Since 1988, physicians in England and Wales have been required by law to report clinically suspected cases of rubella to the proper officer at the local health authority (usually a public health consultant in a Health Protection Unit [HPU]). Since late 1994, when a report is received, the HPU sends an oral fluid kit to the primary-care physician or patient for confirmatory testing. The kit is then returned by prepaid envelope to the Virus Reference Department at the Health Protection Agency Centre for Infections for analysis. A request form contains vaccination history and, until July 2003, some brief clinical features (presence of a rash, fever, conjunctivitis, cough, and lymphadenopathy [type not specified]). Oral fluid testing was also used to test cases that were not formally reported as part of outbreaks in 3 universities associated with imported virus from Greece in 1999 (17). A similar process is used for measles (and mumps) (18,19). If there is a strong clinical or epidemiologic suspicion of rubella in samples tested for measles and for measles in samples tested for rubella, dual testing is performed.

Oral (crevicular) fluid specimens, obtained by wiping a specially designed sponge swab (oral test kit [Oracol; Malvern Medical Developments, Worcester, UK]) around the gum margins, were tested for rubella-specific IgM initially by using a solid-phase IgM–antibody capture radioimmunoassay (20). After 2002, an in-house assay for rubella IgG was introduced (21), and after 2003, all samples taken within 1 week after symptom onset that were negative for rubella IgM and rubella IgG were tested by reverse transcription–PCR for rubella virus (14). In 2006, the rubella solid-phase IgM–antibody capture radioimmunoassay was replaced by a commercial enzyme immunoassay (22).

Results of testing were sent to the reporting physician, and copies were sent to the relevant HPU. Confirmed cases were defined as samples positive for rubella-specific IgM in oral fluid or detection of rubella virus genome by PCR in persons without a history of receipt of rubella vaccine in the previous 6 weeks. These cases were reconciled with confirmed rubella infections (positive for rubella IgM in serum) reported to the Health Protection Agency Centre for Infections, from laboratories in England and Wales, and duplicates are removed. Since 1999, residual samples from cases reported by local laboratories are requested to be sent to the national reference laboratory for confirmation by an alternative IgM assay (with or without avidity testing) (23). Cases with negative results for the second IgM test or with high avidity are then excluded from the confirmed total. Further details (including travel and contact history) are requested, and vaccination status is checked for all confirmed case-patients.

Data obtained during January 1995–July 2003 were analyzed to estimate the sensitivity and specificity of a clinical case definition. The WHO definition of a case of rubella is a generalized maculopapular rash and fever and arthralgia/arthritis or cervical, suboccipital, or postauricular lymphadenopathy (5). Because information for arthritis was not routinely obtained, the accuracy of a modified case definition based on rash, fever, and lymphadenopathy was calculated against the standard of presence or absence of rubella-specific IgM in an oral fluid sample. The sensitivity, specificity, and positive predictive value were compared by patient age, sex, and year of report.

Data obtained during January 1999–December 2008 from 3 sources (clinically reported cases, confirmation in oral fluid samples, and laboratory reports) were then compared with respect to age, sex, vaccination status, and region. Rates were calculated by using 2001 population estimates from the Office for National Statistics. The incidence rate for cases confirmed positive by oral fluid was adjusted for the proportion of reported cases tested in each region and compared with the rate from laboratory reports alone. All analyses were conducted by using Stata/SE version 9.2 (StataCorp LP, College Station, TX, USA). Proportions were compared by using the χ² test.

Before vaccination was introduced, epidemics of rubella occurred regularly and caused mild rash illness, predominantly in children. In 1970, introduction of a selective vaccination policy in the United Kingdom aimed to reduce the risk for infection in early pregnancy and the risk for fetal death and CRS. Despite the success of the selective policy, MMR was adopted into the routine childhood vaccination schedule to eliminate circulating rubella and to further reduce the risk for CRS.

Since 1988, a clinical diagnosis of rubella has been reportable by registered medical practitioners in England and Wales under the statutory Notification of Infectious Diseases; there is no case definition. When an infection is commonly occurring in an area, the positive predictive value of a clinical diagnosis may be sufficient for accurate surveillance (24). However, because rubella has become less common, an increasing proportion of reported cases are likely to be caused by other infections that have similar clinical manifestations. The rash of rubella may be temporary and can resemble the rash caused by other viruses. For example, infection with parvovirus B19, human herpesvirus 6 (roseola infantum), and human herpesvirus 7 all involve rash and fever and may be misdiagnosed as rubella (25,26).

We have confirmed the low sensitivity and specificity of the clinical case definition and that this definition is not affected by age, sex, and period of reporting. Despite some missing clinical information and the absence of information about arthralgia, this finding suggests that the WHO clinical case definition is not sufficiently accurate for surveillance in the postvaccine era. This finding also emphasizes the need to have laboratory confirmation of all clinically diagnosed cases to accurately monitor rubella elimination (27).

Over the 10-year period of elimination, only ≈1 of 100 persons reported with clinically diagnosed rubella and who underwent oral fluid testing had confirmed cases. In addition, reported cases differed from laboratory-confirmed cases with respect to patient age, sex, vaccination status, and geographic distribution. We have therefore shown that surveillance based only on clinical reports would substantially overestimate the true incidence of rubella, particularly in children, and therefore give a misleading epidemiologic picture. Furthermore, we have shown that testing of oral fluid is acceptable in the United Kingdom and can be used to augment routine serologic diagnosis. Approximately one third of confirmed rubella cases were diagnosed by testing of oral fluid, which improved ascertainment of confirmed infections in children and men. In addition, by using PCR, we obtained genotype information on 12 samples that would have otherwise not been available.

Currently, there is only 1 commercial assay for testing rubella IgM in oral fluid, and this assay does not have an In Vitro Diagnostics license, thus limiting its use in some countries. However, in many regions, WHO is evaluating this assay as a tool for surveillance of infection (28; K. Brown, pers. comm.) Although the UK system relies upon a well-organized postal service, alternative approaches for delivering and receiving specimens directly from the patient’s home or family practice may be required in other countries considering the use of oral fluid.

In addition to antibody testing, oral fluid can be used for rubella RNA detection in samples obtained early during infection (13) and for genotyping and molecular epidemiologic studies (14,15). Tests for detecting rubella-specific IgM and RNA in oral fluid samples are also suitable for confirming a diagnosis of CRS (11). The same system is also being used to monitor measles and mumps incidence and to inform MMR vaccine policy in England and Wales (18,19,29,30).

Oral fluid testing can also be used to evaluate the completeness of rubella surveillance. Since 1999, the number of reports of rubella and oral fluid tests performed annually has remained constant, and the proportion of cases tested has remained high. When combined with a low rate of confirmation, including cases diagnosed as clinical rubella, in a country with free universal access to high-quality primary-care physicians, this finding suggests that surveillance of confirmed rubella is nearly complete in England and Wales. Despite this suggestion, annual incidence of confirmed rubella remains <1 per 1 million population, which is the goal for elimination (4).

In recently published surveillance guidelines, WHO has recommended IgM detection, which can be performed with serum and oral fluid (31). These guidelines also describe performance indicators to assess the quality of national surveillance systems in the elimination phase. These indicators include a laboratory investigation rate (proportion of clinically suspected cases with adequate specimens for IgM testing) >80% and a detection rate for the number of clinically suspected rubella cases investigated and discarded by laboratory testing >2/100,000 population/year. Data from the enhanced surveillance program show that for ≈84% of reported cases, oral fluid was tested, and 2,208 clinically suspected rubella cases per 100,000 population were investigated and discarded. This high discard rate would be feasible only with noninvasive testing and contributes to the high quality of the UK enhanced surveillance program. Information about the low rate of rubella supplements surveillance that confirms that CRS incidence in the United Kingdom was 0.14/100,000 live-born infants in 2007 (32), which was far below the WHO elimination goal of 1/100,000 live-born infants (4).

We confirmed that a clinical case definition alone is not sufficiently specific for surveillance of rubella in the elimination era and that laboratory confirmation by testing serum samples is biased and incomplete. Since 1999, a substantial proportion of confirmed cases of rubella identified through the enhanced surveillance scheme have occurred in unvaccinated men. With the availability of oral fluid testing, a high number and high proportion of suspected cases have been tested. However, numbers of confirmed rubella cases in children remain low, which is consistent with high levels of vaccine coverage and low levels of susceptibility in this younger age group (33). The enhanced oral fluid surveillance system has proven valuable for accurately assessing progress toward achieving the WHO goal of eliminating circulating rubella and CRS from the population of England and Wales.