Congenital Rubella Syndrome Patients Research Articles

Characteristics of Hearing Impairment in Patients with Suspected Congenital Rubella Syndrome at the ENT Clinic of Prof. Dr. I.G.N.G Ngoerah Hospital Denpasar, Indonesia

Asymptomatic rubella virus infection can cause delays in the diagnosis of rubella in pregnant women, leading to the development of congenital rubella syndrome (CRS). The clinical manifestations of congenital rubella syndrome are called the rubella triad, which includes heart problems, eye problems, and hearing disorders. Sensorineural hearing loss is the most common type of hearing loss in children with rubella infection. This study aimed to determine the characteristics of hearing loss in CRS patients. This study used a retrospective descriptive research design, utilizing secondary data from the medical records of patients with CRS who underwent hearing examinations at the Ear, Nose, Throat (ENT) Polyclinic of Prof. dr. I.G.N.G. Ngoerah Hospital Denpasar, Indonesia. The study found that the most common age group among suspected CRS patients was 6 - 12 months (51.42%), the majority of these patients were male (62.86%), the most frequent clinical signs and symptoms in suspected CRS patients were congenital heart disease (CHD) as a major criterion (60%), and microcephaly as a minor criterion (77.14%). Based on the CRS case criteria, none of the suspected CRS patients were diagnosed with confirmed CRS, with most cases being classified as clinical CRS (65.71%). The hearing loss in suspected CRS patients was entirely sensorineural type with the majority of cases being bilaterally and to a very severe degree (53.57%)

Congenital rubella syndrome surveillance in India, 2016–21: Analysis of five years surveillance data

BackgroundIn India, facility-based surveillance for congenital rubella syndrome (CRS) was initiated in 2016 to estimate the burden and monitor the progress made in rubella control. We analyzed the surveillance data for 2016–2021 from 14 sentinel sites to describe the epidemiology of CRS. MethodWe analyzed the surveillance data to describe the distribution of suspected and laboratory confirmed CRS patients by time, place and person characteristics. We compared clinical signs of laboratory confirmed CRS and discarded case-patients to find independent predictors of CRS using logistic regression analysis and developed a risk prediction model. ResultsDuring 2016–21, surveillance sites enrolled 3940 suspected CRS case-patients (Age 3.5 months, SD: 3.5). About one-fifth (n = 813, 20.6%) were enrolled during newborn examination. Of the suspected CRS patients, 493 (12.5%) had laboratory evidence of rubella infection. The proportion of laboratory confirmed CRS cases declined from 26% in 2017 to 8.7% in 2021. Laboratory confirmed patients had higher odds of having hearing impairment (Odds ratio [OR] = 9.5, 95% confidence interval [CI]: 5.6–16.2), cataract (OR = 7.8, 95% CI: 5.4–11.2), pigmentary retinopathy (OR = 6.7, 95 CI: 3.3–13.6), structural heart defect with hearing impairment (OR = 3.8, 95% CI: 1.2–12.2) and glaucoma (OR = 3.1, 95% CI: 1.2–8.1). Nomogram, along with a web version, was developed. ConclusionsRubella continues to be a significant public health issue in India. The declining trend of test positivity among suspected CRS case-patients needs to be monitored through continued surveillance in these sentinel sites.

Cochlear implants evaluation for congenital rubella syndrome patients in Dr. Soetomo Academic Medical Center

Congenital rubella syndrome (CRS) is an infection caused by rubella virus that transmitted to the fetus during pregnancy which can cause congenital hearing loss. Cochlear implant is an effective therapy in children with severe to profound bilateral hearing loss. Categories of Auditory Performance (CAP) method is a receptive scale assessment of auditory stimulation that can be applied to all children regardless of age, before and after cochlear implant. Evaluating the results of cochlear implants using CAP-II in patients with CRS. A retrospective descriptive study were conducted to samples taken from medical records of CRS patients who had cochlear implants in 2011-2018 at ORL-HNS department of Dr. Soetomo Academic Medical Center. Evaluation of CAP-II results was performed 6 months, 12 months and 24 months after cochlear implant. Eleven CRS patient who underwent cochlear implant during 2011-2018. Six months after cochlear implant showed the highest scale was 6. At 12-months evaluation showed the highest scale was 7, while at 24-months evaluation showed the highest scale was 8. Cochlear implants provide good auditory performance based on CAP-II scale in sensorineural hearing loss of CRS patients.

Parenchymal calcification is associated with the neurological prognosis in patients with congenital rubella syndrome.

Congenital rubella syndrome (CRS) results from maternal rubella virus infection in early pregnancy. Abnormal neuroimaging findings have been analyzed in a small number of CRS patients in the past; however, their clinical significance has been poorly addressed. Therefore, we have investigated the neuroimaging findings of 31 patients with CRS from previous studies. The most common finding was parenchymal calcification, which was observed in 18 of 31 patients (58.1%). A multivariable logistic regression model showed that it was associated with psychomotor or mental retardation (p=0.018), suggesting that parenchymal calcification in CRS could be a prognostic factor.

Congenital Cytomegalovirus Infection Initially Managed as Congenital Rubella Syndrome

Congenital cytomegalovirus (CMV) infection (cCMV) is challenging to differentiate from congenital rubella syndrome (CRS) clinically. Virus detection and serological tests are needed. However, they are often not readily available or are expensive. This is a case of a five-month-old male with bilateral cataracts. He was jaundiced at birth and started having seizure episodes at one month of age. He was also diagnosed with right inguinal hernia and had abnormal bilateral hearing tests. Both eyes were noted to have leukocoria at two months of age. There was dazzle on both eyes and sclerae were anicteric. Examination revealed dense cataracts on both eyes, but their ocular ultrasound results were essentially normal. Due to the bilateral hearing loss and bilateral cataracts, CRS was initially considered despite the absence of heart abnormality since there were reported CRS cases without the complete triad. However, possible coinfection or another disease was considered due to the presence of jaundice, seizures, and hernia, which were never seen in our previous CRS patients nor were reported in the literature. The patient underwent cataract extraction on both eyes without intraocular lens implantation (IOL) as recommended for CRS cataracts to prevent severe inflammation. TORCH (TOxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex) test was negative for rubella but positive for CMV. As such, the patient would have benefitted from early IOL implantation. The patient was then referred to a national medical center for possible treatment. However, since the patient already tested negative for CMV polymerase chain reaction (PCR) there, systemic antiviral therapy was no longer initiated. This case presented the challenge of clinically differentiating cCMV and CRS.

Congenital Rubella Syndrome profile of audiology outpatient clinic in Surabaya, Indonesia.

Congenital Rubella Syndrome (CRS) consists of hearing impairment, ophthalmology abnormalities, and congenital heart disease in children, resulting from rubella infection during pregnancy. Rubella vaccine has been implemented as national immunization program in Indonesia since 2017, and needed to be evaluated. This study aimed to report the CRS patients’ profile of Audiology Outpatient Clinic in Surabaya. A descriptive study from patient’s medical record was conducted in Dr. Soetomo Hospital Surabaya from January 2016 to December 2017. CRS was categorized using World Health Organization classification. Suspected infants with CRS burden were assessed by Otoacoustic Emission and rubella antibody test. Ninety five infants suspected with CRS classified as laboratory- confirmed CRS (58.95%), clinically confirmed CRS (15.79%), and discarded CRS (25.26%). Clinical manifestations included combination of congenital heart disease and hearing impairment (17.89%), congenital heart disease, ophthalmology abnormalities, and hearing impairment (16.84%), and hearing impairment and ophthalmology abnormalities (13.68%). The data show a high burden of CRS in Surabaya. These implies the urgent need for national rubella immunization program.

Polymerase Chain Reaction and Serology Test to Detect Rubella Virus in Congenital Rubella Syndrome Patients with Hearing Loss

Rubella infections in pregnant women, especially during the first trimester, often lead to manifest as congenital rubella syndrome (CRS). This syndrome consists of several inherited disorders such as deafness, cataracts, and cardiac abnormalities. Deafness is the most common manifestation of CRS, 70-90% of all cases with deafness type are sensory neural deafness. The mechanism of hearing loss due to rubella virus is caused by hypoxia resulting from endothelial vascular damage in cochlea, followed by cell death in the organ of Corti and stria vascularis.Cochlea’s stria damage makes alterations in the composition of endolymph. This study aimed to confirm rubella infection using PCR and serological tests in patients with CRS who were clinically deaf. A suspected CRS reported was a 2-month-old patient with an unclear response to surround sound. The patient had been already diagnosed with congenital cataracts before. Prenatal, perinatal and postnatal history was evaluated. Hearing screening was done by OAE (Biological), and AABR (Beraphone). Anti-rubella IgM and IgG was obtained from blood serum. PCR was carried out from a throat swab and the eye-lens specimen. OAE and AABR results ‘refer’ to both sides of the ear indicated a sensorineural hearing loss. The serological examination of IgM was positive with an index of 15.00 and IgG rubella positive with a titer> 500 IU / ml. Positive results from the rubella virus were identified from the throat swab and lens specimens using the PCR method. Detection of rubella virus in CRS sufferers with clinical deafness of both ears gives positive results using PCR and serology methods. In the future PCR can be potential for prenatal diagnosis of rubella virus aimed at the provision of early prevention.

Epidemiology of Congenital Rubella Syndrome (CRS) in India, 2016-18, based on data from sentinel surveillance.

BackgroundGovernment of India is committed to eliminate measles and control rubella/congenital rubella syndrome (CRS) by 2020. In 2016, CRS surveillance was established in five sentinel sites. We analyzed surveillance data to describe the epidemiology of CRS in India.Methodology/Principal findingsWe used case definitions adapted from the WHO-recommended standards for CRS surveillance. Suspected patients underwent complete clinical examination including cardiovascular system, ophthalmic examination and assessment for hearing impairment. Sera were tested for presence of IgM and IgG antibodies against rubella. Of the 645 suspected CRS patients enrolled during two years, 137 (21.2%) were classified as laboratory confirmed CRS and 8 (1.2%) as congenital rubella infection. The median age of laboratory confirmed CRS infants was 3 months. Common clinical features among laboratory confirmed CRS patients included structural heart defects in 108 (78.8%), one or more eye signs (cataract, glaucoma, pigmentary retinopathy) in 82 (59.9%) and hearing impairment in 51. (38.6%) Thirty-three (24.1%) laboratory confirmed CRS patients died over a period of 2 years. Surveillance met the quality indicators in terms of adequacy of investigation, adequacy of sample collection for serological diagnosis as well as virological confirmation.Conclusions/SignificanceAbout one fifth suspected CRS patients were laboratory confirmed, indicating significance of rubella as a persistent public health problem in India. Continued surveillance will generate data to monitor the progress made by the rubella control program in the country.

Clinical profile of congenital rubella syndrome in Yogyakarta, Indonesia.

Congenital rubella syndrome (CRS) has many severe neurological manifestations and other systemic consequences. Although various studies have been done in Indonesia, there are no conclusive results on CRS incidence. The aim of this study was therefore to investigate the incidence, clinical manifestations and outcomes of CRS in Yogyakarta, Indonesia. A descriptive study involving a review of congenital anomalies associated with CRS was carried out at Dr Sardjito Hospital, Yogyakarta, Indonesia, from July 2008 to June 2013. CRS was categorized according to the World Health Organization (WHO) classification. This study involved children aged <1year old, and was conducted at the outpatient clinic, pediatric and neonatology wards. A total of 201 children met the criteria for suspected CRS during the 5year study. Of those patients, 6% were classified as having laboratory-confirmed CRS, 21.4% as having clinically compatible CRS, and 72.6% as having discarded CRS (i.e. a suspected case that does not meet the criteria for CRS). The estimated incidence of laboratory-confirmed CRS and laboratory-confirmed and clinically compatible CRS in Yogyakarta, Indonesia during the study period was 0.05:1,000 and 0.25:1,000 live births, respectively. Of the laboratory-confirmed CRS patients, 83.3% of children had congenital heart disease (CHD), 75% had hearing impairment, 66.7% had congenital cataract and 50% had microcephaly. Furthermore, none of the mothers was vaccinated against rubella. The incidence of CRS in infants in Yogyakarta Indonesia is considered high, with most clinical manifestations being CHD, hearing impairment and congenital cataract. This emphasizes the necessity for epidemiological study of CRS in other hospitals and the importance of establishing a national rubella vaccination program in Indonesia.

Lacrimal drainage anomalies in congenital rubella syndrome.

PurposeThe objective of this study was to ascertain the lacrimal drainage anomalies in a cohort of patients suffering from congenital rubella syndrome (CRS).MethodsThis was a retrospective case series performed in patients with CRS presenting with associated lacrimal drainage anomalies (LDA) over 6 years from 2011 to 2016. All the patients were confirmed as having CRS after clinical and laboratory testing. Data collected include demographics; associated lacrimal, ocular, and systemic anomalies; interventions performed for lacrimal anomalies; and their anatomical and functional outcomes.ResultsEighty five patients were diagnosed as having CRS during the study period, and of these 23 eyes of 12 patients with associated LDA were included in the study. The prevalence of LDA was 14% in CRS. The mean age at presentation was 15.5 weeks, and all except one had bilateral presentation. Seventeen eyes were diagnosed with simple congenital nasolacrimal duct obstruction (CNLDO) and the remaining six eyes had complex CNLDO with buried probes. Additional lacrimal anomalies noted in the six complex CNLDO cases included punctal agenesis (n=3), atonic sac (n=3), incomplete punctal canalization (n=2), and single canalicular wall hypoplasia (n=1). At a mean follow-up of 12.54 months, anatomical and functional success were noted in 91.3% (21/23 eyes).ConclusionSimple CNLDO was the most common of the LDA in CRS. Buried probe was universal among the cases with complex CNLDO. All CRS patients should be screened for lacrimal anomalies to initiate appropriate interventions for successful outcomes.

Gene expression profiling of rubella virus infected primary endothelial cells of fetal and adult origin.

BackgroundRubella 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.ResultsMore 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”.ConclusionSince 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-016-0475-9) contains supplementary material, which is available to authorized users.

Late Clinical Manifestations of Congenital Rubella Syndrome (CRS), an experience from Oman, 1980¬¬ 2015

BackgroundCongenital rubella syndrome (CRS) is a major cause of severe birth and late onset defects worldwide. A national CRS registry was established in Oman to conduct long term follow-up of CRS cases. MethodsThe CRS national registry includes all CRS cases reported to the Ministry of Health since 1980 and are based on the WHO CRS case definition. CRS patients received annual clinical assessments.ResultsOf 104 reported CRS cases, 85 (82%) were clinically or laboratory-confirmed. Out of the confirmed cases, 46 (54%) patients were successfully contacted and received clinical evaluation. Twenty (24%) of the confirmed cases were lost to follow-up and 19 (22%) were deceased. Among deceased cases, 7 (28%) died from cardiovascular causes, 3 (12%) from meningitis/encephalitis, 2 (9%) from pneumonia, 1 (3%) from, head injury and 12 (48%) had unknown causes.Out of the evaluable patients, 19 (41%) had late-onset symptoms manifestations of CRS detected from 8-23 years of age; 3 (16%) had endocrine function defects: 2 (11%) had thyroid disorders and 1 (5%) had type 2 diabetes mellitus, 3 (16%) had seizures disorders, One (5%) case each of systolic murmur, elevated blood pressure, pulmonary atresia and left ventricular failure were reported. Three (16%) hepatosplenomegaly, 1 (5%) late onset sensorineural hearing impairment, 1 (5%) hypospadias and 1(5%) autism (reported as CRS-related) 18 (39%) had cerebral palsy, 10 (22%) and 5 (11%) had severe to profound and moderate mental retardation were reported. respectively. Seventy two percent of the CRS cases survived up to 30 years.ConclusionsCardiovascular, neurological manifestations and endocrine function defect were the most common late CRS manifestations. The long survival of CRS cases were attributed to early medical and rehabilitation interventions. Identification and follow-up of the CRS cases provided an opportunity to assess late or unrecognised manifestations of congenital rubella and support earlier clinical intervention.Keywords Congenital Rubella Syndrome; CRS; late manifestations of CRS; disability; Expanded Program on Immunization; Oman

Localization of Viral Antigens Improves Understanding of Congenital Rubella Syndrome Pathophysiology

Rubella virus (RV) is responsible for benign postnatal and deadly antenatal infections. Its involvement in developmental defects in children following congenital transmission was first made by Sir Norman McAlister Gregg in 1941. Indeed, the maternal primary infection results in an RV viremia and placental transfer. If it occurs before 12 weeks of gestation, during organogenesis, it can result in severe fetal damage causing miscarriage or malformations primarily affecting the cardiovascular system, eyes, ears and the central nervous system; it is fatal in nearly one third of cases during the first year of life (Tondury and Smith, 1966). This severe RV infection acquired in utero early in pregnancy is named as Congenital Rubella Syndrome or CRS. In 2014, 141 CRS cases were reported from 114 countries mostly from South-East Asia (n = 86/141), although reporting is probably inconsistent according to the authors themselves (Grant et al., 2015). This number had been estimated as closer to 100,000 cases each year in developing countries alone (Cutts and Vynnycky, 1999). To better understand the pathogenesis of CRS in the absence of an animal model, the first histopathological explorations were conducted in some of the 20,000 fetuses infected during the 1964–1965 epidemics in the US when about 12.5 M Rubella cases were reported (National Communicable Disease Center, 1969). Although these studies identified histological lesions in the heart, blood vessels, crystalline lens, ears, brain, teeth and liver consistent with clinical features and sequelae of CRS, they did not solved the mechanisms of virus teratogenicity (Tondury and Smith, 1966, Esterly and Oppenheimer, 1969). In particular, until recently, the exact nature of the cell types infected with RV remained unknown.

Study of Cardiovascular Malformation in Congenital Rubella Syndrome in Two Tertiary Level Hospitals of Bangladesh

Background: Congenital Rubella infection is a serious disabling problem for children resulting in Congenital Rubella Syndrome (CRS). The exact pattern of the CRS related cardiovascular malformation has not yet been well established in Bangladesh. The objective of this study was to observe the pattern of cardiovascular malformation in Congenital Rubella Syndrome. Methodology: This cross-sectional study was conducted in Dhaka Shishu (Children) Hospital and National Institute of Cardiovascular Diseases (NICVD). Total 40 suspected CRS cases were recruited from both indoor and outpatient departments of the two study hospitals. Serum samples were tested for rubella-specific IgM and IgG, visual and hearing assessment, chest radiography and colour doppler echocardiography were performed at appropriate specialized centres. Results: The mean (±SD) age of the study population (n=40) was 6.6 (±5.7) months (range: 0–24 months), 68% children were male and 32% were female. Congenital heart disease (CHD) was found in 78% children. Patent ductus arteriosus was the commonest (47.5%) structural defect followed by pulmonary stenosis (22%), atrial septal defect (17.5%) and ventricular septal defect (17%). The chest X-ray of CHD cases showed cardiomegaly in 71% cases and patchy opacity and/or consolidation in 65% cases. Regarding serological assessment of the 37 patients (3 patients rejected blood collection), 60% cases showed IgG positive and 28% cases revealed positive IgM. Conclusions: Various forms of cardiovascular malformation are present in CRS patients. Treatment modalities differ in each type of CHD and its early detection can reduce childhood mortality and morbidity. DOI: http://dx.doi.org/10.3329/bjch.v38i3.22822 Bangladesh J Child Health 2014; VOL 38 (3) :137-141

Mortality Associated With Pulmonary Hypertension in Congenital Rubella Syndrome

Outbreaks of rubella and congenital rubella syndrome (CRS) continue to arise in various countries where a rubella-containing vaccine is not included in the national immunization program. After a large-scale rubella outbreak in 2011, CRS cases emerged in Vietnam. The aim of this study was to clarify the clinical features of these cases with an emphasis on cardiovascular complications and outcomes. From October 2011 to September 2012, we conducted a prospective surveillance study of infants <12 months of age who had manifestations suggesting CRS at the only referral hospital in Khanh Hoa Province. These infants underwent standard examinations, echocardiography, cranial ultrasonography, automated auditory brainstem responses, blood cell count measurements, and rubella-specific antibody testing. Detected cardiovascular defects were regularly followed with echocardiography. We enrolled 38 cases of CRS characterized by a low birth weight (71%), cardiovascular defects (72%), cataracts (13%), hearing impairment (93%), purpura (84%), hepatosplenomegaly (68%), and thrombocytopenia (76%). Patent ductus arteriosus, the most common cardiovascular complication, was often associated with progressive pulmonary hypertension (PH). As of January 2013, 13 infants (34%) had died, and PH was significantly more frequent among the fatalities (P = .004); however, therapeutic closure of the ductus reversed the PH in several cases. PH-associated mortality is high among infants who have CRS in Vietnam. Providing proper assessments, continuous follow-up, and timely intervention for cardiovascular defects is critical for the management of CRS patients. Echocardiography is of diagnostic and prognostic value and can support better clinical management of CRS, even in a developing country setting.

Congenital Rubella Syndrome With Autistic Disorder

Congenital rubella syndrome (CRS) consists of a group of abnormalities that develop in children as a result of maternal infection with rubella virus. CRS may lead to new physical symptoms during adolescence or adulthood, referred to as "late manifestations". Psychiatric disorders are often seen among CRS patients, with an incidence of 4.12-7.3% for autism. We report a case of adolescent CRS with autism. A 20-year-old man had received treatment with antipsychotics and antidepressants since the age of 12 years because of unstable moods, violence, and stereotypic behavior. During follow-up, he developed some insidious-onset physical problems, including hyperlipidemia, dyspnea, constipation, torticollis and a tilted trunk. Under careful survey and evaluation, some physical problems were recognized as side effects of psychotropics, which gradually subsided after adjustment of the medications, and some of the problems were considered partially as manifestations of CRS, such as progressive pulmonary artery stenosis-related dyspnea. We managed some of the patient's physical problems and then he received catheterization for pulmonary artery stenosis. His general physical condition improved and some further improvement in psychiatric status was noted thereafter. Because of a high comorbidity rate for patients with autistic disorder, the clinician should be aware of the possibility of CRS if the patient has multiple congenital physical abnormalities with a history of maternal rubella infection. If patients develop physical symptoms in adolescence, awareness of late manifestations of CRS and differentiation from the adverse effects of psychotropic medications are essential. In addition to psychiatric treatment, management of physical problems associated with CRS would be beneficial for the patients' psychiatric condition.

Congenital rubella, diabetes and HLA

Keywords Congenitalrubella.HLA.Type1diabetes.VirusAbbreviationCRS Congenital rubella syndromeTo the Editor: In a recent Editorial, Edwin Gale reviewedthe congenital rubella syndrome (CRS) and the postulatedrole of viruses in type 1 diabetes, pulling together most ofthe literature that links congenital rubella and diabetes [1].He concluded that the case appears sound for type 2diabetes, but is at most only suggestive for type 1 diabetes.However, he did not reveal the whole story, in particular,the evidence for HLA associations with diabetes in CRS.Gale quotes Menser et al. [2] on the incidence ofdiabetes following CRS, but fails to mention that theseinvestigators also reported that the HLA A1-B8 haplotypewas present in 44% (eight out of 18) of their CRSparticipants with diabetes. HLA A1-B8 was first docu-mented as being increased in frequency in insulin-depen-dent diabetes just 2 months earlier in the same journalin 1974 [3]. In the CRS participants, this haplotype waspresent in 75% (three out of four) who were insulin-dependent, with ages at onset of 1.5, 12, 12 and 24 years,and in 36% (five out of 14) who were on oral agents or dietalone, with ages of onset of 28–34 years. The frequency ofHLA A1-B8 in the background white population is 10%.Gale states that these studies were carried out ‘by authorswith no special interest in diabetes’, but in fact co-authorJ.A. Burgess was, and still is, a diabetologist.HLA A1-B8 (-DR3-DQ2) is the classic autoimmunehaplotype—associated not only with susceptibility to type 1diabetes in the non-CRS population but also with otherautoimmune diseases such as myasthenia gravis, systemiclupus erythematosus, chronic active hepatitis and coeliacdisease—and has been associated with the epidemiology ofrubella [4, 5]. The CRS–diabetes–HLA association wasconfirmed in the New York cohort of 274 patients [6]. Inthis case, Gale acknowledges the high rate of insulin-requiring diabetes following the rubella epidemic of 1964–1966 in New York, but judges that ‘given the interest of theinvestigators, the sample may have included a dispropor-tionate number of children with diabetes’, and, ‘ascertain-ment bias may have contributed to this very high rate, whichis otherwise unexplained’. In the context of a critical eval-uation of the literature, these statements appear distinctlysubjective. The New York data strengthened the associationof CRS with type 1 diabetes, because not only was thefrequency of HLA DR3 higher in the CRS patients, but alsothe frequency of HLA DR2, known to be protective againsttype 1 diabetes in non-CRS populations [7], was decreased.Further evidence for an autoimmune mechanism in CRS-associated diabetes comes from other studies not includedin the review. These demonstrated that T cell clones fromboth CRS and non-CRS type 1 diabetic individuals, raisedin response to epitopes in the islet autoantigen glutamicacid decarboxylase, reacted to peptides from rubella virus[8]. There are several cogent reasons why CRS could haveset the stage for type 2 diabetes. Babies with CRS were‘small for dates’ and had a reduced beta cell mass, and may

Forty-Year Observation of 280 Japanese Patients With Congenital Rubella Syndrome

There was a rubella epidemic in 1964–1965 in Okinawa, Japan. By 2004, 280 subjects were diagnosed with congenital rubella syndrome (CRS). All 280 patients followed over this 40-year period developed cataracts, sensory deafness, and/or heart disease. We measured islet cell surface antibody (ICSA), islet cell antibody (ICA), and anti-GAD65, IA-2, and insulin antibodies. Three (1.1%) (patients 1, 2, and 3) of these 280 CRS patients developed type 1 diabetes (positive autoantibodies to pancreatic β-cells). Patients 1 and 2 had diabetic ketoacidosis and type 1 diabetes. Patient 3 was diagnosed with diabetes at 18 years of age …

CD4 + and CD8 + T-cell clones from congenital rubella syndrome patients with IDDM recognize overlapping GAD65 protein epitopes : Implications for HLA class I and II allelic linkage to disease susceptibility

To fully characterize human glutamic acid decarboxylase (GAD)65 protein T-cell epitopes associated with insulin-dependent diabetes mellitus (IDDM), CTL clones specific to GAD65 protein antigens were isolated from two congenital rubella syndrome (CRS)-associated IDDM patients. Overlapping nonamer T-cell epitopes recognized by both CD4 + or CD8 + CTL clones within peptides GAD65(252-266) and GAD65(274-286) were identified as sequences bounded by GAD65(255-266) with 6/9 overlapping residues, and GAD65(276-285) with 8/9 overlapping residues, respectively, using two panels of overlapping peptide analogs in cytotoxicity assays. HLA restrictive elements of the T-cell clones were also identified using a panel of B cell lines with different HLA phenotypes as targets in cytotoxicity assays. The antigenic GAD65 peptides elicited cytotoxic responses of peptide-specific CD4 + T-cell clones in the context of HLA DRB1∗0404. The CD8 + T-cell clone specific to GAD65(255-263) was found to be restricted by HLA A3 and A11. Similarly, the CD8 + T-cell clone specific to GAD65(277-285) killed peptide-sensitized target cells expressing HLA B35 and B15. The observed HLA restriction of these overlapping epitopes implies that a tandem of [DRB1∗0404-A11(3)] and/or a tandem of [DRB1∗0404-B35(15)] might predispose CRS patients to development of IDDM.

The role of rubella-immunoblot and rubella-peptide-EIA for the diagnosis of the congenital rubella syndrome during the prenatal and newborn periods.

Rubella infection during the first trimester of pregnancy can cause the congenital rubella syndrome (CRS). Patients with CRS were shown to have a decreased humoral and cellular immunity. It is not known whether asymptomatic newborns who had experienced intrauterine infection with rubella virus (RV) differ in their antibody response from newborns with CRS. In this study we compared both groups for a difference which might be a useful diagnostic criterion for CRS during the prenatal and newborn periods. We used the nonreducing Rubella-Immunoblot and the Rubella-IgG-Peptide-Enzyme Immunoassay (EIA) to determine the antibodies directed to rubella proteins E1, E2 and C. The results showed that only newborns with CRS who had experienced RV infection during the first 12 weeks of gestation showed significantly reduced levels of antibodies directed to both the linear RV E1 epitope (SP 15) and the topographic RV E2 epitope. Asymptomatic newborns infected mostly later than week 10 of gestation showed normal levels of antibodies. These data suggest that the lack of antibody response in CRS is linked to the immaturity of the fetal immune system during the first trimester of gestation. Rubella-IgG-Peptide-EIA and Rubella-Immunoblot should be used additionally for CRS diagnosis in the prenatal/newborn periods. These results may have an impact on the early treatment of late-onset symptoms of CRS patients.