8.5.13 Rubella 827

8.5.13 Rubella 827

8.5.13  Rubella 827 8.5.13  Rubella Pat Tookey and J.M. Best ESSENTIALS Rubella is caused by an enveloped RNA virus, for which humans are the only known host. Transmission is by airborne droplet spread, with infection seen predominantly in spring and early summer in temperate zones. Postnatally acquired infection—​presents after incubation of
14–​21  days with rash (maculopapular, usually beginning on
the face before spreading to the trunk and extremities), lymph- adenopathy (suboccipital and posterior cervical), and mild fever. Sore throat, coryza, cough, conjunctivitis, and arthralgia may be seen. The illness is usually mild. Management is symptomatic. Rubella in pregnancy—​in the first 10 weeks of gestation
this is associated with a 90% risk of congenital fetal abnormal- ities, most typically comprising sensorineural hearing loss, alone or combined with cataracts and/​or cardiac anomalies. Clinical diagnosis is unreliable, hence rapid investigation is essential when a woman develops a rubella-​like illness in the first 16 weeks of pregnancy, comprising (1)  testing of maternal serum for rubella IgG and IgM antibodies; and sometimes (2) amniotic fluid and/​or fetal blood testing; and (3) ultrasonography to de- tect fetal defects. If a fetus is infected, termination of pregnancy is considered. Prevention—​live attenuated rubella vaccines provide protec- tion to about 95% vaccinees and are usually given in combin- ation with measles or measles and mumps vaccines. Vaccination of greater than 80% of children is required to prevent circulation of rubella virus. Healthcare workers and women of childbearing
age whose rubella status is unknown (including recent immi- grants) should also be targeted for measles, mumps, and rubella vaccination. Immunization of pregnant women is contraindi- cated, but women found to be susceptible at antenatal testing should be offered measles, mumps, and rubella vaccination after delivery. Introduction Rubella is a mild exanthematous disease of little clinical signifi- cance. However, infection in early pregnancy can result in multiple congenital abnormalities, often referred to as ‘congenital rubella syndrome’. As a result of the widespread use of rubella vaccine, con- genital rubella syndrome is now rare in many countries. Aetiology Rubella is caused by rubella virus, an enveloped RNA virus, which is classified in its own genus Rubivirus within the family Togaviridae. There are no major antigenic differences among ru- bella virus isolates, although at least seven genotypes have been described. Epidemiology Humans are the only known host for rubella virus. In temperate zones the infection is seen predominantly in spring and early summer. Before the introduction of rubella vaccine, rubella was endemic in virtually all countries. Epidemics were superimposed on the endemic infection every 4 to 9 years and pandemics every 10–​30 years. In most populations, in the absence of a mass im- munization programme, 10–​20% of women are still susceptible to rubella infection when they reach childbearing age. A review by the World Health Organization in 2008 estimated that more than 110 000 infants were born with congenital rubella syndrome each year with the highest burden being in the WHO African and Southeast Asian regions. Postnatally acquired infection The rash usually begins on the face and spreads to the trunk and then the extremities; the pink maculopapular lesions are initially discrete but later tend to coalesce. The suboccipital and posterior cervical lymph nodes are characteristically enlarged. Mild fever, sore throat, coryza, cough, and conjunctivitis may be present; symptoms are usually mild and last 3–​7 days. There may be a pro- drome with malaise and fever, especially in adults. There is no spe- cific treatment. Transient arthralgia with or without arthritis occurs in up to 70% of postpubertal women, but is less common in men and chil- dren. Less common complications include thrombocytopenia with or without purpura, postinfectious encephalitis, transverse myelitis, and rarely the Guillain–​Barré syndrome. When rubella is acquired in early pregnancy congenital infection might occur (see next). Rubella is clinically indistinguishable from several other infec- tions and 20–​50% of infections are subclinical. Therefore, a his- tory of clinically diagnosed rubella infection is unreliable. The incubation period is 14–​21 days. The exact mode of trans- mission is uncertain but airborne spread by the respiratory route is likely and close contact is usually necessary for transmission. Individuals are most infectious just before the onset of symptoms, and the infectious period lasts from about a week before to a week after the rash appears. Infection usually produces lifelong immunity; however, when rubella is circulating reinfection may occur and is usually asymptomatic. Congenital infection Risk to the fetus The possible consequences of rubella in pregnancy are the birth of an infant with congenital rubella infection with or without congenital defects, the birth of a normal infant, or spontaneous abortion. Infection before conception is not a risk to the fetus. Spontaneous abortion may occur when rubella is acquired early in pregnancy. When maternal infection occurs during the first 10 weeks of pregnancy the rate of fetal infection is about 90%; it then declines until the last few weeks of pregnancy when the rate rises

828 section 8  Infectious diseases again. Virtually all of those infected during the first 10 weeks of pregnancy are likely to have congenital defects, but the risk de- clines over the next 6 weeks. After 16 weeks’ gestation, even sen- sorineural hearing loss and growth retardation are rare, and no abnormalities have been demonstrated following serologically confirmed maternal infection after 18 weeks’ gestation. Most pro- spective studies of the risk to the fetus have been carried out on women with symptoms, but asymptomatic primary infection is thought to carry a similar risk. Following maternal reinfection in pregnancy the risk of transmis- sion to the fetus is probably less than 10% and the risk of damage less than 5%, although it may be higher following symptomatic reinfection. Clinical features Congenital rubella is typically associated with cataracts, cardiac anomalies, and sensorineural hearing loss, and the term congenital rubella syndrome refers to this classic triad of defects. The terato- genic effects may result in a variety of defects (Box 8.5.13.1), but sensorineural hearing loss alone or combined with other abnor- malities is most common. Severe multiple problems are more likely when infection occurs early in pregnancy. Some defects, particularly sensorineural hearing loss, may not develop or become apparent until late infancy or childhood. Other reported late-​onset problems include diabetes mellitus, thyroid dysfunction, autism, and other behavioural and psychi- atric disorders. A  rare progressive rubella panencephalitis has also been reported. Laboratory diagnosis The diagnosis of congenital rubella infection is relatively easy if suspected early, but more difficult to confirm after 3 months of age. The presence of rubella IgM antibody in early infancy is vir- tually diagnostic of congenital infection because acquired infec- tion is rare at this age. Using sensitive assays, rubella IgM may be detected in 85% of infected infants at 3–​6 months and about 30% at 6–​12 months of age. The presence of IgG antibody alone is not diagnostic since it is likely to indicate passively transferred ma- ternal antibody, but persistence of IgG between 6 and 12 months is strongly suggestive of congenital infection. When abnormalities present late, a presumptive diagnosis can be made based on a com- patible clinical picture and the presence or persistence of rubella IgG antibodies in a young child who has not yet been vaccinated. Congenital infection can also be diagnosed by detection of virus during the first months of life when it can be isolated or detected by polymerase chain reaction from a variety of specimens including nasopharyngeal swabs, urine, oral fluid, and conjunctival fluid. Congenitally infected infants shed large amounts of virus from the oropharynx and may be a source of infection for many months; viral shedding occasionally persists for more than a year. Management of rubella-​like illness during pregnancy Appropriate management of a rash illness in pregnancy will de- pend on the local epidemiology of rubella. Routine antenatal rubella antibody screening is not designed to identify rubella in- fection in pregnancy, and specific diagnostic investigations are needed. Pregnant women with a rubella-​like rash should be in- vestigated simultaneously for rubella and parvovirus B19, since they are clinically indistinguishable and even women previously reported to be immune should be investigated in case of laboratory error. Blood should be tested for rubella IgG and IgM antibodies. Rising IgG or detectable IgM antibody indicates recent infection; a positive IgM result alone should be confirmed with a second serum sample. Pregnant women who are susceptible or of unknown ru- bella antibody status and are in contact with a rubella-​like illness should also be investigated as rapidly as possible. The detection of rubella IgM in a woman without a rash or history of contact should be interpreted with caution as rubella IgM may persist for some months or even years after infection or vaccination, or the IgM may be due to cross-​reaction with autoantibodies or other viral IgM antibodies. Investigations must be done in consultation with a virologist who should be aware of the date and type of con- tact, stage of pregnancy, and history of previous immunization and testing. Prenatal diagnosis of congenital infection using amniotic fluid and/​or fetal blood may sometimes be indicated. Ultrasound examination may detect such defects as microcephaly, dystrophic calcification, cataracts, microphthalmos, hepatosplenomegaly, and intrauterine growth restriction. Box 8.5.13.1  Most common defects associated with congenital rubella Classic triad • Deafness -​ Sensorineural -​ Central auditory • Abnormalities of the cardiovascular system -​ Patent ductus arteriosus -​ Pulmonary stenosis -​ Pulmonary arterial hypoplasia • Abnormalities of the eye -​ Retinopathy -​ Cataracts -​ Microphthalmos -​ Iris hypoplasia Other defects • Growth retardation • Microcephaly • Mental retardation • Speech defects Other signs in the neonatal period and infancy • Low birthweight • Hepatosplenomegaly • Jaundice • Meningoencephalitis • Rash • Thrombocytopenia with or without purpura • Adenopathies • Bony radiolucencies • Hypogammaglobulinaemia • Pneumonitis

8.5.13  Rubella 829 Prevention Rubella can be prevented by live attenuated rubella vaccines. The RA27/​3 strain is commonly used and this produces antibodies in about 95% of recipients; protection is probably lifelong in most vaccinees. Rubella vaccine is usually combined with measles or mea- sles and mumps (MMR) vaccines. In children, rubella vaccine causes few side effects. Low-​grade fever and rash are occasionally reported, and transient arthralgia has been seen in about 3% of vaccinees; there have also been rare re- ports of myositis and vasculitis. Joint symptoms are more common in adult women, affecting up to 60% of vaccinees, but are transient and less severe than following naturally acquired rubella. When rubella vaccines were first licensed in the late 1960s, universal childhood vaccination was implemented in the United States of America with the aim of eliminating rubella. A different strategy was pursued elsewhere, and the selective programmes established in Australia and some European countries targeted prepubertal girls and women of childbearing age. This provided individual protection while allowing the continued circulation of wild virus and the acquisition of natural immunity by most individ- uals. When the combined MMR vaccine became available, many countries with high vaccine uptake moved to a universal offer of MMR vaccine for children in the second year of life, usually with a second dose offered preschool or later. The MMR vaccine was introduced into the United Kingdom schedule in 1988, and uptake by the age of 24 months reached 92% between 1992 and 1996. The schoolgirl programme was discon- tinued in 1996 and replaced by the offer of a second MMR for four-​ year-​olds. Uptake of MMR subsequently declined to a low point of 80% in 2003, because of unfounded concerns about safety; however, by 2005 there were signs of recovery and uptake had increased to over 92% by 2011/​12. Although the circulation of rubella virus has dropped to very low levels since the introduction of MMR, prolonged periods of low vaccine uptake may lead to outbreaks of rubella in the future, putting susceptible pregnant women in the United Kingdom at risk. Nevertheless, there have been dramatic declines in the num- bers of susceptible pregnant women, rubella-​associated termin- ations, and children born with congenital rubella syndrome. Fewer than five congenitally infected infants were reported on average each year between 1990 and 1999, compared with about 50 per year in the 1970s. Between 2000 and 2014 about 20 cases were identified, and in over half of these the infant’s mother acquired infection abroad. Termination of pregnancy associated with rubella disease or contact is also now a rare occurrence. In 2012 the World Health Organization published a strategic plan for the global elimination of measles, rubella, and congenital rubella, with the goal of achieving both measles and rubella elimination in at least five of the six WHO Regions by 2020, and laying out specific strategies focusing on vaccination coverage, evaluation, and surveil- lance, outbreak management, public engagement, and research and development. This built on previous initiatives, particularly the ex- perience gained in the WHO Region of the Americas, where, with no evidence of endemic transmission of rubella or congenital rubella in five consecutive years, elimination of rubella and congenital ru- bella was confirmed in 2015. The WHO European Region renewed its commitment to the elimination goal in 2014 with the adoption of a European Vaccine Action Plan 2015–​2020, and reported that 23 of the Region’s 53 member states had interrupted endemic transmis- sion of rubella, based on 2013 reporting. Vaccination in pregnancy There have been persistent concerns that the vaccine virus might be teratogenic if given during pregnancy. Although vaccinees cannot infect other susceptible individuals, the virus can cross the placenta. Data from studies of children born to several hundred women inadvertently vaccinated up to 3 months before conception or during pregnancy show less than 3% with serological evidence of congenital infection, and no reported case of abnormalities attrib- utable to congenital rubella. At least 80 of these infants were born to women vaccinated in the month of conception, probably the period of greatest vulnerability. These data suggest that the likely maximum theoretical risk of rubella-​associated abnormalities is less than 5%. Likely developments • Elimination of rubella by further countries • Introduction of rubella vaccine in additional countries worldwide • Use of mathematical models to guide rubella vaccination strat- egies in different countries • Use of genotyping to track the source of rubella outbreaks as coun- tries approach elimination of rubella virus • Development of techniques for the diagnosis of congenital rubella syndrome after the age of 3 months FURTHER READING Banatvala JE, Brown DWG (2004). Rubella. Lancet, 363, 1127–​37. Banatvala JE, Peckham C (eds) (2007). Rubella viruses: perspectives in medical virology, vol. 15. Elsevier, London. Best JM, Icenogle JP, Brown DWG (2009). Rubella. In: Zuckerman AJ, et al. (eds) Principles and practice of clinical virology, 6th edition, pp. 561–​92. John Wiley & Sons, Chichester. Cooper LZ, Alford CA (2006). Rubella. In:  Remington JS, et  al.
(eds) Infectious diseases of the fetus and newborn infant, 6th edition, pp. 894–​926. Elsevier, Saunders, Philadelphia, PA. Department of Health (2013). Rubella. In: Immunisation against in- fectious disease—​‘the green book’. https://​www.gov.uk/​government/​ collections/​immunisation-​against-​infectious-​disease-​the-​green-
​book Goodson JL, et  al. (2011). Rubella epidemiology in Africa in the prevaccine era, 2002–​2009. J Infect Dis, 204(Suppl 1), S215–​25. HPA Rash Guidance Working Group (2011). Guidance on viral rash in pregnancy: investigation, diagnosis and management of viral rash illness, or exposure to viral rash illness, in pregnancy. http://​www.hpa. org.uk/​web/​HPAwebFile/​HPAweb_​C/​1294740918985 Robertson SE, et al. (2003). Rubella and congenital rubella syndrome: global update. Pan Am J Public Health, 14, 306–​15. World Health Organization (2012). Global measles and rubella: strategic plan: 2012–​2020. WHO, Geneva. http://​www.measlesrubellainitiative. org/​wp-​content/​uploads/​2013/​06/​Measles-​Rubella-​Strategic-​ Plan.pdf