , Bodemer C , Bonilla FA , Vaz LE , Krol AL , Klein C , Seppanen M , Nugent DJ , Singh J , Ochs HD . J Clin Immunol 2019 39 (1) 81-89 The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies. |
Prevalence of granulomas in patients with primary immunodeficiency disorders, United States: Data From National Health Care Claims and the US Immunodeficiency Network Registry
Leung J , Sullivan KE , Perelygina L , Icenogle JP , Fuleihan RL , Lanzieri TM . J Clin Immunol 2018 38 (6) 717-726 PURPOSE: Granulomas are a potentially severe condition that can last for several years in persons with primary immunodeficiency disorders (PIDD). We assessed the prevalence of granulomas in patients with PIDD. METHODS: We used the Truven Health MarketScan(R) 2005-2015 Commercial Claims and Encounters and 2006-2015 Medicaid databases and the US Immunodeficiency Network (USIDNET) PIDD registry (a program of the Immune Deficiency Foundation). Our study population consisted of persons age < 65 years with PIDD, defined as persons with >/= 2 claims with a diagnostic code for PIDD in MarketScan databases, or patients enrolled in USIDNET. Granulomas were identified using diagnostic codes in MarketScan or provider report in USIDNET. We calculated annual prevalence of PIDD and of granulomas among PIDD patients. RESULTS: We identified 247,474 and 40,395 persons with PIDD among commercially and Medicaid-insured persons, respectively. PIDD prevalence was 6.0/10,000 in 2005 and 11.7/10,000 in 2015 among commercially insured persons and 5.5/10,000 in 2006 and 9.6/10,000 in 2015 among Medicaid-insured persons. The prevalence of granulomas among PIDD patients was 1.2 and 1.5% among commercially and Medicaid-insured persons, respectively. In USIDNET, prevalence of granulomas was 4.4% (177/4021). The proportion with granulomas was similar across age groups in MarketScan, but varied from 2 to 9% in USIDNET. The reported prevalence of granulomas differed depending on PIDD condition: 1-2% in the MarketScan data and 0-13% in USIDNET. CONCLUSION: Granuloma prevalence in PIDD patients was 1-4%. Our study provides an estimate of the proportion of PIDD patients and suggests that granulomas are an uncommon occurrence among patients with PIDD. |
Nitazoxanide may modify the course of progressive multifocal leukoencephalopathy
Hautala TJ , Perelygina L , Vuorinen T , Hautala NM , Hagg PM , Bode MK , Rusanen HT , Renko MH , Glumoff V , Schwab N , Schneider-Hohendorf T , Murk JL , Sullivan KE , Seppanen MRJ . J Clin Immunol 2017 38 (1) 4-6 Progressive multifocal leukoencephalopathy (PML) caused by human neurotrophic polyomavirus (JCV) is a central nervous system (CNS) disease in immunodeficient patients. PML is associated with a poor prognosis and the only intervention leading to clearance of the virus is removal of iatrogenic immune suppression. In particular, the prognosis is dismal in patients with severe primary immunodeficiency (PID) [1]. However, our clinical experience described in this case report supports the possibility that nitazoxanide, a broad-spectrum antiparasitic and antiviral drug [2], may have helped in controlling the JCV in a single patient with PML associated with combined PID. This antiviral effect of nitazoxanide may have been produced by induction of innate immunity, downregulation of viral receptors, or interference with maturation of viral proteins [2, 3]. | A female patient suffering from psychomotor retardation, bilateral optic nerve atrophy, and refractive amblyopia due to untreated hyperopia developed lymphopenia (0.5–0.9 × 109/l, reference range (ref) 1.2–3.5 × 109/l) in her adolescence. Despite a normal CD19+ count (96–159 × 106/l, ref 80–616 × 106/l), B cell maturation was defective (marginal zone 0.48–0.8 × 106/l, 0.5% of all CD19+, ref 7.2–30.8%; switched memory B cells 0.67–1.1 × 106/l, 0.7%, ref 6.5–29.2%) with no response to pneumococcus antigens. She had low concentrations of IgA (0.6 g/l) and IgG (3.1 g/l), while IgE and IgM were undetectable. CD3+CD4+ T cell counts were 256 × 106/l (ref 404–612 × 106/l) and CD3+CD8+ T cells were 220 × 106/l (ref 220–1129 × 106/l) with a reduced CD4/CD8 ratio of 1.16. Percentage of recent thymic emigrant CD45RA+CD62L+CD31+ T cells (24 × 106/l, 0.5% of all CD3+, ref 14.4–38.3%) was low. Cells responded poorly to concanavalin A, phytohaemagglutinin, or pokeweed mitogen. The percentage of CD4−CD8− (1.2%) double negative T cell and natural killer cell count (139–143 × 106/l, ref 84–724 × 106/l) were normal. These findings suggested a diagnosis of combined primary immunodeficiency. Molecular karyotyping found no deletions. Whole exome sequencing (WES) of the patient’s, her parents’, and unaffected brother’s DNA failed to find a known condition. The parents originated from a restricted geographical region with a degree of consanguinity seen in WES. |
Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency
Perelygina L , Hautala T , Seppanen M , Adebayo A , Sullivan KE , Icenogle J . Antiviral Res 2017 147 58-66 Persistent rubella virus (RV) infection has been associated with various pathologies such as congenital rubella syndrome, Fuchs's uveitis, and cutaneous granulomas in patients with primary immune deficiencies (PID). Currently there are no drugs to treat RV infections. Nitazoxanide (NTZ) is an FDA-approved drug for parasitic infections, and has been recently shown to have broad-spectrum antiviral activities. Here we found that empiric 2-month therapy with oral NTZ was associated in the decline/elimination of RV antigen from lesions in a PID patient with RV positive granulomas, while peginterferon treatment had no effect. In addition, we characterized the effects of NTZ on cell culture models of persistent RV infection. NTZ significantly inhibited RV replication in a primary culture of human umbilical vein endothelial cells (HUVEC) and Vero and A549 epithelial cell lines in a dose dependent manner with an average 50% inhibitory concentration of 0.35 mug/ml (1.1 muM). RV strains representing currently circulating genotypes were inhibited to a similar extent. NTZ affected early and late stages of infection by inhibiting synthesis of cellular and RV RNA and interfering with intracellular trafficking of the RV surface glycoproteins, E1 and E2. These results suggest a potential application of NTZ for the treatment of persistent rubella infections, but more studies are required. |
Estimating the burden of rubella virus infection and congenital rubella syndrome through a rubella immunity assessment among pregnant women in the Democratic Republic of the Congo: Potential impact on vaccination policy
Alleman MM , Wannemuehler KA , Hao L , Perelygina L , Icenogle JP , Vynnycky E , Fwamba F , Edidi S , Mulumba A , Sidibe K , Reef SE . Vaccine 2016 34 (51) 6502-6511 BACKGROUND: Rubella-containing vaccines (RCV) are not yet part of the Democratic Republic of the Congo's (DRC) vaccination program; however RCV introduction is planned before 2020. Because documentation of DRC's historical burden of rubella virus infection and congenital rubella syndrome (CRS) has been minimal, estimates of the burden of rubella virus infection and of CRS would help inform the country's strategy for RCV introduction. METHODS: A rubella antibody seroprevalence assessment was conducted using serum collected during 2008-2009 from 1605 pregnant women aged 15-46years attending 7 antenatal care sites in 3 of DRC's provinces. Estimates of age- and site-specific rubella antibody seroprevalence, population, and fertility rates were used in catalytic models to estimate the incidence of CRS per 100,000 live births and the number of CRS cases born in 2013 in DRC. RESULTS: Overall 84% (95% CI 82, 86) of the women tested were estimated to be rubella antibody seropositive. The association between age and estimated antibody seroprevalence, adjusting for study site, was not significant (p=0.10). Differences in overall estimated seroprevalence by study site were observed indicating variation by geographical area (p0.03 for all). Estimated seroprevalence was similar for women declaring residence in urban (84%) versus rural (83%) settings (p=0.67). In 2013 for DRC nationally, the estimated incidence of CRS was 69/100,000 live births (95% CI 0, 186), corresponding to 2886 infants (95% CI 342, 6395) born with CRS. CONCLUSIONS: In the 3 provinces, rubella virus transmission is endemic, and most viral exposure and seroconversion occurs before age 15years. However, approximately 10-20% of the women were susceptible to rubella virus infection and thus at risk for having an infant with CRS. This analysis can guide plans for introduction of RCV in DRC. Per World Health Organization recommendations, introduction of RCV should be accompanied by a campaign targeting all children 9months to 14years of age as well as vaccination of women of child bearing age through routine services. |
Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies
Perelygina L , Plotkin S , Russo P , Hautala T , Bonilla F , Ochs HD , Joshi A , Routes J , Patel K , Wehr C , Icenogle J , Sullivan KE . J Allergy Clin Immunol 2016 138 (5) 1436-1439 e11 Cutaneous granulomas are a well-recognized pathologic feature in patients with various primary immunodeficiency diseases (PIDs) and may be self-limited or can progress to a persisting granulomatous disorder.1,2 Rubella virus (RV) vaccine strain RA27/3 has been recently detected in disseminated cutaneous granulomas of 2 patients with ataxia telangiectasia (AT) and a patient with Simpson-Golabi-Behmel syndrome (who had combined immunodeficiency [CID]).3 However, a more detailed study of a larger series of granuloma cases in patients with different PIDs was required to confirm and extend this observation. | Patients with cutaneous granulomas and with diverse PIDs were selected from the United States Immune Deficiency Network registry. Additional cases (cases 1 and 11) were recruited from the Clinical Immunology Society immune deficiency Listserv. Presence of RV in granuloma-containing tissue samples (Fig 1, A–C) was examined by immunofluorescence staining with 2 different RV capsid-specific antibodies (see this article’s Methods section in the Online Repository at www.jacionline.org) by a reader blinded to the diagnosis. Seven out of 14 patients (50%) exhibited positive RV antigen staining (Table I), whereas the tissue samples of 5 non-PID granuloma patients were negative. |
Gene expression profiling of rubella virus infected primary endothelial cells of fetal and adult origin.
Geyer H , Bauer M , Neumann J , Ludde A , Rennert P , Friedrich N , Claus C , Perelygina L , Mankertz A . Virol J 2016 13 (1) 21 BACKGROUND: Rubella virus (RV) infection is usually a mild illness in children and adults. However, maternal infection during the first trimester of pregnancy can lead to congenital rubella syndrome (CRS) in the infant. Fetuses with CRS show damage to the endothelium of the heart and blood vessels; thus, it has been speculated that the clinical manifestations associated with CRS may be a result of endothelial cells persistently infected with RV. Here, we compared the effects of RV infection on gene expression in primary endothelial cells of fetal (HUVEC) and of adult (HSaVEC) origin by transcriptional profiling. RESULTS: More than 75 % of the genes differentially regulated following RV infection were identical in both cell types. Gene Ontology (GO) analysis of these commonly regulated genes showed an enrichment of terms involved in cytokine production and cytokine regulation. Increased accumulation of inflammatory cytokines following RV infection was verified by protein microarray. Interestingly, the chemokine CCL14, which is implicated in supporting embryo implantation at the fetal-maternal interface, was down-regulated following RV infection only in HUVEC. Most noticeably, when analyzing the uniquely regulated transcripts for each cell type, GO term-based cluster analysis of the down-regulated genes of HUVEC revealed an enrichment of the GO terms "sensory organ development", "ear development" and "eye development". CONCLUSION: Since impairment in vision and hearing are the most prominent clinical manifestations observed in CRS patients, the here detected down-regulated genes involved in the development of sensory organs sheds light on the molecular mechanisms that may contribute to the teratogenic effect of RV. |
Immunolocalization and distribution of rubella antigen in fatal congenital rubella syndrome
Lazar M , Perelygina L , Martines R , Greer P , Paddock CD , Peltecu G , Lupulescu E , Icenogle J , Zaki SR . EBioMedicine 2015 3 86-92 BACKGROUND: An estimated 100,000 cases of congenital rubella syndrome (CRS) occur worldwide each year. The reported mortality rate for infants with CRS is up to 33%. The cellular mechanisms responsible for the multiple congenital defects in CRS are presently unknown. Here we identify cell types positive for rubella virus (RV) in CRS infants. METHODS: Cells and organs involved in RV replication were identified in paraffin-embedded autopsy tissues from three fatal case-patients by histopathologic examination and immunohistochemical (IHC) staining using a rabbit polyclonal RV antibody. Normal rabbit antisera and RV antisera preabsorbed with highly purified RV served as negative controls. RESULTS: RV antigen was found in interstitial fibroblasts in the heart, adventitial fibroblasts of large blood vessels, alveolar macrophages, progenitor cells of the outer granular layer of the brain, and in capillary endothelium and basal plate in the placenta. The antibody specificity was verified by IHC staining of multiple tissue sections from other infectious disease cases. RV infection of each cell type is consistent with abnormalities which have been identified in patients with CRS, in the heart, large blood vessels, and brain. Antigen distribution was consistent with inflammatory response to vascular injury and systemic spread of RV. CONCLUSIONS: The identification of RV positive cell types in CRS is important to better understand the pathology and pathogenesis of CRS. |
Differences in Establishment of Persistence of Vaccine and Wild Type Rubella Viruses in Fetal Endothelial Cells.
Perelygina L , Adebayo A , Metcalfe M , Icenogle J . PLoS One 2015 10 (7) e0133267 Both wild type (WT) and vaccine rubella virus (RV) can pass through the placenta to infect a human fetus, but only wtRV routinely causes pathology. To investigate possible reasons for this, we compared establishment of persistence of wtRV and RA27/3 vaccine strains in fetal endothelial cells. We showed that yields of RA27/3 and wtRV were similar after the first round of replication, but then only vaccine-infected cultures went through a crisis characterized by partial cell loss and gradual decline of virus titer followed by recovery and establishment of persistent cultures with low levels of RA27/3 secretion. We compared various steps of virus replication, but we were unable to identify changes, which might explain the 2-log difference in RA27/3 and wtRV yields in persistently infected cultures. Whole genome sequencing did not reveal selection of virus variants in either the wtRV or RA27/3 cultures. Quantitative single-cell analysis of RV replication by in situ hybridization detected, on average, 1-4 copies of negative-strand RNA and ~50 copies of positive-strand genomic RNA in cells infected with both vaccine and WT viruses. The distinct characteristics of RA27/3 replication were the presence of large amounts of negative-strand RV RNA and RV dsRNA at the beginning of the crisis and the accumulation of high amounts of genomic RNA in a subpopulation of infected cells during crisis and persistence. These results suggest that RA27/3 can persist in fetal endothelial cells, but the characteristics of persistence and mechanisms for the establishment and maintenance of persistence are different from wtRV. |
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