Case report: Rubella virus-associated cutaneous granuloma in an adult with TAP1 deficiency.

Rubella virus-associated granulomas commonly occur in immunocompromised individuals, exhibiting a diverse range of clinical presentations. These manifestations can vary from predominantly superficial cutaneous plaques or nonulcerative nodules to more severe deep ulcerative lesions, often accompanied by extensive necrosis and significant tissue destruction. TAP1 deficiency, an exceedingly rare primary immune-deficiency disorder, presents with severe chronic sino-pulmonary infection and cutaneous granulomas. This report highlights the occurrence of rubella virus-associated cutaneous granulomas in patients with TAP1 deficiency. Notably, the pathogenic mutation responsible for TAP1 deficiency stems from a novel genetic alteration that has not been previously reported. This novel observation holds potential significance for the field of diagnosis and investigative efforts in the context of immunodeficiency disorders.

Catarata congênita nas infecções intrauterinas mais comuns (STORCH): revisão de literatura / Congenital cataract in the most common intrauterine infections (STORCH): a review of the literature

RESUMO Objetivo: O objetivo deste estudo foi revisar os aspectos clínicos e patológicos da catarata congênita secundária às infecções por sífilis, toxoplasmose, rubéola, citomegalovírus e herpes simples. Métodos: Trata-se de uma revisão de literatura, na qual foram incluídos artigos de periódicos indexados às bases de dados PubMed®, Cochrane, Lilacs, Embase e SciELO de 2010 a 2023. Resultados: Foram encontrados 45 artigos, e, após seleção, restaram 9 artigos. Além disso, foram adicionados artigos para enriquecer a discussão. A infecção por sífilis está relacionada a alterações corneanas. O citomegalovírus e a toxoplasmose estão relacionados com a coriorretinite e/ou microftalmia. A rubéola é responsável por causar catarata, glaucoma, microftalmia e retinite em sal e pimenta. Conclusão: Foram abordadas as principais etiologias infecciosas e seu quadro clínico na CC. O melhor tratamento para CC é cirúrgico associado a acompanhamento clínico, mas a prevenção é a maneira mais eficaz de combater a CC de etiologia infecciosa. O diagnóstico precoce e o tratamento efetivo previnem alterações e sequelas visuais irreversíveis. Nesse contexto, mostram-se importantes as ações de políticas públicas para o melhor desfecho clínico e melhor qualidade de vida.

ABSTRACT Objective: To review the clinical and pathological aspects of CC secondary to infections by syphilis, toxoplasmosis, rubella, cytomegalovirus, herpes simplex. Methods: This is a literature review. Articles from journals indexed to PubMed, COCHRANE, LILACS, EMBASE and SCIELO from 2010 to 2023 were included. Results: A total of 45 articles were found, which, after selection, remained in 9 articles. Some articles were included to enrich the discussion in this topic. The infection caused by syphilis is related to corneal changes. Cytomegalovirus and Toxoplasmosis due to chorioretinitis and/or microphthalmia. Rubella is responsible for causing cataracts, glaucoma, microphthalmia, and salt and pepper retinitis. Conclusion: The main infectious etiologies and their clinical status in CC were addressed. The best treatment for CC is surgery associated with clinical follow-up, but prevention is the most effective way to combat CC of infectious etiology. Early diagnosis and effective treatment prevent irreversible visual changes and sequelae. In this context, public policy actions are important for the best clinical outcome and better quality of life.

Cutaneous granulomas associated with rubella virus: A clinical review.

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.

Rubella virus-associated necrotizing neutrophilic granuloma in a patient with common variable immunodeficiency.

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.

Spontaneous Regression of Choroidal Neovascularization in a Girl with Rubella Retinopathy.

Rubella retinopathy is usually a benign disorder with low impact on visual acuity. However, choroidal neovascularization can occur in these patients threatening their vision. We report the case of a 6-year-old girl with rubella retinopathy who developed a neovascular membrane and was successfully managed with observation. Decision to treat or observe in these patients must be carefully weighed, with both options being valid depending mainly on the location of the neovascular complex.

Contribution of parvovirus B19 in suspected cases of measles/rubella in Osaka, Japan, between 2011 and 2021.

Erythema infectiosum, caused by human parvovirus B19 (B19V), is difficult to diagnose by its clinical symptoms and is often misdiagnosed as measles or rubella. Timely confirmation of measles/rubella or other viral etiologies via laboratory tests can provide an accurate picture of the infection status, which can appropriate response. The purpose of this study was to determine the contribution of B19V as an etiological agent for fever-rash in suspected cases of measles and rubella in Osaka Prefecture between 2011 and 2021. Of 1356 suspected cases, 167 were confirmed with measles and 166 with rubella using nucleic acid testing (NAT). Of the remaining 1023 cases, 970 from which blood specimens could be obtained were screened by real-time polymerase chain reaction for B19V, from which 136 (14%) tested positive. Of the positives cases, 21% were young children (9 years and younger), while 64% were adults (20 years and older). Phylogenetic tree analysis showed that 93 samples belonged to genotype 1a. The importance of B19V in the etiology of fever-rash illness was revealed in this study. The importance of laboratory diagnosis by NAT in maintaining the status of measles elimination and to eliminate rubella was reaffirmed.

The epidemiology and disease burden of congenital TORCH infections among hospitalized children in China: A national cross-sectional study.

BACKGROUND: Congenital TORCH (Toxoplasma gondii (T. gondii), rubella virus (RV), cytomegalovirus (CMV), and herpes simplex virus (HSV)) infections are associated with a variety of adverse prenatal and neonatal events, including miscarriage, malformations and developmental abnormalities, and they remain an issue that cannot be neglected in China. However, the current research focuses more on the general screening of TORCH in women of childbearing age, and the medical information of children hospitalized due to congenital and perinatal TORCH infections has not been described in detail. This study summarized and analyzed the epidemiological characteristics, clinical manifestations, length of stay (LOS), and the disease burden of hospitalized children diagnosed with congenital TORCH infections in 27 children's hospitals in China. METHODOLOGY: Based on the face sheet of discharge medical records (FSMRs) of hospitalized children in 27 tertiary children's hospitals collected in the Futang Research Center of Pediatric Development and aggregated into FUTang Update medical REcords (FUTURE), we summarized and analyzed the epidemiological characteristics, clinical manifestations, LOS, the disease burden (in US dollars, USD) and potential risk factors for hospitalized children diagnosed with congenital toxoplasmosis, congenital rubella syndrome, congenital cytomegalovirus infection, and congenital HSV in 27 children's hospitals in China from 2015 to 2020. RESULTS: One hundred seventy-three patients aged 0-<1 year were hospitalized for congenital TORCH infections. Among infections with TORCH, hospitalization with congenital toxoplasmosis was the least common, with only five cases were reported (2.89%), while the LOS was the highest. The proportion of patients with congenital rubella syndrome (CRS) was 15.61%, and 86% of children hospitalized with CRS had cardiovascular malformations, and the economic burden was the highest. Congenital CMV infection cases accounted for the largest proportion (76.30%). Overall, 5.20% of patients were infected with HSV, and the expense of hospitalization for congenital HSV infection was relatively low. CONCLUSION: In the present study, the hospitalization proportion due to congenital TORCH infection was extremely low (17.56 per 100,000 neonates), indicating that China's congenital TORCH infection prevention and control policies remain effective. The lowest proportion of patients was hospitalized with congenital toxoplasmosis, while the LOS was the longest. The economic burden of CRS was heavy, and infants are recommended be vaccinated against RV in a timely manner. Congenital CMV infections accounted for the largest proportion of patients, suggesting that the disease burden of congenital CMV infection cannot be ignored, and the prevention of congenital CMV infection during pregnancy is still an important issue that needs to pay attention. The expense of hospitalization for congenital HSV infection was relatively low, while the disease burden increases significantly when patients develop complications. These data illustrate the importance of improving screening for congenital TORCH infections in the early diagnosis and treatment of neonatal patients.

A case of wild-type rubella-associated cutaneous granuloma in ataxia telangiectasia.

Granulomatous skin disease is known to be associated with various primary immunodeficiencies, including ataxia telangiectasia (AT). Recent reports of persistence of live vaccine strain rubella within such cutaneous granulomas have raised concern regarding the safety of vaccination. Here we report a case of cutaneous granuloma in association with AT, demonstrating wild type, rather than vaccine strain rubella. This supports the persistence of rubella as a causative mechanism, but suggests it is not vaccine strain-specific, and thus may impact the decision of those considering not vaccinating this subset of children.

Iridian anterior segment OCT in rubella uveitis syndrome and cytomegalovirus anterior uveitis: a comparative study.

PURPOSE: To compare iris affectation in cytomegalovirus anterior uveitis (CMVAU), rubella virus-associated uveitis (RVU), and healthy contralateral eyes, using swept-source anterior segment optical coherence tomography (SS-AS-OCT). MATERIALS AND METHODS: A comparative, transversal, retrospective study examining 60 eyes from 30 patients-18 eyes (17 patients) with CMVAU, 14 eyes (13 patients) with RVU, and 28 healthy eyes-was performed. Six-millimeter cross-sectional SS-AS-OCT B-scans were obtained in each iris quadrant. Images were exported to ImageJ®. Qualitative and quantitative analyses were done: stromal thickness (ST), smooth index (SI), and optical density (OD) of pigment epithelium. Comparisons between measurements and clinical-demographic parameters were performed using SPSS®. RESULTS: Qualitative analysis showed extensive damage in iris stroma but was unable to differentiate between both uveitis. RVU eyes had a lower mean ST (315.72 µm ± 42.4) compared to those with CMVAU (348.6 µm ± 46) (p = 0.047) and a lower ST in the upper (338.9 µm ± 38.52)/(386.25 µm ± 47.2) (p = 0.005) and temporal (281.5 µm ± 57.3)/(326.43 µm ± 62.3) (p = 0.016) quadrants. Mean (0.94 ± 0.02)/(0.9 ± 0.03) (p = 0.001), temporal (0.94 ± 0.02)/(0.89 ± 0.03) (p < 0.001), and nasal SI (0.094 ± 0.02)/(0.9 ± 0.04) (p = 0.005) were higher in RVU. OD was similar in both uveitis. In healthy eyes, mean ST (376.8 µm ± 39.7) was higher and mean SI was lower (0.87 ± 0.04) than in RVU (p < 0.001) and CMVAU eyes (p = 0.032). Mean OD was higher in healthy eyes (911 ± 130) than in CMVAU eyes (800 ± 200) (p = 0.037). CONCLUSIONS: The quantitative analysis of the SS-AS-OCT iris images allows for the differentiation between healthy eyes and those with CMVAU and RVU, as well as between both uveitis.

Cytokine Changes in the Aqueous Humor in Rubella-Related Fuchs Heterochromic Iridocyclitis.

This retrospective study is aimed at determining the correlation between cytokine levels and virus status in the aqueous humor of 38 patients with Fuchs heterochromic iridocyclitis (FHI) with/without a viral presence between May 2017 and January 2020. The levels of cytokines were analyzed in the groups with and without virus-related FHI. Among the patients, 50% had rubella virus, 5.26% had cytomegalovirus, and 2.63% had herpes simplex virus infections. The expression of interleukin-6 (IL-6) and IL-8 was significantly higher, and that of basic fibroblast growth factor (bFGF) was significantly lower in the virus-positive group than in the virus-negative group (P = 0.015, P = 0.001, and P = 0.001, respectively). Although there was no significant difference in the mean expression of vascular cell adhesion protein 1 (VCAM-1), IL-10, and vascular endothelial growth factor (VEGF), that of VCAM-1 and IL-10 was higher (M = 1338 and M = 1390, respectively; M = 6.225 and 10.600, respectively) and that of VEGF was lower (M = 134.5 and M = 38.70, respectively) in the virus-positive group than in the virus-negative group. Similar findings were observed for the expressions of IL-6, IL-8, and bFGF in the rubella-positive and rubella-negative groups. Viral presence was highly related to FHI, especially that of the rubella virus. High levels of inflammatory cytokines and low levels of neovascularization-related factors are involved in rubella-related FHI. These study findings could be helpful in the diagnosis and treatment of FHI.

Association between maternal infections during pregnancy and congenital defects in their offspring: a population-based case-control study in Bogota and Cali, Colombia 2001-2018.

Infections are frequent during pregnancy and their teratogenic role is well documented in Toxoplasmosis, other infections, Rubella, Cytomegalovirus, and Herpes simplex (TORCH). However, the in-utero development effects of the rest of the infections that affect pregnant women are unknown. We described a cohort of patients with major Birth Defects (BD) and the exposure to infections during pregnancy from the information of Congenital Defects Surveillance Programs of two Colombian cities (Bogota and Cali) between 2001 and 2018. We evaluated associations between groups of maternal infections and BD among 3096 cases and 7446 controls that were registered. BD presentation was more frequent as isolated (64.3%), polymalformed (23.2%), and syndromic (12.4%). Infections during pregnancy were present in 52.5% of cases and 44.6% of controls. The most common single infection between cases and controls was vaginal infection. The most common polyinfection was vaginal and urinary tract infection. We found an association between BD and vaginal infections with an odds ratio (OR) 1.18 (CI 1.08-1.30), urinary tract infections OR 1.16 (CI 1.05-1.28), gastrointestinal infections OR 2.06 (IC 1.18-3.59), respiratory infections OR 1.56 (IC 1.28-1.9) and viral infections OR 1.88 (IC 1.18-3.0). Knowing the teratogenic effect of infections is important to extend prevention, screening, timely diagnosis, and appropriate treatment to pregnant women.

Granulomatous Dermatitis Associated With Rubella Virus Infection in an Adult With Immunodeficiency.

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.

The period from prodromal fever onset to rash onset in laboratory-confirmed rubella cases: a cross-sectional study.

BACKGROUND: In resource-limited settings, where rubella is endemic, it is difficult to determine which sporadic case should be tested for rubella. The study aimed to provide useful evidence to help screen rubella cases for real-time reverse transcriptase-polymerase chain reaction (RT-PCR) examination for rubella in resource-limited settings. METHOD: Suspected rubella patients identified by a physician and brought to the notice of the Ryugasaki public health center or the Tsuchiura public health center were enrolled from April 2018 through December 2019. The inclusion criterion was a confirmed rubella diagnosis based on laboratory tests. We studied the distribution of the time from the onset of fever until the onset of rash. RESULTS: The study included 86 cases with simultaneous presentation of fever and rash. Twenty-nine cases had confirmed rubella based on the laboratory diagnosis. Among these, the time from the onset of fever until the onset of rash was limited to - 1 day to 2 days. The number of rubella cases was the highest when the onset of rash was on the following day of the onset of fever. Of the 78 patients who underwent the RT-PCR test, 48% tested positive for rubella among those with a time from the onset of fever to the onset of rash between - 1 day and 2 days (22 out of 46, 95% confidence interval 34-62%); no positive results (0 out of 30, 95% confidence interval - 14%) were seen in patients with a time from fever to rash onset ≥3 days. CONCLUSION: The period from the onset of fever to the onset of rash was limited to - 1 day to 2 days among confirmed rubella patients. If the period from onset of fever to the onset of rash was ≥3 days for a patient, the likelihood of rubella was low.

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

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.

Prenatal cytomegalovirus, rubella, and Zika virus infections associated with developmental disabilities: past, present, and future.

Prenatal infections have long been recognized as important, preventable causes of developmental disabilities. The list of pathogens that are recognized to have deleterious effects on fetal brain development continues to grow, most recently with the association between Zika virus (ZIKV) and microcephaly. To answer clinical questions in real time about the impact of a novel infection on developmental disabilities, an historical framework is key. The lessons learned from three historically important pathogens: rubella, cytomegalovirus, and ZIKV, and how these lessons are useful to approach emerging congenital infections are discussed in this review. Congenital infections are preventable causes of developmental disabilities and several public health approaches may be used to prevent prenatal infection. When they cannot be prevented, the sequelae of prenatal infection may be treatable. WHAT THIS PAPER ADDS: The list of prenatal infections associated with developmental disabilities continues to increase. Lessons learned from rubella, cytomegalovirus, and Zika virus have implications for new pathogens. Severity of illness in the mother does not correlate with severity of sequelae in the infant.

Rubella virus-associated chronic inflammation in primary immunodeficiency diseases.

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.

Spatiotemporal proximity of rubella cases to the occurrence of congenital rubella syndrome in Yogyakarta, Indonesia.

INTRODUCTION: Rubella infection during early pregnancy may cause fatal consequences such as congenital rubella syndrome (CRS). The incidence rate (IR) of CRS confirmed cases in Yogyakarta, Indonesia between July 2008 and June 2013 was high at 0.05 per 1,000 live births. This study aimed to discover the spatiotemporal pattern of rubella and CRS and also identify whether the proximity of rubella cases was associated with the occurrence of CRS cases. METHODS: This observational research used a spatiotemporal approach. We obtained CRS and rubella surveillance data from Dr. Sardjito Hospital, Provincial, and District Health Offices in Yogyakarta, Indonesia during January-April 2019. The home addresses of rubella and CRS cases were geocoded using the Global Positioning System. Average of the nearest neighbour and space-time permutation analyses were conducted to discover the spatiotemporal patterns and clusters of rubella and CRS cases. RESULTS: The peak of rubella cases occurred in 2017 (IR: 22.3 per 100,000 population). Twelve confirmed cases of CRS were found in the 2016-2018 period (IR: 0.05 per 1,000 live births). The occurrence of CRS in Yogyakarta was detected 6-8 months after the increase and peak of rubella cases. The spatiotemporal analysis showed that rubella cases were mostly clustered, while CRS cases were distributed in a dispersed pattern. Rubella cases were found within a buffer zone of 2.5 km from any CRS case. CONCLUSIONS: Rubella cases were spatiotemporally associated with the occurrence of CRS in Yogyakarta. We recommend strengthening the surveillance system of CRS and rubella cases in order to contain any further spreading of the disease.