Rubella Reappraisal

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					3 Desember 1977                             SA     MEDIESE         TYDSKRIF                                               953

                                      Rubella                   a Reappraisal
                                     S. WYNCHA K,              J. BARRO ,      A. KTPPS

                           SUMMARY                                ness and is often present for several days before the rash.
                                                                  The suboccipital or postauricular groups of lymph nodes
  Rubella infection is reviewed and new information about
                                                                  are most frequently enlarged. Fever, coryza and con·
  congenital infection, possible sources of infection in
                                                                  junctivitis are often !Jresent.
  pregnant women and the optimum ages and population
  groups for rubella vaccination is considered.
                                                                    Some strains of rubella virus are more likely to cause
    Investigations required to confirm a suspected and
                                                                  complication than others. Arthritis is not uncommon,
  possibly 'silent' infection during pregnancy are outlined.
                                                                  particularly among '10ung women, and usually involves the
                                                                  knee and hand joints. The arthritis is simultaneous with,
                                                                  or may precede, the rash. There is a persistence of joint
  5. AIr. med. l., 52, 953 (1977).                                pain in about 25 uo of these cases, ometimes resembling a
                                                                  carpal tunnel syndrome. Purpura is the next most common
RubelJa, a mild and common illness, is notorious for its          complication and may appear soon after the onset of the
teratogenic effects. Strenuous efforts to produce a rubella       rash. It may be associated with thrombocytopenia or with
vaccine succeeded, and this was licensed in the USA in            increased capillary fragility. Encephalitis, a rare compli-
1969 and is now included in the immunization schedules            cation occurring in about I in 5 000 cases, usually re-
of many countries. Since this is all common knowledge,            solves, but may leave a permanent change in the patient's
why should we appraise rubella now?                               EEG tracings.
   Recent work has shown that the situation is more                 Rubella is spread by droplet inhalation and is most in-
complex than was realized. Clinically unrecognized rubella        fectious during the incubation period in the week before
infection in a susceptible pregnant woman may result in           the rash appears, when the virus is present in the naso-
a congenitally infected baby. After an apparently normal          pharynx, urine and blood. In this way the pregnant
pregnancy and birth, deafness and/or other defects may            female may suffer a placental infection. The further ad-
become detectable only some years later owing to a 'silent'       vanced the pregnancy, the less likely it is that there will
congenital rubella infection.' The source of infection for        be fetal damage.
the pregnant woman has always been thought to be her
own and other children, but there is now some evidence                         CONGENITAL RUBELLA
that adults are more important in this respect than               The teratogenicity of the rubella virus was first deduced
                                                                  by Gregg,' an Australian ophthalmologist, in 1941. He
  The epidemiology of rubella varies from one country
                                                                  associated an increase in congenital cataracts with a
to another and congenitally acquired rubella is much less         rubella epidemic some months before, and established that
common in Japan than in Western countries," possibly
                                                                  all the mothers of the affected children had suffered
because of a reduced teratogenicity of the virus strains          rubella in early pregnancy.
there, or the particular HL-A subtypes of the population!
The optimal age and population group in which rubella                it was soon confirmed that if a pregnant woman ha
vaccination gives effective protection to the fetus is still      rubella at the time of fetal organogenesis, severe congenital
controversial' ewly studied rubella strains' appear to have       malformations may result. The classic 'congenital rubella
advantages over the attenuated strains presently used in          syndrome' includes cardiac abnormalities, deafness and
vaccines, in that, with no loss of antigenicity, they cause       cataracts. There are many other clinical manifestations of
fewer symptoms in the joints and may prove to be non-             congenital rubella affecting different tissues; including
teratogenic. This new knowledge is of immediate relevance         lungs, liver, blood, skin, central nervous system, lymph
to the practitioner of family medicine.                           nodes and immune system. They may be disseminated
                                                                  or localized in a single organ or in several organs. The
                                                                  virus has the ability to reduce mitotic frequency in viTro
                    CLINICAL COURSE                               and in vivo. The congenitally infected child may be sig-
The incubation period of 14'- 21 days is followed by a            nificantly smaller than the non-infected' and the virus
maculopapular rash which first appears about the face             may coexist with high titres of antibody" in the infected
and rapidly spreads downwards. Within 3 days the rash             child, but when virus excretion stops there is often a
fades. Lymphadenopathy may be the first sign of the ill-          sudden growth spurt.'·
                                                                     The late onset of the sequelae of congenital infection is
                                                                  also well known, and they may become apparent after
MRC/UCT Virus Research Unit and Department of Patholog}',
   University of Cape Town                                        months or years. These persistent infections include chronic
  . \VYNCHA. TK. D.PHll... F.I~ST.P_                              fluctuating rubelliform rash and generalized interstitial
J. BARRON. ~l.SC., ~l.B. CH.B.                                    pneumonitis." Mental retardation and psychiatric disorders
A. KIPPS,    ~LD., F.R.C. PATH.                                   are relatively common, while subacute sclerosing panen-
Dale received:   3 June 1977                                      cephalitis is rare."
 954                                          SA     MEDICAL          JOURNAL                                3 December 1977

   The true incidence of congenital rubella defects is not         guard. Certain enteroviruses and other viruses may also
apparent at birth. In a detailed studv Peckham' followed           cau e a rubella-like illness, with the typical rash and
up apparently normal children born to mothers who were              lymphadenopathy, and serological evidence must be present
in contact with rubella during pregnancy. She examined             to confirm infection in a pregnant patient, even if the patient
23 children at the age of 2 years, and found a wide                believes that she was infected with rubella in childhood.
range of defects. Eighty-five of these children were re-           Samples of blood for determination of rubella antibodies
examined when they were between 6 and 8 year of age,                 hould be taken immediately an infection is suspected,
and 7 were found to have hearing defects not previously            and then at appropriate intervals in the course of the ill-
present. This deafness, in all ca es irreversible, was bilateral   ness. The precise duration of the pregnancy at the time
in 3 children. Serological te ts indicated that all 7 children     of the suspected infection must be known. After a preg-
had been infected with congenital rubella. These finding           nant woman has had contact with a rubella-like illness,
stres the importance of long-term follow-up studies in             the dates of exposure and of appearance of the various
children with clinically silent rubella. If deafness results,      symptoms in the patient must be known. A woman can
the child's development may be severely affected, 0 early          contract rubella only if she was seronegative at the time
detection of hearing loss is vital to allow appropriate help       of exposure." A significant rise in the antibody titre con-
to be given to the child and to prevent superimpo ed               firms infection by rubella virus. Serum samples are taken
emotional problems.                                                weekly for about 3 weeks, starting immediately after ex-
    The manner in which the rubella virus causes deafness          posure. If a pregnant woman does contract rubella, the
 is not known. It may affect the central nervous system"           only certain way of knowing if the fetus has been affected
 a a result of a persistent virus infection or as a slowly         i by isolation of rubella virus from the amniotic fluid.
 developing lesion of the vascular supply. Information             An increase in the levels of nonspecific IgM and IgA
 about this slow action is sparse, because of the lack of          in the fluid has recently been shown to be unreliable in
 a suitable experimental animal model.                             deducing fetal infection."
                                                                      While awaiting results of the serological tests, a preg-
                                                                   nant woman at risk may be comforted by the information
              SEROPOSITIVE INFANTS                                 that most urban dwellers of her age are already immune
                                                                   and that casual contact with an established case of rubella
Long-term follow-up examination should be considered if            is unlikely to result in infection. But prolonged exposure
the neonate or infant is seropositive, a these children are        in the home or elsewhere, such as a school or a hospital,
at risk of developing later complications. In some hospitals       increases the risk of infection by a factor of about 5."
the cord blood is tested as a routine. Tn infants who were
initially eropositive, rubella antibody usually persists for
   or more years, but it may disappear by the age of 2                             RUBELLA VACCINE
or 3. 18
   Banatvala" has described the serological tests available         An attenuated live rubella virus suitable for use as a
for detecting antibodies to rubella. The best method of            vaccine was first produced in 1966." After administration
confirming congenital rubella infection is by isolation of          the virus may be excreted into the nasopharynx. There
the viru from the urine. Thi is possible only in the first         are now several different live attenuated virus vaccines
few weeks after birth and is technically difficult." How-          available, which have been passed through various cell
ever, this procedure may be necessary if there is a con-            lines. The vaccines are usually free of clinical reactions,
current agammaglobulinaemia.                                       although they may cause arthritis or arthralgia in about
                                                                   40°{, of those vaccinated, and they produce high antibody
   Tn the UK it has been found that the presence of per-
                                                                   levels which normally persist for longer than 4 years.
sistent rubella antibodies before the age of 3 years usually
                                                                   Although these vaccines often result in virus excretion,
denotes an intra-uterine infection, because natural in-
                                                                   they have not yet been proved to be a source of infection
fections before the 4th birthday occur in only 5 - 7% of
                                                                   to others.
children lS
                                                                       Rubella vaccine, in common with all other live virus
                                                                   vaccines, should never be given to any woman who is
       PREG ANT WOME               AND RUBELLA                     pregnant or who may become pregnant within 3 months.
                                                                   Tt has been reported from the USA that 317 women who
The main concern of many public health virological                 were vaccinated became pregnant just before or soon after
 laboratories is the accurate diagnosi of rubella, especially      administration of the vaccine." Of these, 138 had their
in the pregnant woman and her contacts. The diagnosis              pregnancies terminated by abortion and the rubella virus
is usually made by the finding of a rising antibody titre.         was isolated from a variety of tissues in 8 of the fetuses.
This can be established only if serial serum samples are           Thus attenuated live virus vaccines in current use can un-
available. Tn cases where they cannot be obtained, rubella         doubtedly cross the placenta and cause a chronic fetal
fgM should be estimated."                                          infection. The chance of congenital infection in a baby
   Tt is important to appreciate that a rubella infection may      after such a vaccination is between 5'% and 10%.19 Yet
present atypically, without a rash or any other recognizable       it is still not known whether vaccination may result in
sign or ymptom, in the pregnant woman and in other.                the major malformations found in children with intra-
Hence, a clinical diagnosis is not always an adequate safe-        uterine rubella infection.'"
3 Desember 1977                          SA     MEDIESE        TYDSKRIF                                                           955

             AGE AT VACCINATIO                                found in Europe and the Americas. An explanation for
                                                              fewer reports of rubella teratogenicity in Japan may arise
The optimum age at which a rubella vaccine should be          from other factors. In Japan intra-uterine rubella in-
given has been a matter of controversy. There are two         fection is not a sufficient reason for a therapeutic abortion.
schools of thought, both with the aim of reducing the         The Japanese may have a different susceptibility to fetal
possibility of intra-uterine rubella. In the USA mas          rubella.' Susceptibility to rubella may be linked to certain
immunity is sought by vaccinating all children between        HL-A subtypes (HL-AI and HL-A8) which are relatively
the ages of I and II years, thereby reducing the pool of      rare in the Japanese· It has also been shown that three
infection among the children wbence pregnant mothers          Japanese strains of rubella virus do induce significantly
may become infected. Susceptible mothers have been            higher levels of interferon in human placental tissue culture
vaccinated in the immediate postpartum period. In the         than do USA strains.' Currently available Japanese vaccines
   K, some other Western European countries and Australia,    compare favourably with others in producing high levels
selective vaccination of girls between the ages of II and     of rubella antibody and they are well tolerated.· Further
14 years has been practised. This is intended to cause        epidemiological evidence is awaited before it is certain
maximum antibody titres during tbe years when pregnancy       that the Japanese vaccine To-336 lacks any significant
is most likely to occur. Adults who are especially at risk,   teratogenic potential.
such as doctors, nurses and teachers, are also vaccinated
in botb programmes.
   These two types of vaccination schedules have been in        IMMUNITY FOLLOWING VACCINATIO
force since 1970. In the USA the numbers of reported
cases of both rubella and congenital rubella have de-         The assessment of immunity to rubella infection has, until
creased dramatically since 1969. and large-scale epidemics    recently, relied almost entirely on the demonstration of
have not occurred since that time. Yet in spite of this,      antibodies to the viral antigen. Little i known of the
there has been at least one well-documented, localized        development and measurement of cell-mediated immunity
epidemic of rubella (in Casper, Wyoming), during 1973.        after rubella vaccination. Rossier et al.," however, have
where, although most of the schoolchildren had been           drawn attention to the cell-mediated immune responses to
vaccinated, the risk of infection in pregnant women was       rubella virus in non-immune and naturally immune persons.
not significantly reduced! Further evidence, from Boston      as well as in vaccinated individuals. They found that after
in 1975,' also suggests that pregnant women are now in-       natural infections young adults had evidence of both
fected with rubella, mainly by other adults. This was         humoral and cell-mediated immunity, whereas a high
deduced from observations that primiparas were more           proportion of vaccinated persons showed no detectable cell-
likely to suffer rubella infection during pregnancy than      mediated immunity 4 - 5 years after vacrination, despite
women with one or more children. Gregg' also had ob-          the presence of rubella antibodies.
served this in 1941. The British National Congenital             These observations may well have a bearing on the
Rubella Surveillance Programme published a similar find-      high incidence of re-infection in 80% of vaccinated
ing in 1976, namely that 42% of children with con-            children in closed communities during epidemics of rubella
genital rubella were first-born."                             (evidenced by a 4-fold rise in rubella antibodies), and
   Hence, hopes that mass rubella vaccination would           only 4°~ re-infections among the naturally immune
emulate the success of diphtheria immunization in pro-        persons." Future studies on cell-mediated immunity in
ducing comprehensive immunity have not been realized.         rubella may stimulate a reconsideration of the suitability
Tt seems that it is preferable to vaccinate females who are   of vaccines presently available and may also add some
 oon likely to become pregnant and who will be pro-           weight to the decision to vaccinate all susceptible females
tected while vaccine-induced antibody levels remain high,      just before they enter the child-bearing period.
so girls aged 11 - 14 should be vaccinated.' Children who
are vaccinated at an early age may well be susceptible to                                  REFERENCES
infection by the time they become pregnant.
                                                                l. Peckham, C. S. (1972): Arch. Dis. Childh., 47, 57!.
   A recent survey of the first 6 years of the British         2. Schoenbaum, S. C., Biano, S. and Mack, T. (1975): J. Amer. med.
rubella vaccination programme" indicates that 71 % of              Ass., 233, 15!.
                                                               3. Polter, J. E., Banatvala, J. E. and Best, J. M. (1973): Brit. med. J.,
girls aged 11 - 14 years received vaccine. The uptake of           1. 197.
                                                               4. Honeyman. M. C., Dorman, D. C., Menser, M. A. et al. (1975):
vaccine varied between 61°b and 81~b according to region           Tissue Antigens,S. 12.
and between 48°{, and 72% according to type of school          5. Dudgeon, J. A. (1975): Practitioner, 215. 299.
                                                               6. Best, J. M .• Banatvala, J. E. and Bowen, J. M. (1974): Brit. med.
attended. So there has obviously been difficulty, in this          J., 3, 22l.
well-organized Western society, in attaining the required      7. Gregg,      . M. (1941): Trans. ophthal. Soc. AusLr., 3. 35.
                                                                   Cooper, L. ill Krugman, S. and Gershon, A. A., ed. (l9r): In-
level of protection, which must be virtually 100% to be            jections of (he Fetus and the Newborn Infant.        Yew York: AIan
                                                                   R. Lis.
effective in preventing congenital rubella infections in       9. Dudgeon, J. A., Butler, N. R. and Plotkin, S. A. (1964): Bri!.
communities where males and young children are not                 med. J., 2, 155.
                                                              10. Marshall, W. C. ill Dudgeon, J. A.. ed. (1973): IlIIrauterille In-
vaccinated.                                                        fectiolls. London: EJsevier.
                                                              I J. Forre t, J. M. and Menser, M. A. (1975): Aus!. paedial. J .. 11, 6-.
                                                              12. Ame, M. D., Plotkin, . A., Winchester, R. A. et al. (1970): J.
                                                                   Amer. med. As., 213, 419.
        NO ·TERATOGENIC VACCINES                              13. Hardy, J. B., Sever, J. L. and Gelke on, M. R. (1969): J. Pedial.,
                                                                   75, 213.
There is a strong possibility that some strains of rubella    14. Banatvala, J. E. (1972): Postgrad. med. J., 48, July suppl., p. 11.
                                                              15. Dudgeon, J. A., Peckham, C, S., Marshall, W. C. et al. (1973):
virus from Japan may be less teratogenic than those                Health Trends. 5, 75.
 956                                                 SA     MED1CAL               JOURNAL                                       3 December 1977

 16. Cederqvist, L. L., Zervoudakis, l. A., Ewool, L. C. et     al. (1977) :   21. Dudgeon. J. A. (National Congenital Rubel1a Survel1iance Programme.
     Brit. med. J., I. 615.                                                          London) (I 976): Personal communication.
 17. Parkman, P. D., Meyer, H. M., Kirschstein, R. L. et        al. (1966):    22. Peckham. C. S.. Marshall, W. C. and Dudgeon, J. A. (1977): Brit.
      ew Engl. J. Med., 275, 569.                                                    med. J .. I. 760.
     Modlin, J. F., Brandling-Bennett, A. D., Witte. J. J. et   al. (1975) :   23. Rossier. E., Phipps, P. H., Polley. J. R. et al. (1977): Canad. med.
     Pediatrics. 55, 20.                                                             Ass. J., 116, 463.
 19. Modlin. J. F., Hernnann. K.. Brandling-Bennetl. A. D. eT   al. (1976) :   2-1-. Horstman. D. M .. Liebhaber, H .. le BOllvier, G. L. el al. (1970):
     New Engl. J. Med., 294, 972.                                                    New Engl. J. Med.. 283. 771.
 20. Siegel, M. (1976): Amer. 1. Obstet. Gynec .. 124, 327.

                    The Epidemiology of Rubella In Cape Town
  A. KIPPS,          J. W. MOODIE,              S. WYNCHANK,                      MARGARET HODGKISS,                           A. F. MALAN

                              SUMMARY                                           physicians to collate all information on rubella for clinical
                                                                                evaluation, except a paper by McDonald and Heese,'
   This preliminary study indicates that a high proportion of
                                                                                giving an account of the clinical diagnosis of congenital
   adult females in Cape Town are immune to rubella, and
                                                                                rubella syndrome in 4 babies admitted to the Red Cross
   that, unlike the situation in the UK, natural rubella in-
                                                                               War Memorial Children's and Groote Schuur Hospitals
   fections are common before 4 years of age. At least 10
                                                                                between 1956 and 1965.
   children with the congenital rubella syndrome have been
                                                                                  An epidemic in spring-summer 1975 was followed in
   seen in the Cape Town group of teaching hospitals in a
                                                                                1976 by the admission of 3 babies with signs suggestive
   5 Y2-year period since October 1971. Continuous sero-
                                                                               of congenital rubella infection. These 3 children were
   logical surveillance is essential in order to implement the
                                                                                born in April and May 1976 and were apparently in-
   most effective programme of immunization in any
                                                                               fected in l/lerO during the epidemic. At the same time
   particular area and also to be able to determine whether
                                                                               normal babies were born to 2 mothers who had had
   the vaccine is successfully preventing the birth of children
                                                                               clinical evidence of rubella early in pregnancy.
   with congenital rubella infection.
                                                                                  This cluster of cases stimulated us to record other con-
                                                                               firmed or suspected cases of congenital rubella in this
   5. A fr. med. 1., 52, 956 (1977).                                           area in recent years.
                                                                                  In the absence of some system of surveillance and case
Information on the epidemiology of rubella in the Re-                          reporting it is difficult to give even a crude estimate of
public of South Africa is woefully incomplete. The disease                     the rate of rubella attacks or to draw a baseline for the
is not notifiable and there are no available reports of                        incidence of congenital rubella infections. Without this
nationwide epidemics or of the incidence of congenital                         type of information it is not possible to confirm the
rubella infections in the general population. James' re-                       wisdom or necessity of vaccinating all prepubertal school-
corded 'the fairly frequent appearance of polyarthritis' in                    girls of the different racial groups, or to decide whether
patients during 'possibly the worst epidemic of rubella                        any particular immunization programme is in fact achiev-
to have occurred in this part of the country' (Cape Town).                     ing what it was intended to do.
which lasted about 9 months from mid-1963 to the end of                           Fortunately it is possible, by testing serum for the
summer 1964. There was no response to his appeal to                            presence of rubella antibodies, to establish the immune
                                                                               status of the individuals in the various age groups within
                                                                               the communities, and to design an appropriate programme
MRC/Ucr Virus Research Unit and Department of Paedia-                          to protect the unborn children of pregnant mothers from
   trics and Child Health, University of Cape Town                             the dangers caused by rubella virus. It goes without saying
A. KIPPS, l\f.D., F.R.C.PATH.                                                  that there should be reference laboratories in at least the
J. "',I. MOODIE. M.D.
S. WYNCHANK, D.PHIL., F.Il'ST.P.                                               major municipal centres for the investigation of all babies
MARGARET HODGKISS, DIP. :MED. TECH.                                            suspected of having congenital infection, for the assess-
A. F. MALAN, M.MED. (PAED.)                                                    ment of the immune status of prepubertal females, and
Date received: 3 June 1977.                                                    for the serological confirmation of rubella in pregnancy.


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