The congenital rubella syndrome and diabetes

Although rubella is among the more benign epidemic viruses of childhood, infection in pregnancy may invade the fetus, which has no effective immune defence against it. The result is a persistent viraemia, and clinical consequences include low birthweight, deafness, blindness and learning disability, although many patients escaped most of these ill-effects. The congenital rubella syndrome (CRS) has now been eliminated by routine vaccination of prepubertal girls in most parts of the world, but it retains its interest as a possible model of virus-induced type 1 diabetes. Unfortunately, the great majority of clinical reports predated the distinction between type 1 and type 2 diabetes and modern methods of immunogenetic analysis, and it is therefore impossible to ascertain the proportion with what would now be called type 1A (immune-mediated) diabetes. Review of the literature does, however, suggest a heterogeneous clinical presentation, with a range of possible aetiological factors including low birthweight, pancreatic dysplasia and marked insulin resistance. Some of those affected might be considered to have had 'classic' type 1 diabetes, but the true relationship between the CRS and autoimmune diabetes will probably never be known.

Historical aspects

Rubella, first described in 1814, has clinical features intermediate between those of measles and scarlet fever. In German it was previously known as Röteln and in English as German measles. The virus appears in the circulation after an incubation period of 7–9 days, and is shed via the nasopharynx and stools. Clinical onset is preceded by flu-like symptoms, low fever and arthralgia, followed by eruption of small pinkish-red spots, which typically appear on the face 16–21 days after exposure before spreading to the rest of the body. The condition sometimes presents without a rash, making bedside diagnosis impossible, and up to 40% of patients may never realise that they have been affected. The virus disappears from the serum as antibodies appear, some 3 weeks after infection.[1][2]

Norman Gregg, an Australian ophthalmologist, first described the consequences of rubella infection in pregnancy in the 1940s,[3] although the link between the clinical syndrome and rubella was (according to legend) established by mothers sitting with their children in his waiting room.

Congenital rubella syndrome

Congenital Rubella Syndrome
Congenital Rubella Syndrome
Congenital rubella syndrome (CRS) results in a range of transient abnormalities at birth, which need not concern us now, congenital defects including sensorineural deafness, congenital heart disease, cataract, choroidoretinitis, growth retardation, microcephaly, mental retardation and urogenital abnormalities. The classic diagnostic triad was cataracts, cardiac abnormalities and deafness. Delayed consequences include diabetes, thyroid disorders, behavioural disorders and panencephalitis.[4] About 40% of children weighed less than 2.5 kg at birth, and most failed to catch up with their peers subsequently.

The syndrome really came to clinical attention in the course of a pandemic that reached the USA in 1964. It is estimated that some 20,000 women might have been exposed to rubella in the first trimester of pregnancy, and 600 children with CRS were reported in New York alone. This resulted in introduction of a live attenuated vaccine for prepubertal girls, but coverage is limited and up to 100,000 children may be affected worldwide each year.4

Pathology of CRS

Rubella virus
Rubella virus
Rubella is an RNA virus with a lipid envelope. The ring effect or ‘toga’ this produces under the electron microscope caused it to be classed with the Togaviridae, within which it forms a separate genus, Rubivirus. It was first identified and cultured in the early 1960s and exists in a number of similar strains that are serologically indistinguishable; humans are the only known natural host, although experimental rubella can be induced in other species.

Congenital rubella is characterised by persistent viraemia, and virus can be cultured from the throat, tears and urine of affected children at birth. Viral shedding cannot be detected after 1 year of age in 90% of cases but may sometimes persist for years. Diagnosis is based upon detection of virus or rubella-specific antibody in early infancy.

Infection of the placental tissue and fetus is almost inevitable when infection occurs within the first 2 months of pregnancy, and 67–85% of confirmed first trimester infections lead to some form of fetal damage.[1]

Virus penetrates almost all tissues and, once established, persists throughout gestation, even though the fetus can mount an effective immunoglobulin response and is additionally protected by maternal IgG following the acute phase of the infection. Neonates with the syndrome have impaired cell-mediated immunity, and persistent infection within lymphocytes is believed to explain the failure to clear the virus.[5]

There are two main theories as to why rubella induces abnormalities in the fetus. The first is that viral replication impairs proliferation and growth of developing clones of cells at a critical stage of fetal development. Although analysis of aborted fetal material shows that only a small proportion of fetal cells actually harbour virus, cultures derived from these cells grow slowly and produce a growth-inhibiting substance in vitro. The organs of infants with the syndrome are small and contain a reduced number of cells. Viral infection therefore induces general growth delay, with focal consequences in specific tissues that may be more susceptible to infection. The second hypothesis is that direct tissue damage occurs as the result of cell necrosis, as observed in tissues including the eye and vascular endothelium. This leads to immune-mediated changes, including mononuclear infiltrates, in tissues such as the lung and brain.

Diabetes and CRS

Although some early reports suggested that diabetes affected some 20% or more of children with CRS, this is likely to be a considerable overestimate, and a recent review was able to identify only 20 case reports.[4] Others are mentioned, with fewer clinical details, in case series. It was concluded that CRS undoubtedly predisposes to diabetes in later life. A high proportion of the reported cases, mostly described in very brief summary in those presenting under the age of 5 years, and in children who were for the most part markedly underweight at birth. These were often reported to be in diabetic ketoacidosis at diagnosis, and were invariably treated with insulin. Some adolescents and young adults presented in much the same way, whereas others did not require insulin therapy and some at least had an insulin-resistant form of diabetes. Others again had impaired glucose tolerance, although numbers are hard to ascertain owing to the use of differing diagnostic criteria. Those diagnosed later in life usually did not require insulin.

The main evidence for an immune-mediated type of diabetes came from a centre in New York which found that 15/272 children with the CRS required continuous insulin therapy, while one other used insulin intermittently, and 14 others had abnormal glucose tolerance. The centre was known to have a special interest in diabetes, which may have affected the referral pattern. Separate analysis showed an excess of the type 1 susceptibility allele HLA-DR3 and an absence of the protective allele HLA-DR2 in those affected with diabetes, and the authors conclude that rubella infection had increased the penetrance of type 1 diabetes. This frequently cited study does however stand alone in the literature, and few clinical details of the individual cases were provided.[6][7]

Summary and conclusion

Diabetes can be classed among the delayed complications of CRS, but the overall incidence of insulin-requiring childhood-onset diabetes is more likely to have been in the range 1–3%, compared with higher values cited in the literature. At this remove of time, and in the absence of stored sera (a requested search was unsuccessful), it is not possible to estimate how many of these children had immune-mediated diabetes. Other intrauterine viruses have, however, been associated with early-onset diabetes (see section on Cytomegalovirus and Diabetes), and potential mechanisms include pancreatic dysgenesis and massive viraemia as well as autoimmunity. Lesser degrees of glucose intolerance appear to have been much more common (inclusion of glucose intolerance as well as overt diabetes gave rise to the higher estimates in the literature) and presented with non-insulin requiring diabetes later in life.

In conclusion, diabetes associated with CRS was heterogeneous, with a number of distinctive variants that do not fit easily into the standard definitions of either type 1 or type 2 diabetes. Congenital rubella does show that a virus can predispose to diabetes, but does not, at this remove of time, show us how.

References

  1. ^ Wolinsky JS, McCarthy M (1995) Rubella. In: Porterfield JS (ed) Handbook of Infectious Diseases - Exotic Viral Infections. Chapman and Hall, London, pp 19–45

  2. ^ O’Donnell N. History of the congenital rubella syndrome. J Vocat Rehabil 1996;6:149–57

  3. ^ Burgess MA. Gregg’s rubella legacy 1941–1991. Med J Australia 1991;155:355–6

  4. ^ Gale EAM. Congenital rubella – citation virus or viral cause of type 1 diabetes? Diabetologia 2008;51:1559–66

  5. ^ Olsen GB et al. Abnormalities of in vitro lymphocyte responses during rubella virus infections. J Exp Med 1968;128:47–68

  6. ^ Rubinstein P et al. The HLA system in congenital rubella patients with and without diabetes. Diabetes 1982;31:1088–91

  7. ^ Ginsberg-Fellner F et al. Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome. Rev Infect Dis 1985;7(Suppl 1):S170–S176

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