Etiological analysis of discarded measles in the context of a measles outbreak among a highly immunized population.

BACKGROUND: Measles can lead to serious complications and remains an important cause of morbidity and mortality worldwide. In this study we aimed to assess the etiological diagnosis of discarded measles cases in the context of an outbreak among a highly immunized population. METHODS: We conducted a retrospective observational study of discarded measles cases from an outbreak that occurred from October 2006 to July 2007 in Catalonia. A confirmed case was defined as having a positive measles serum IgM result and/or a positive result by RT-PCR in urine and/or nasopharyngeal swab; or an epidemiological link to a confirmed case. Serum specimens were tested by a commercially available indirect-format and by an in-house capture-format measles IgM enzyme immunoassays. RESULTS: Testing of 89 samples discarded for measles determined the etiologies for 10 (11.2%), including one rubella, three human herpes virus 6, and six measles infections. Of 381 confirmed cases in the outbreak, 10% had received at least one dose of the measles-mumps-rubella vaccine versus 54% of the discarded for measles (OR: 0.09; 95% CI: 0.06, 0.14; p < 0.001). CONCLUSIONS: Highly sensitive surveillance systems are critical to identifying cases, responding to outbreaks and verifying progress towards measles elimination. Molecular tools for measles detection and differential diagnosis, and collection of appropriate specimens for molecular and serological testing are essential to correctly diagnose suspected measles infection.

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

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.

Descriptive epidemiology of rubella disease and associated virus strains in Uganda.

Rubella virus causes a mild disease; however, infection during the first trimester of pregnancy may lead to congenital rubella syndrome (CRS) in over 80% of affected pregnancies. Vaccination is recommended and has been shown to effectively reduce CRS incidence. Uganda plans to introduce routine rubella vaccination in 2019. The World Health Organization recommends assessing the disease burden and obtaining the baseline molecular virological data before vaccine introduction. Sera collected during case-based measles surveillance from January 2005 to July 2018 were tested for rubella immunoglobulin M (IgM) antibodies. Sera from confirmed rubella outbreaks from January 2012 to August 2017 were screened using real-time reverse-transcription polymerase chain reaction (RT-PCR); for positive samples, a region within the E1 glycoprotein coding region was amplified and sequenced. Of the 23 196 suspected measles cases serologically tested in parallel for measles and rubella, 5334 (23%) were rubella IgM-positive of which 2710 (50.8%) cases were females with 2609 (96.3%) below 15 years of age. Rubella IgM-positive cases were distributed throughout the country and the highest number was detected in April, August, and November. Eighteen (18%) of the 100 sera screened were real-time RT-PCR-positive of which eight (44.4%) were successfully sequenced and genotypes 1G and 2B were identified. This study reports on the seroprevalence and molecular epidemiology of rubella. Increased knowledge of former and current rubella viruses circulating in Uganda will enhance efforts to monitor the impact of vaccination as Uganda moves toward control and elimination of rubella and CRS.

Use of FTA Cards To Transport Throat Swabs and Oral Fluid Samples for Molecular Detection and Genotyping of Measles and Rubella Viruses.

The genetic characterization of measles viruses is an important tool for measles surveillance. Reverse cold chain requirements for the transportation of samples to reference laboratories are challenging in resource-limited settings. FTA cards facilitate the transport of virologic samples at ambient temperature as noninfectious material; however, the utility of FTA cards for the detection and genotyping of measles virus from clinical samples has not been evaluated. Throat swabs (TS) and oral fluid (OF) samples were collected from suspected measles cases in the Democratic Republic of the Congo. Virus detection (reverse transcription-quantitative real-time PCR [RT-qPCR]) and genotyping (endpoint RT-PCR) were compared for samples from 238 suspected cases; these samples were either transported using the reverse cold chain or at ambient temperature on FTA cards. Virus detection showed excellent positive agreement for OF samples compared to TS (95.3%; confidence interval [CI], 91.6 to 97.4), in contrast to 79.4% (CI, 73.5 to 84.3) for TS on FTA, and 85.5% (CI, 80.2 to 89.6) for OF on FTA compared to OF samples. Genotyping results obtained for a subset of samples indicated that 77.3% of all TS and 71.0% of OF samples would produce genotype information compared to 41.6% of TS and 41.3% of OF on FTA cards. Similar results were found for 16 measles-negative samples that were confirmed as rubella cases. Measles genotype B3 and rubella genotype 2B were detected. FTA cards have limited utility for virologic surveillance of sporadic cases of measles; however, they can be a useful tool for the expansion of virologic surveillance in countries where the reverse cold chain is not available.

First report of the genomic characterization of rubella viruses circulating in Cameroon.

Rubella is an acute and contagious viral infection whose gravidity resides in infection during pregnancy, which can result in miscarriage, fetal death, stillbirth, or infants with congenital malformations. This study aimed to describe the genome of rubella viruses (RUBVs) circulating in Cameroon. Throat swabs were collected from health districts as part of the measles surveillance program from 2010 to 2016 and sent to the Centre Pasteur of Cameroon. Samples were amplified by genotyping reverse transcription polymerase chain reaction (RT-PCR) in the search of two overlapping fragments of the gene that encodes the E1 envelope glycoprotein of RUBV. PCR products were sequenced and phylogenetic analysis was performed with MEGA 6 software. Overall, 9 of 43 samples (20.93%) were successfully amplified and sequenced but only eight sequences could be exploited for phylogenetic analysis with respect to the required fragment length of 739 nucleotides. Analysis of viral sequences from Cameroon with other epidemiologically relevant sequences from around the world showed that all RUBVs belonged to lineage L1 of genotype 1G. Cameroon sequences clustered with viruses from West Africa including Nigeria, Ivory Coast, and Ghana with a percentage similarity of 95.4% to 99.2%. This study will enable an update on the molecular epidemiology of RUBV in Cameroon and help in monitoring circulating RUBV for a better implementation of elimination strategies.

Genetic Characterization of Measles and Rubella Viruses Detected Through Global Measles and Rubella Elimination Surveillance, 2016-2018.

All six World Health Organization (WHO) regions have established measles elimination goals, and three regions have a rubella elimination goal. Each region has established a regional verification commission to monitor progress toward measles elimination, rubella elimination, or both, and to provide verification of elimination* (1,2). To verify elimination, high-quality case-based surveillance is essential, including laboratory confirmation of suspected cases and genotyping of viruses from confirmed cases to track transmission pathways. In 2000, WHO established the Global Measles and Rubella Laboratory Network (GMRLN) to provide high-quality laboratory support for surveillance for measles, rubella, and congenital rubella syndrome (3). GMRLN is the largest globally coordinated laboratory network, with 704 laboratories supporting surveillance in 191 countries (4). This report updates a previous report and describes the genetic characterization of measles and rubella viruses during 2016-2018 (5). The genetic diversity of measles viruses (MeVs) and rubella viruses (RuVs) has decreased globally following implementation of measles and rubella elimination strategies. Among 10,857 MeV sequences reported to the global Measles Nucleotide Surveillance (MeaNS) database during 2016-2018, the number of MeV genotypes detected in ongoing transmission decreased from six in 2016 to four in 2018. Among the 1,296 RuV sequences submitted to the global Rubella Nucleotide Surveillance (RubeNS) database during the same period, the number of RuV genotypes detected decreased from five in 2016 to two in 2018. To strengthen laboratory surveillance for measles and rubella elimination, specimens should be collected from all confirmed cases for genotyping, and sequences from all wild-type measles and rubella viruses should be submitted to MeaNS and RubeNS in a timely manner.

Epidemiology of rubella infection and genotyping of rubella virus in Cote d'Ivoire, 2012-2016.

Rubella is a contagious disease caused by the rubella virus (RuV) that can lead to serious birth defects when women are infected in early pregnancy. This study aimed to describe the epidemiology and genetic diversity of rubella viruses in Cote d'Ivoire (CIV). Blood or oral fluid samples collected from suspected measles cases were first tested for the presence of measles specific IgM antibodies by enzyme-linked immunosorbent assay (ELISA). All measles IgM negative or indeterminate samples were tested for rubella IgM antibody using ELISA. Rubella-IgM-positive samples were tested by real-time reverse transcription polymerase chain reaction (RT-PCR) for the presence of rubella virus RNA. Real-time RT-PCR-positive RNA samples were used as template to amplify the 739 nt region used for rubella genotyping. PCR-positive samples were sequenced and phylogenetic analysis performed. Between 2012 and 2016, 4121 serums and 126 oral fluids were collected through the measles surveillance system. Of these, 3823 and 108 respectively were measles IgM negative or indeterminate. Subsequent testing for rubella found that 690 of 3823 (18%) serum samples and 25 of 108 (23%) oral fluid samples were rubella IgM-positive. The 739 nt segment of the E1 glycoprotein gene was amplified and sequenced for two serums and seven oral fluids samples. Phylogenetic analysis showed that the rubella viruses from CIV belonged to genotypes 1G (eight samples) and 2B (one sample). Rubella virus genotype 2B was found in CIV for the first time. These data contribute to baseline information on rubella virus strains found in CIV before the introduction of rubella vaccine.

Genotypes of rubella virus and the epidemiology of rubella infections in the Democratic Republic of the Congo, 2004-2013.

Rubella is a viral infection that may cause fetal death or congenital defects, known as congenital rubella syndrome (CRS), during early pregnancy. The World Health Organization (WHO) recommends that countries assess the burden of rubella and CRS, including the determination of genotypes of circulating viruses. The goal of this study was to identify the genotypes of rubella viruses in the Democratic Republic of the Congo (DRC). Serum or throat swab samples were collected through the measles surveillance system. Sera that tested negative for measles IgM antibody were tested for rubella IgM antibody. Serum collected within 4 days of rash onset and throat swabs were screened by real-time RT-PCR for rubella virus RNA. For positive samples, an amplicon of the E1 glycoprotein gene was amplified by RT-PCR and sequenced. 11733 sera were tested for rubella IgM and 2816 (24%) were positive; 145 (5%) were tested for the presence of rubella RNA by real-time RT-PCR and 10 (7%) were positive. Seventeen throat swabs were analyzed by RT-PCR and three were positive. Sequences were obtained from eight of the positive samples. Phylogenetic analysis showed that the DRC rubella viruses belonged to genotypes 1B, 1E, 1G, and 2B. This report provides the first information on the genotypes of rubella virus circulating in the DRC. These data contribute to a better understanding of rubella burden and the dynamics of rubella virus circulation in Africa. Efforts to establish rubella surveillance in the DRC are needed to support rubella elimination in Africa. J. Med. Virol. 88:1677-1684, 2016. © 2016 Wiley Periodicals, Inc.

Epidemiological and molecular investigation of a rubella outbreak, Romania, 2011 to 2012.

We describe a rubella outbreak that occurred in Romania between September 2011 and December 2012. During this period 24,627 rubella cases, 41.1% (n=10,134) of which female, were notified based on clinical criteria, and a total of 6,182 individuals were found serologically positive for IgM-specific rubella antibody. The median age of notified cases was 18 years (range: <1-65) and the most affected age group 15 to 19 years (n=16,245 cases). Of all notified cases, 24,067 cases (97.7%) reported no history of vaccination. Phylogenetic analysis of 19 sequences (739 nucleotides each), from 10 districts of the country revealed that the outbreak was caused by two distinct rubella virus strains of genotype 2B, which co-circulated with both temporal and geographical overlap. In addition to the 6,182 IgM-positive rubella cases, 28 cases of congenital rubella syndrome (CRS) were identified, including 11 neonatal deaths and one stillbirth. The outbreak underscores the need to encourage higher vaccination uptake in the population, particularly in women of reproductive age, and to strengthen epidemiological and laboratory investigations of suspected rubella cases. Genetic characterisation of wild-type rubella virus is an essential component to enhance surveillance and here we report rubella virus sequences from Romania.

Congenital rubella syndrome in child of woman without known risk factors, New Jersey, USA.

We report a case of congenital rubella syndrome in a child born to a vaccinated New Jersey woman who had not traveled internationally. Although rubella and congenital rubella syndrome have been eliminated from the United States, clinicians should remain vigilant and immediately notify public health authorities when either is suspected.

Genomic analysis of the Chinese genotype 1F rubella virus that disappeared after 2002 in China.

Genotype 1F was likely localized geographically to China as it has not been reported elsewhere. In this study, whole genome sequences of two rubella 1F virus isolates were completed. Both viruses contained 9,761 nt with a single nucleotide deletion in the intergenic region, compared to the NCBI rubella reference sequence (NC 001545). No evidence of recombination was found between 1F and other rubella viruses. The genetic distance between 1F viruses and 10 other rubella virus genotypes (1a, 1B, 1C, 1D, 1E, 1G, 1J 2A, 2B, and 2C) ranged from 3.9% to 8.6% by pairwise comparison. A region known to be hypervariable in other rubella genotypes was also the most variable region in the 1F genomes. Comparisons to all available rubella virus sequences from GenBank identified 22 nucleotide variations exclusively in 1F viruses. Among these unique variations, C9306U is located within the recommended molecular window for rubella virus genotyping assignment, could be useful to confirm 1F viruses. Using the Bayesian Markov Chain Monte Carlo (MCMC) method, the time of the most recent common ancestor for the genotype 1F was estimated between 1976 and 1995. Recent rubella molecular surveillance suggests that this indigenous strain may have circulated for less than three decades, as it has not been detected since 2002.

Phylogenetic analysis of rubella viruses identified in Uganda, 2003-2012.

Molecular data on rubella viruses are limited in Uganda despite the importance of congenital rubella syndrome (CRS). Routine rubella vaccination, while not administered currently in Uganda, is expected to begin by 2015. The World Health Organization recommends that countries without rubella vaccination programs assess the burden of rubella and CRS before starting a routine vaccination program. Uganda is already involved in integrated case-based surveillance, including laboratory testing to confirm measles and rubella, but molecular epidemiologic aspects of rubella circulation have so far not been documented in Uganda. Twenty throat swab or oral fluid samples collected from 12 districts during routine rash and fever surveillance between 2003 and 2012 were identified as rubella virus RNA positive and PCR products encompassing the region used for genotyping were sequenced. Phylogenetic analysis of the 20 sequences identified 19 genotype 1G viruses and 1 genotype 1E virus. Genotype-specific trees showed that the Uganda viruses belonged to specific clusters for both genotypes 1G and 1E and grouped with similar sequences from neighboring countries. Genotype 1G was predominant in Uganda. More epidemiological and molecular epidemiological data are required to determine if genotype 1E is also endemic in Uganda. The information obtained in this study will assist the immunization program in monitoring changes in circulating genotypes.

Analysis of whole genome sequences of 16 strains of rubella virus from the United States, 1961-2009.

Rubella virus is the causative agent of rubella, a mild rash illness, and a potent teratogenic agent when contracted by a pregnant woman. Global rubella control programs target the reduction and elimination of congenital rubella syndrome. Phylogenetic analysis of partial sequences of rubella viruses has contributed to virus surveillance efforts and played an important role in demonstrating that indigenous rubella viruses have been eliminated in the United States. Sixteen wild-type rubella viruses were chosen for whole genome sequencing. All 16 viruses were collected in the United States from 1961 to 2009 and are from 8 of the 13 known rubella genotypes. Phylogenetic analysis of 30 whole genome sequences produced a maximum likelihood tree giving high bootstrap values for all genotypes except provisional genotype 1a. Comparison of the 16 new complete sequences and 14 previously sequenced wild-type viruses found regions with clusters of variable amino acids. The 5' 250 nucleotides of the genome are more conserved than any other part of the genome. Genotype specific deletions in the untranslated region between the non-structural and structural open reading frames were observed for genotypes 2B and genotype 1G. No evidence was seen for recombination events among the 30 viruses. The analysis presented here is consistent with previous reports on the genetic characterization of rubella virus genomes. Conserved and variable regions were identified and additional evidence for genotype specific nucleotide deletions in the intergenic region was found. Phylogenetic analysis confirmed genotype groupings originally based on structural protein coding region sequences, which provides support for the WHO nomenclature for genetic characterization of wild-type rubella viruses.

Evidence used to support the achievement and maintenance of elimination of rubella and congenital rubella syndrome in the United States.

On 29 October 2004, an expert panel was convened to review the status of elimination of rubella and congenital rubella syndrome (CRS) in the United States. Primarily based on 5 types of information presented--epidemiology of reported cases, molecular epidemiology, seroprevalence, vaccine coverage, and adequacy of surveillance--the panel unanimously agreed that rubella virus is no longer endemic in the United States. Since 2004, new data continue to support the conclusion that elimination has been achieved and maintained. In documenting elimination in the United States, each of the 5 types of data provided evidence for elimination and collectively provided much stronger evidence than any one type could individually. As countries document the elimination of rubella and CRS, many sources and types of data will likely be necessary. Rigorous data evaluation must be conducted to look for inconsistencies among the available data. To maintain elimination, countries should maintain high vaccine coverage, adequate surveillance, and rapid response to outbreaks.

Virologic surveillance for wild-type rubella viruses in the Americas.

The goal of eliminating rubella from the Americas by 2010 was established in 2003. Subsequently, a systematic nomenclature for wild-type rubella viruses (wtRVs) was established, wtRVs circulating in the region were catalogued, and importations of wtRVs into a number of countries were documented. The geographic distribution of wtRVs of various genotypes in the Americas, interpreted in the context of the global distribution of these viruses, contributed to the documentation of rubella elimination from some countries. Data from virologic surveillance also contributed to the conclusion that viruses of genotype 2B began circulating endemically in the Americas during 2006-2007. Viruses of one genotype (1C), which are restricted to the Americas, will likely disappear completely from the world as they are eliminated from the Americas. Efforts to expand virologic surveillance for wtRVs in the Americas will also provide additional data aiding the elimination of rubella from the region. For example, identification of vaccine virus in specimens from rash and fever cases found during elimination can identify such cases as vaccine associated.

Status of global virologic surveillance for rubella viruses.

The suspected measles case definition captures rubella cases. Therefore, measles surveillance will be improved in the course of the control and eventual elimination of rubella transmission. One aspect of rubella control, virologic surveillance, is reviewed here. A systematic nomenclature for rubella viruses (RVs) based on 13 genotypes has been established and is updated when warranted by increases in information about RVs. From 2005 through 2010, the genotypes of RVs most frequently reported were 1E, 1G, and 2B, and genotypes 1a, 1B, 1C, 1h, 1j, and 2C were less frequently reported. Virologic surveillance can support rubella control and elimination. Synopses of rubella virologic surveillance in various countries, regions, and globally are given, including characterization of viruses from imported cases in a country that has eliminated rubella and studies of endemic viruses circulating in countries without rubella control objectives. Current challenges are discussed.

Improved diagnostic and multiplex RT-qPCR for detecting rubella viral RNA.

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.

Exogenous Rubella Virus Capsid Proteins Enhance Virus Genome Replication.

Enhanced replication of rubella virus (RuV) and replicons by de novo synthesized viral structural proteins has been previously described. Such enhancement can occur by viral capsid proteins (CP) alone in trans. It is not clear whether the CP in the virus particles, i.e., the exogenous CP, modulate viral genome replication. In this study, we found that exogenous RuV CP also enhanced viral genome replication, either when used to package replicons or when mixed with RNA during transfection. We demonstrated that CP does not affect the translation efficiency from genomic (gRNA) or subgenomic RNA (sgRNA), the intracellular distribution of the non-structural proteins (NSP), or sgRNA synthesis. Significantly active RNA replication was observed in transfections supplemented with recombinant CP (rCP), which was supported by accumulated genomic negative-strand RNA. rCP was found to restore replication of a few mutants in NSP but failed to fully restore replicons known to have defects in the positive-strand RNA synthesis. By monitoring the amount of RuV RNA following transfection, we found that all RuV replicon RNAs were well-retained in the presence of rCP within 24 h of post-transfection, compared to non-RuV RNA. These results suggest that the exogenous RuV CP increases efficiency of early viral genome replication by modulating the stage(s) prior to and/or at the initiation of negative-strand RNA synthesis, possibly through a general mechanism such as protecting viral RNA.

Association of Persistent Rubella Virus With Idiopathic Skin Granulomas in Clinically Immunocompetent Adults.

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.

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.