Multiplex Bead Assay for the Serological Surveillance of Measles and Rubella.

There is increasing interest in evaluating antibody responses to multiple antigen targets in a single assay. Immunity to measles and rubella are often evaluated together because immunity is provided through combined vaccines and because routine immunization efforts and surveillance for measles and rubella pathogens are combined in many countries. The multiplex bead assay (MBA) also known as the multiplex immunoassay (MIA) described here combines the measurement of measles- and rubella-specific IgG antibodies in serum quantitatively according to international serum standards and has been successfully utilized in integrated serological surveillance.

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.

Diagnostic accuracy of commercially available serological tests for the detection of measles and rubella viruses: a systematic review and meta-analysis.

Measles and rubella serological diagnoses are done by IgM detection. The World Health Organization Global Measles and Rubella Laboratory Network previously endorsed Siemens Enzygnost enzyme-linked immunosorbant assay kits, which have been discontinued. A recommended replacement has not been determined. We aimed to search for suitable replacements by conducting a systematic review and meta-analysis of IgM detection methods that are currently available for measles and rubella. A systematic literature search was performed in Medline, Embase, Global Health, Cochrane Central, and Scopus on March 22 and on 27 September 2023. Studies reporting measles and/or rubella IgM detection with terms around diagnostic accuracy were included. Risk of bias was assessed using QUADAS tools. Meta-DiSc and R were used for statistical analysis. Clinical samples totalling 5,579 from 28 index tests were included in the measles meta-analysis. Sensitivity and specificity of the individual measles studies ranged from 0.50 to 1.00 and 0.53 to 1.00, respectively. Pooled sensitivity and specificity of all measles IgM detection methods were 0.94 (CI: 0.90-0.97) and 0.94 (CI: 0.91-0.97), respectively. Clinical samples totalling 4,983 from 15 index tests were included in the rubella meta-analysis. Sensitivity and specificity of the individual rubella studies ranged from 0.78 to 1.00 and 0.52 to 1.00, respectively. Pooled sensitivity and specificity of all rubella IgM detection methods were 0.97 (CI: 0.93-0.98) and 0.96 (CI: 0.93-0.98), respectively. Although more studies would be ideal, our results may provide valuable information when selecting IgM detection methods for measles and/or rubella.

The Utility of Maternal TORCH Screening Due to Obstetrical Indications in Detecting Congenital Infections: A Retrospective Observational Study.

BACKGROUND: The diagnostic yield of TORCH screening for obstetrical indications is unclear. We evaluated TORCH testing results among women with intrauterine growth restriction (IUGR), polyhydramnios and oligohydramnios; and associations with congenital infections in neonates. METHOD: This retrospective single-center study included all the women diagnosed with IUGR, polyhydramnios or oligohydramnios who underwent serological TORCH testing during 2010-2019. TORCH screening included Toxoplasma, cytomegalovirus (CMV), rubella IgM and IgG. The data, which were cross-referenced with data of neonates with congenital TORCH infections during the same period, included indications for neonatal testing, sonographic findings and neonatal ophthalmologic and hearing findings. RESULT: Six women of 771 (0.8%) were diagnosed with primary TORCH infection: 4 (0.5%) with toxoplasmosis, and 2 (0.3%) with CMV. None had a confirmed congenital infection. The rates of positive maternal TORCH screening in IUGR and polyhydramnios were 2.1% and 0.6%, respectively. Maternal TORCH infection was not identified in any woman with oligohydramnios or severe polyhydramnios. None of the neonates with congenital infection were screened for TORCH during pregnancy due to polyhydramnios, oligohydramnios or IUGR. Among the neonates with congenital CMV, the most common indication for performing neonatal CMV polymerase chain reaction was suspected primary maternal infection during pregnancy due to symptomatic CMV. No incidences of congenital rubella were noted in the last decade in our medical center. CONCLUSION: Our results suggest that routine TORCH screening in pregnancies complicated with IUGR, polyhydramnios or oligohydramnios should be avoided. Suggestive maternal symptoms and specific fetal sonographic features should prompt testing for CMV and Toxoplasma infection.

Difficulty in Serologic Screening for Subclinical Rubella during Pregnancy.

In Japan, rubella antibodies are tested in all pregnant women to detect subclinical infections. This study aimed to assess the validity of measuring rubella antibodies for detecting subclinical rubella among pregnant women in Japan. This single-center retrospective study measured rubella hemagglutination inhibition (HI) titers and rubella-specific IgM antibody index (IgM) values. IgM values were measured by conducting enzyme immunoassay, and IgM-values >1.2 were considered positive. Of 14,965 included pregnant women, 186 (1.2%) were IgM-positive. Only one patient was clinically diagnosed with rubella (HI titer, 1:2,048; IgM value, 10) and developed fever and skin rash. She decided to terminate her pregnancy without undergoing repeated blood tests. Of the IgM-positive patients, 136 (73.1%) had rubella HI titers of < 1:256. The correlation coefficient between rubella HI and IgM titers was weakly positive (0.2527; P < 0.0001). This study showed that a single combination of rubella HI and rubella-specific IgM measurements alone could not detect subclinical rubella. Creating awareness among pregnant women by informing them that almost all rubella-specific IgM-positive individuals without symptoms are not acutely infected could decrease their anxiety and prevent unnecessary pregnancy termination.

A comparison of measles-rubella-zoster reaction, oligoclonal IgG bands, oligoclonal kappa free light chains and kappa index in multiple sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate the diagnostic performance of the measles-rubella-zoster reaction (MRZR) in a large real-world multiple sclerosis (MS) cohort. Second, to compare MRZR with the determination of oligoclonal IgG bands (OCB), oligoclonal kappa free light chain bands (oKFLC), and the KFLC index. METHODS: A single-center retrospective study was conducted at the University Hospital Ostrava (Czech Republic). Patients were eligible if aged ≥18 years with a determined clinical diagnosis. IgG antibodies against measles (M), rubella (R), and varicella zoster (Z) viruses were determined in paired CSF and serum using ELISA and MRZR indicated as positive if at least two components had an antibody index >1.4. OCB and oKFLC were detected by means of isoelectric focusing, and KFLC CSF and serum concentrations for calculation of the KFLC index were determined immunochemically. RESULTS: A total of 1,751 patients were included in the analyzed data set, which comprised 379 MS patients and 1,372 non-MS controls. The frequency of positive MRZR was higher in MS than in non-MS cases (MS 32.2 % vs non-MS 2.8 %; p < 0.001). This corresponded to a specificity of 97.2 % (95 % CI 96.1-98.0) and sensitivity of 32.2 % (95 % CI 27.5-37.2) and overall accuracy of 83.1 % (95 % CI 81.3-84.8). In comparison, the highest sensitivity of 95.6% (95 % CI 93.0-97.5) was for OCB with specificity of 86.9 % (95 % CI 84.9-88.7), followed by oKFLC with sensitivity and specificity of 94.7 % (95 % CI 91.5-96.9) and 78.4% (95 % CI 75.7-80.8), respectively, and the KFLC index with sensitivity of 92.5 % (95 % CI 86.6-96.3) and specificity of 93.5 % (95 % CI 90.5-95.9). DISCUSSION: MRZR remains a very specific test for the diagnosis of MS but has low sensitivity, which disallows its independent use. In contrast, OCB showed the highest sensitivity and thus remains the gold standard for the diagnosis of MS.

Fundus imaging features of congenital rubella retinopathy.

PURPOSE: To evaluate the clinical characteristics of congenital rubella retinopathy (CRR) with modern fundus imaging. METHODS: Single-center case series. Eleven patients (2005-2020) at the Emory Eye Center with known or presumed CRR. Trained image readers reviewed fundus imaging (color fundus photography, widefield pseudocolor imaging, near-infrared reflectance imaging, autofluorescence imaging, and spectral-domain optical coherence tomography) for pre-specified features suggestive of CRR. RESULTS: Eleven patients with confirmed (63.6%) or presumed (36.3%) CRR were identified. All were female with median (range) age of 53 (35-67) years. Six (54.5%) were born during the 1964-1965 United States rubella epidemic. All had congenital hearing loss. Two (18.2%) had a congenital heart defect. Eleven (50.0%) eyes had salt-and-pepper retinal pigmentary changes. Twenty-two eyes (100.0%) had irregularly distributed regions of speckled hypoautofluorescence. One eye (4.5%) had a presumed macular neovascularization. CONCLUSION: Modern fundus imaging demonstrates characteristic features of CRR, even when pigmentary changes are not readily apparent on examination. Widefield autofluorescence findings of irregularly distributed speckled hypoautofluorescence are particularly revealing. This series of newly diagnosed adults with CRR may represent the milder end of the phenotypic spectrum of this condition, highlighting imaging findings that may aid in diagnostically challenging cases of CRR.

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 uveitis at a tertiary care hospital in Germany between 2013 and 2019.

Uveitis is a process of intraocular inflammation that may involve different sections of the uveal tract. Apart from systemic or localized immune-mediated diseases, infections are key players in the etiology of uveitis and entail different treatment strategies. Rubella virus (RuV) is a recognized causative agent for the development of Fuchs uveitis, representing a major cause of virus-associated intraocular inflammation. A cohort of 159 patients diagnosed with different forms of uveitis between 2013 and 2019 was subjected to diagnostic antibody testing of the aqueous or vitreous humor. The diagnostic panel included RuV, cytomegalovirus, herpes simplex virus, varicella-zoster virus, and toxoplasmosis. Within this cohort, 38 RuV-associated uveitis (RAU) patients were identified based on a pathologic Goldman-Witmer coefficient indicative of an underlying RuV infection. With a mean age of 45.9 years, the RAU patients were younger than the non-RAU patients (56.3, p < 0.001). The evaluation of clinical parameters revealed a predominance of anterior uveitis and late sequalae such as cataract and glaucoma among the RAU patients. In 15 of the patients a history of prior RuV infections could be confirmed. The study underlines the importance of long-term surveillance of RuV associated diseases that originate from infections before the introduction of RuV vaccination programs.

TORCH Infections.

Perinatal and neonatal infections are a significant cause of morbidity and mortality. As such, early recognition and workup when there is clinical concern is essential to supporting affected neonates. This article aims to focus specifically on the effects of toxoplasmosis, rubella, cytomegalovirus, herpes, and other agents (TORCH) infections, discussing epidemiology, diagnostics, and treatment if available. [Pediatr Ann. 2023;52(11):e400-e406.].

Ocular Involvement in Congenital Infections - TORCH. / Augenbeteiligung bei kongenitalen Infektionen ­ TORCH.

This review summarises the ophthalmological findings in congenital infections. Intrauterine infections are an important cause of childhood blindness. The most common infections are grouped under the acronym TORCH, which stands for Toxoplasma gondii, others, rubella, CMV, and herpes simplex. Overall, these infections are not very common in first-world countries during pregnancy, but are of particular importance because of the threat to vision. Diagnosis of infection or reactivation is a gynaecological challenge. However, ophthalmological examination of newborns can be appropriately targeted if the causative agent is known. The most important therapeutic agents used in the newborn are summarised.

Differential diagnosis of fever and rash cases negative for measles and rubella to complement surveillance activities.

In the quest to eliminate measles virus (MV) and rubella virus (Ruv), every suspected case must be properly identified and diagnosed. Since 2017, in Milan (Italy), a total of 978 measles and rubella suspected cases (fever and rash) were investigated and 310 were not laboratory confirmed (discarded cases). To improve surveillance activities, we investigated the presence in discarded cases of 8 other viral pathogens commonly associated with rash: human herpesvirus 6 (HHV-6) and 7 (HHV-7), parvovirus B19 (B19V), enterovirus (EV), Epstein-Barr virus (EBV), human adenovirus (HAdV), cytomegalovirus (HCMV), and SARS-CoV-2. Differential diagnosis was carried out on 289 discarded cases by multiplex real-time PCR assays. At least one pathogen was detected in 188 cases (65.1%) with HHV-7 being the most frequently detected virus. No difference in the number of detected infections overtime was observed and infections were identified in all age groups. As expected, most HHV-6, EV, HAdV, and HCMV-positive cases were found in children aged 0-4 years and HHV-7 was most frequent in the 15-39 age group. In light of the World Health Organization measles elimination goal, the introduction of laboratory methods for differential diagnosis is required for the final classification of clinically compatible cases. The used screening panel allowed us to increase the percentage of virus-positive cases to 87.5%, allowing us to clarify viral involvement and epidemiology, improve diagnosis, and strengthen surveillance activities. As all investigated pathogens were detected, this diagnostic panel was a suitable tool to complement MV and RuV surveillance activities.

Trends in Participation in Rubella Antibody Testing among Working-Aged Men during Annual Health Check-Ups from 2019 to 2022 in Japan.

In 2019, the Japanese government established a scheme for rubella antibody testing of men born between 1962 and 1978 during workplace health check-ups. However, the use of vouchers for rubella antibody testing was limited. Health check-up data analyses are needed to determine the reason why rubella antibody testing is not widely used. In this study, we aimed to describe changes in rubella antibody test-taking behavior during health check-ups during the first 3 years of the rubella catch-up campaign in Japan. In 2019, 2020, and 2021 (2020 in some areas) vouchers were sent to men born during the fiscal years 1972-1978, 1966-1971, and 1962-1965, respectively. We calculated the prevalence in men born between 1962 and 1978 who underwent rubella antibody testing during mandatory health check-ups under the Industrial Health and Safety Act. Rubella antibody testing uptake was relatively high (approximately 15%) in all three age groups soon after the distribution of the vouchers and then declined to below 2% during the second and third years. Further population-based approaches with continuous public engagement are required in workplaces to effectively promote and expand the rubella vaccination program in Japan.

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.

Seroprevalence of high incidence congenital infections among pregnant women in Coatepeque, Guatemala and surrounding areas, 2017-2018.

Maternal infections during pregnancy can potentially cause birth defects and severe adverse effects in infants. From 2017 to 2018, we investigated the seroprevalence of five antibodies among 436 mother-infant pairs enrolled in a pregnancy cohort study in Coatepeque, Guatemala. Upon enrollment (< 20 weeks gestational age) and shortly after delivery, we measured the prevalence of IgG and IgM antibodies against Toxoplasma gondii (T. gondii), rubella, and cytomegalovirus (CMV) in mothers and newborns and used rapid tests to detect HIV and syphilis (Treponema pallidum) in mothers. The mean cohort age was 24.5 years. Maternal T. gondii IgM and IgG seropositivity was 1.9% and 69.7%, respectively. No women were positive for HIV, syphilis, or rubella IgM. Maternal rubella IgG seropositivity was 80.8% and significantly increased with age. Maternal CMV IgM and IgG seropositivity were 2.3% and 99.5%, respectively. Of the 323 women tested at both timepoints, IgM reactivation occurred in one woman for T. gondii infection and in eight for CMV. No newborn was seropositive for CMV IgM or rubella IgM. One newborn was seropositive for T. gondii IgM. Congenital T. gondii and CMV infections are important public health issues for pregnant women, newborns, and healthcare providers in Coatepeque and Guatemala.

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.

Shedding of rubella virus in postsymptomatic individuals; viral RNA load is a potential indicator to estimate candidate patients excreting infectious rubella virus.

BACKGROUND: Since the first isolation of rubella virus (RuV) in 1962, comprehensive data regarding the quantitative evaluation of RuV shedding remain unavailable. In this study, we evaluated the shedding of viral RNA and infectious virus in patients with acute RuV infection. STUDY DESIGN: We analyzed 767 specimens, including serum/plasma, peripheral blood mononuclear cells (PBMCs), throat swabs, and urine, obtained from 251 patients with rubella. The viral RNA load and the presence of infectious RuV were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and virus isolation. RESULTS: Virus excretion peaked 0-2 days after rash onset and decreased over time. The median viral RNA load dropped to an undetectable level on day 3 after rash onset in serum/plasma, day 2 in PBMCs, days 10-13 in throat swabs, and days 6-7 in urine. Infectious virus could be isolated for up to day 2 after rash onset in serum/plasma, day 1 in PBMCs, days 8-9 in throat swabs, and days 4-5 in urine. The minimum viral RNA load that allowed virus isolation was 961 copies/mL in serum/plasma, 784 copies/mL in PBMCs, 650 copies/mL in throat swabs, and 304 copies/mL in urine. A higher viral RNA load indicated a higher likelihood of the presence of infectious virus. CONCLUSION: These findings would contribute to improve algorithms for rubella surveillance and diagnosis. In addition, this study indicates that the results of RT-qPCR enable efficient rubella control by estimating candidate patients excreting infectious virus, which could help prevent viral transmission at an early stage and eliminate rubella ultimately.

Congenital Rubella syndrome: A short report and literature review.

Rubella infections are rarely seen where immunization programmes are in place. Congenital rubella syndrome is however still observed where the vaccination programme against rubella is not administered or interrupted. We present such a case, with typical clinical anomalies including congenital cataracts, sensorineural hearing loss and bone lesions. The diagnosis was verified by detection of rubella immunoglobulin M positivity in the mother in the first trimester and positive rubella serology in both baby and mother.