Fetal rubella pathology

doi:10.1016/S0022-3476(66)80204-4

The Journal of Pediatrics

Volume 68, Issue 6, June 1966, Pages 867-879

https://doi.org/10.1016/S0022-3476(66)80204-4 Get rights and content

Histologic evidence of disease was found in 68 per cent of the fetuses obtained in good condition by therapeutic interruption following maternal rubella during the first trimester. The manifestations interpreted as disease consisted of cell damage and necrosis without inflammatory or fibrotic response. Sporadic foci of cellular damage were found in the chorionic epithelium, endothelial lining of the blood vessels and heart, myocardial cells, skeletal muscle cells, and, in particular, cells of the developing lens, inner ear, and teeth. The rubella-induced defects appear to be a consequence of cellular damage resulting in defective form and/or function of the developing tissue. The route of fetal entry of the virus is apparently via disease in the chorion with subsequent spread to other fetal tissues which may show evidence of disease months after the acquisition of the infection.

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Cited by (100)

Rubella virus infection in endothelial cells reduces angiogenesis via interferon beta-induced CXCL10
2023, iScience
Rubella virus (RuV) infection during pregnancy can lead to abortion, stillbirth, and embryonic defects, resulting in congenital rubella syndrome (CRS). It is estimated that there are still 100,000 cases of CRS per year in developing regions with a mortality rate of over 30%. The molecular pathomechanisms remain largely unexplored. Placental endothelial cells (EC) are frequently infected with RuV. RuV reduced the angiogenic and migratory capacity of primary human EC, as confirmed by treatment of EC with serum from RuV IgM-positive patients. Next generation sequencing analysis revealed the induction of antiviral interferon (IFN) type I and III and CXCL10. The RuV-induced transcriptional profile resembled the effects of IFN-β treatment. The RuV-mediated inhibition of angiogenesis was reversed by treatment with blocking and neutralizing antibodies targeting CXCL10 and the IFN-β receptor. The data identify an important role for antiviral IFN-mediated induction of CXCL10 in the control of EC function during RuV infection.
Rubella Virus
2018, Principles and Practice of Pediatric Infectious Diseases
Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management
2018, The Lancet Infectious Diseases
Citation Excerpt :
The mechanisms by which rubella virus induces microcephaly remain largely unknown. Most human embryonic tissues can be infected by rubella virus54,65 and brain vessels have been found to degenerate following rubella infection.65–67 These observations suggest that a neurodegenerative mechanism could be a potential underlying cause of rubella-induced microcephaly in human beings.
Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015–16 outbreak of Zika virus and congenital Zika infection brought the world's attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities.
Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency
2017, Antiviral Research
Persistent rubella virus (RV) infection has been associated with various pathologies such as congenital rubella syndrome, Fuchs's uveitis, and cutaneous granulomas in patients with primary immune deficiencies (PID). Currently there are no drugs to treat RV infections. Nitazoxanide (NTZ) is an FDA-approved drug for parasitic infections, and has been recently shown to have broad-spectrum antiviral activities. Here we found that empiric 2-month therapy with oral NTZ was associated in the decline/elimination of RV antigen from lesions in a PID patient with RV positive granulomas, while peginterferon treatment had no effect. In addition, we characterized the effects of NTZ on cell culture models of persistent RV infection. NTZ significantly inhibited RV replication in a primary culture of human umbilical vein endothelial cells (HUVEC) and Vero and A549 epithelial cell lines in a dose dependent manner with an average 50% inhibitory concentration of 0.35 μg/ml (1.1 μM). RV strains representing currently circulating genotypes were inhibited to a similar extent. NTZ affected early and late stages of infection by inhibiting synthesis of cellular and RV RNA and interfering with intracellular trafficking of the RV surface glycoproteins, E1 and E2. These results suggest a potential application of NTZ for the treatment of persistent rubella infections, but more studies are required.
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2017, Plotkin's Vaccines
Immunolocalization and Distribution of Rubella Antigen in Fatal Congenital Rubella Syndrome
2016, EBioMedicine
Citation Excerpt :
Congenital rubella syndrome (CRS) is a serious disease caused by RV infection in utero (Plotkin et al., 2011). During the period of maternal viremia, RV may infect the placenta, pass the placental barrier and enter the fetal bloodstream, possibly through emboli of necrotic endothelial cells originating from infected chorion (Tondury and Smith, 1966; Driscoll, 1969; Ornoy et al., 1973; Lima et al., 1977). If the fetus is infected during the first trimester of pregnancy, the virus usually persists until term in multiple fetal organs causing a spectrum of birth defects that includes hearing impairment, and ocular and cardiovascular abnormalities (Rawls, 1968; Singer et al., 1967; Esterly and Oppenheimer, 1973).
An estimated 100,000 cases of congenital rubella syndrome (CRS) occur worldwide each year. The reported mortality rate for infants with CRS is up to 33%. The cellular mechanisms responsible for the multiple congenital defects in CRS are presently unknown. Here we identify cell types positive for rubella virus (RV) in CRS infants.
Cells and organs involved in RV replication were identified in paraffin-embedded autopsy tissues from three fatal case-patients by histopathologic examination and immunohistochemical (IHC) staining using a rabbit polyclonal RV antibody. Normal rabbit antisera and RV antisera preabsorbed with highly purified RV served as negative controls.
RV antigen was found in interstitial fibroblasts in the heart, adventitial fibroblasts of large blood vessels, alveolar macrophages, progenitor cells of the outer granular layer of the brain, and in capillary endothelium and basal plate in the placenta. The antibody specificity was verified by IHC staining of multiple tissue sections from other infectious disease cases. RV infection of each cell type is consistent with abnormalities which have been identified in patients with CRS, in the heart, large blood vessels, and brain. Antigen distribution was consistent with inflammatory response to vascular injury and systemic spread of RV.
The identification of RV positive cell types in CRS is important to better understand the pathology and pathogenesis of CRS.

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¹: Address, Department of Pediatrics, University of Wisconsin Medical Center, 1300 University Ave., Madison, Wis. 53706.

^**: Aided by a grant from the NationalFoundation, and by Research Career Development Award 5-K 3-HD-14-022-02

View full text

Fetal rubella pathology

Am. J. Obst. & Gynec.

Lancet

Lancet

J. Pediat.

J. Pediat.

J. Pediat.

Pathology of the fetus and infant

Isolation of rubella from a mother and fetus

Pediatrics

Virologic and serologic studies on human products of conception after maternal rubella

New England J. Med.

Congenital cataract following German measles in mother

Tr. Ophth. Soc. Australia

A study of three infants dying from congenital defects following maternal rubella in early stages of pregnancy

J. Path. & Bact.

Rubella and other virus infections during pregnancy

Rubella during pregnancy. A follow-up study of children born after an epidemic of rubella in Sweden, 1951

Acta paediat.