Rubella Virus Infection, the Congenital Rubella Syndrome, and the Link to Autism.

Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%-13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development ('regressive autism'). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.

Predictive Factors of Intraocular Pressure Level Evolution Over Time and Glaucoma Severity in Fuchs' Heterochromic Iridocyclitis.

Purpose: To investigate the clinical and virologic-associated and predictive factors of intraocular pressure (IOP) evolution over time and its severity in Fuchs' heterochromic iridocyclitis (FHC). Methods: Consecutive patients with both clinical FHC and intraocular synthesis of rubella virus (RV)-specific antibodies were included in this study. Specific ocular production of RV antibodies was confirmed using the quotient of serum/aqueous humor ratio of RV IgGs (Crv) and control antiviral IgGs (Cctl), using quantitative serology methods. Epidemiologic, clinical, biological, and virologic data at referral were collected and correlated with IOP values over time, occurrence, and severity of glaucoma. Results: Sixty-eight eyes of 68 patients were included. Mean age at diagnosis was 40.7 ± 11.1 years. Mean follow-up was 4.3 ± 4.3 years. Mean baseline Crv and Cctl values were 12.34 ± 14.67 and 216.70 ± 98.4, respectively. Mean baseline IOP was 17.2 ± 7.2 mm Hg (range, 9-40) and 15.6 ± 5.6 (range, 3-30) 5 years after referral. The predictive factors for pejorative IOP evolution over time and glaucoma severity were male sex (P = 0.03) and decreased Crv (P = 0.04) and presence of iris nodules (P < 0.001) and decreased Cctl (P = 0.02), respectively. Diagnostic delay was associated with increased likelihood of undergoing glaucoma surgery (P = 0.02). Conclusions: Time to diagnosis, male sex, presence of iris nodules at baseline, and decreased Crv and Cctl ratios were associated with increased likelihood of pejorative IOP evolution over time. Given the aggressiveness of glaucoma in FHC, these results provide interesting insight into what category of patients should need the closest screening.

Impact of Maternal BMI on Rubella Nonimmunity at Antenatal Screening.

OBJECTIVE: The aim of this study was to examine the relationship between BMI and the incidence of rubella nonimmunity among pregnant women with regard to the World Health Organization categories. METHODS: This was a retrospective cohort study of 117,063 eligible gravidas, managed between 1998 and 2015 in a university hospital of Hong Kong, China. BMI at antenatal booking was banded using the following World Health Organization definitions: < 18.5 kg/m2 , 18.5 to 24.9 kg/m2 , 25.0 to 29.9 kg/m2 , and ≥30.0 kg/m2 . Maternal rubella nonimmunity status by BMI was assessed. Incidence rates were also assessed after adjusting for maternal advanced age, short stature < 151 cm, mothers' birthplace, and postobstetric history covariates. RESULTS: Rubella nonimmunity incidence increased as the BMI increased (P < 0.001). Gravidas with high BMI were more likely to be nonimmune if born in Hong Kong (odds ratio [OR], 1.234; 95% CI: 1.159-1.315; P < 0.001) compared with those born outside of Hong Kong (OR, 1.066; 95% CI: 0.997-1.141; P = 0.063). After adjusting for covariates, women with BMI ≥ 25 kg/m2 had 1.127 (P < 0.001; 95% CI: 1.074-1.182) greater odds of being nonimmune. CONCLUSIONS: High maternal BMI (≥ 25.0 kg/m2 ) is associated with reduced rubella immunity, an effect confined to gravidas with almost complete vaccine coverage in childhood.

[Progress on mechanism of cell apoptosis induced by rubella virus].

Rubella virus (RV), a member of the family Togaviridae, can induce apoptosis of host cells in vitro. Protein kinases of the Ras-Raf-MEK-ERK pathway and PI3K-Akt pathway play essential roles in virus multiplication, cell survival and apoptosis. Proteins p53 and TAp63 that bind to specific DNA sequences stimulate Bax in a manner to produce functional pores that facilitate release of mitochondrial cytochrome c and downstream caspase activation. In this review, the molecular mechanisms of RV-induced cell apoptosis, including RV-infected cell lines, pathological changes in cell components and apoptosis signaling pathways are summarized.

[Detection of rubella virus RNA in clinical material by real time polymerase chain reaction method].

AIM: Development of a reagent kit for detection of rubella virus RNA in clinical material by PCR-RT. MATERIALS AND METHODS: During development and determination of analytical specificity and sensitivity DNA and RNA of 33 different microorganisms including 4 rubella strains were used. Comparison of analytical sensitivity of virological and molecular-biological methods was performed by using rubella virus strains Wistar RA 27/3, M-33, "Orlov", Judith. Evaluation of diagnostic informativity of rubella virus RNAisolation in various clinical material by PCR-RT method was performed in comparison with determination of virus specific serum antibodies by enzyme immunoassay. RESULTS: A reagent kit for the detection of rubella virus RNA in clinical material by PCR-RT was developed. Analytical specificity was 100%, analytical sensitivity - 400 virus RNA copies per ml. Analytical sensitivity of the developed technique exceeds analytical sensitivity of the Vero E6 cell culture infection method in studies of rubella virus strains Wistar RA 27/3 and "Orlov" by 11g and 31g, and for M-33 and Judith strains is analogous. Diagnostic specificity is 100%. Diagnostic specificity for testing samples obtained within 5 days of rash onset: for peripheral blood sera - 20.9%, saliva - 92.5%, nasopharyngeal swabs - 70.1%, saliva and nasopharyngeal swabs - 97%. Positive and negative predictive values of the results were shown depending on the type of clinical material tested. CONCLUSION: Application of reagent kit will allow to increase rubella diagnostics effectiveness at the early stages of infectious process development, timely and qualitatively perform differential diagnostics of exanthema diseases, support tactics of anti-epidemic regime.

Comparison of rubella virus- and herpes virus-associated anterior uveitis: clinical manifestations and visual prognosis.

PURPOSE: To compare the clinical characteristics and visual prognosis of patients with anterior uveitis (AU) and intraocular fluid analysis positive for rubella virus (RV), herpes simplex virus (HSV), or varicella zoster virus (VZV). DESIGN: Retrospective, observational study. PARTICIPANTS: The study included 106 patients with AU and positive polymerase chain reaction (PCR) results, Goldmann-Witmer coefficients (GWCs), or both, for RV (n = 57), HSV (n = 39), or VZV (n = 10). METHODS: Clinical records of the included patients were analyzed retrospectively; demographic constitution, ophthalmologic characteristics, and visual prognosis were compared. MAIN OUTCOME MEASURES: Age, gender, and diverse clinical and laboratory characteristics, including course and laterality of AU; prevalence of positive results for PCR, GWC, or both; conjunctival redness; corneal edema; history of keratitis; presence of keratic precipitates; synechiae; heterochromia; and grade of inflammation. In addition, complications and visual acuity at 1 and 3 years of follow-up were recorded. RESULTS: All 3 types of viral AU were characterized by unilateral involvement (80%-97%). Rubella virus AU was characterized by younger age at onset and chronic course and typically was associated with cataract at presentation. Heterochromia was present in 23% of RV AU patients. Anterior uveitis associated with HSV or VZV occurred characteristically in older patients and frequently followed an acute course. Clinical features associated with herpetic AU included conjunctival redness, corneal edema, history of keratitis, and development of posterior synechiae. Herpes simplex virus AU often had severe anterior chamber inflammation, whereas the presence of vitritis was more common in RV AU and VZV AU. The prevalence of documented intraocular pressure (IOP) of more than 30 mmHg (25%-50%; P = 0.06) and development of glaucoma (18%-30%; P = 0.686) were similar in all 3 groups. Focal chorioretinal scars were seen in 22% of RV AU eyes, in 0% of HSV AU eyes, and in 11% of VZV AU eyes (P = 0.003). Visual prognosis was favorable for all 3 groups. CONCLUSIONS: These observations identify clinical differences between RV AU, HSV AU, and VZV AU and may be of particular value to ophthalmologists who are unable to carry out intraocular fluid analysis to discriminate between these types of viral AU. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

[Influence of TORCH-infections on the spermatogenesis of men].

The purpose of the given study was to reveal causal relations between infection of the urino-genital tract by intracellular parasites, the so-called TORCH-infections, and the decrease of spermatogenesis. For observation 182 men of reproductive age (from 22 to 38 years) with oligozoospermia and aspermia, without any complaints or clinical symptoms indicating existence of infections of urino-genital tracts, were selected. Out of those, 131 revealed oligozoospermia, i.e. the quantity of spermatozoons was no higher than 20 mln in 1 ml of ejaculate, and 51 revealed - aspermia. For examination of some TORCH infections, medical doctors in charge directed 44 oligozoospermia patients and 15 aspermia patients, who respectively constituted group I and group II. Examinations were carried out for Chlamydia trachomatis--(Ch.t), Herpes simplex virus--(HSV), Ureaplasma urealiticum--(U.u.), Cytomegalovirus--(CMV), and Mycoplasma hominis--(M.h.). In the group with oligozoospermia, cases of infections by Chlamydias (41.5%) and Herpes virus (51.3%) were frequent, but Ureaplasma (56,5%) was more frequent than any infections. Cytomegalovirus occurred in the least number of cases. Making any conclusions on the frequency of infections by M.h. is difficult due to the low number of examinations. Similar picture was observed in Group II as well. Following successful treatment of infections in Group I, 8 patients with Ch.t. and 8 patients with U.u. showed an improved spermogram after several months. Treatment of other infections did not yield tangible results. In Group II spermatogenesis remained without any changes.

The effect of infliximab on antiviral antibody profiles in patients with rheumatoid arthritis.

The duration of humoral immunity in patients treated with immunosuppressive drugs is poorly defined. The objective of the study was to investigate the effect of infliximab on the levels of antiviral antibodies against poliomyelitis, rubella and measles in rheumatoid arthritis (RA) patients. Fifty-two consecutive RA patients being treated with 3 mg/kg infliximab were prospectively studied. The antiviral antibody profiles for measles, rubella and three serotypes of poliomyelitis were tested on the day of the first infusion of infliximab and 6 months later. The study group comprised 36 women and 16 men (mean age 54 years, range 33-81) with a mean disease duration of 15 +/- 9 years. Forty-two (81%) patients were being treated with methotrexate and 22 (42%) were receiving prednisone. All patients had baseline protective levels of antibodies against measles and the three strains of polio, while 48 (92%) patients had protective antibodies against rubella. No significant change in the levels of antiviral antibodies was observed after 6 months of treatment with infliximab: from 3.67 at baseline to 3.87 IU/ml for measles, 169.50-197.0 IU/ml for rubella. No change was noticed for the geometric mean concentrations of antibodies against strains of poliomyelitis: 366-478 IU/ml for the Mahoney polio strain, 906-845 IU/ml for the MEF strain and 175-196 IU/ml for the Sauket strain. Patients with longstanding RA conserve long-term immunity to common viruses despite the use of immunosuppressive drugs. Levels of antiviral antibodies against measles, rubella and polio remain stable under treatment with infliximab.

Encephalitis in a child during atypical course of rubella.

Rubella is usually encountered as a mild viral illness in children and complications are not common. We reported rubella encephalitis in the atypical course of rubella without rash in a 9-year-old boy. He was admitted with a headache, fever, loss of consciousness and bilateral retroauricular lymphadenopathy. The cerebrospinal fluid (CSF) examination showed lymphocytic pleocytosis, increased protein levels and a normal glucose value. Immunoglobulin (Ig) M antibodies against rubella virus were positive in CSF and serum. IgG antibody also became positive in his serum 3 weeks after his admittance. We emphasized that rubella may appear without any rash and cause encephalitis. In unvaccinated children, rubella should be considered in the differential diagnosis of encephalitis.