Indication - Vaccine-preventable diseases
Rubella IgM antibody
First added in 2020
To diagnose active rubella infection or recent exposure
Serum, Plasma, Dried blood spots, Oral fluid
WHO prequalified or recommended products
WHO supporting documents
Manual for the laboratory diagnosis of measles and rubella virus infection https://www.who.int/immunization/monitoring_surveillance/burden/laboratory/Manual_lab_diagnosis_of_measles_rubella_virus_infection_ENG.pdf?ua=1 Manual for the laboratory-based surveillance of measles, rubella, and congenital rubella syndrome https://www.who.int/immunization/monitoring_surveillance/burden/laboratory/manual/en/ Surveillance standards for vaccine-preventable diseases, 2nd edition https://apps.who.int/iris/handle/10665/275754 The immunological basis for immunization series. Module 11: rubella. Geneva: World Health Organization; 2008. https://apps.who.int/iris/handle/10665/43922 WHO. Rubella vaccines: WHO position paper. Weekly epidemiol record. 2011;29(86):301–316. https://www.who.int/wer/2011/wer8629.pdf?ua=1
ICD11 code: 1F02
Summary of evidence evaluation
Rubella IgM testing is a routine part of investigating possible infections, as indicated in WHO measles and rubella surveillance standards. Little evidence was provided that quantifies the usefulness of the rubella IgM test. However, the GMRLN tests approximately 100 000 serum specimens annually using an IgM EIA, signalling the availability of data supporting the use of the test. The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3
Summary of SAGE IVD deliberations
Rubella IgM testing is a routine part of investigating possible infections, as indicated in WHO rubella surveillance standards. Screening for rubella serostatus is recommended, in certain countries, as part of standard prenatal screening if a pregnant woman has no record of past immunity and no proof of immunization. The use of rubella IVDs to ensure eventual eradication is key to reducing inequity globally. The submission does not include data quantifying the usefulness of the test. But SAGE IVD acknowledged that IgM testing is used as a standard diagnostic tool across the world and forms an integral part of the case definition for rubella. Furthermore, while not included in the submission, the recent literature includes a body of recommendations on assay accuracy that document and analyse decades of work with IgM assays. Sensitive and specific assays for detection are available to match a wide range of laboratory and testing capacities.
SAGE IVD recommendation
SAGE IVD recommended the inclusion of the rubella IgM antibody test category in the third EDL: • as a disease-specific IVD for clinical laboratories (EDL 3; Section II.b, Vaccine-preventable diseases); • using an immunoassay format; • to diagnose active rubella infection or recent exposure. The group further recommended that the rubella IgM antibody listing in EDL 3 should be clearly accompanied by a link to WHO guidelines on rubella vaccines, including: • The immunological basis for immunization series. Module 11: Rubella. Geneva: World Health Organization; 2008 (https://apps.who.int/iris/bitstream/handle/10665/43922/9789241596848_eng.pdf?sequence=1) • WHO. Rubella vaccines: WHO position paper. Weekly Epidemiol Record. 2011;29(86):301–316 (https://www.who.int/wer/2011/wer8629.pdf?ua=1).
Details of submission from 2020
Disease condition and impact on patients Rubella is a contagious infectious disease that affects unvaccinated children and young adults. The virus is easily transmitted by respiratory droplets from an infected individual. Childhood infection is often mild and resolves without complication. But if an unvaccinated woman gets rubella in early pregnancy serious consequences can result, including miscarriage, fetal death, stillbirth and having an infant born with CRS. CRS results in a group of devastating birth defects that include blindness, deafness and heart problems. More than 100 000 children are born every year with CRS, mainly in Africa, South-East Asia and the Western Pacific (1, 2). Rubella vaccine is highly effective and safe when used across a population; as a result, endemic rubella transmission has been interrupted in the Americas since 2009. Incomplete rubella vaccination programmes result in continued disease transmission, as evidenced by large outbreaks in recent years in Japan and elsewhere. Countries with high rates of susceptibility to rubella among women of childbearing age are at highest risk for CRS. This risk varies between and within countries based on epidemiological and socioeconomic differences (3). An economic burden study in Romania suggests rubella outbreaks have high costs and considerable economic impact (4). Does the test meet a medical need? If a person tests positive for IgM, a recent or current infection is detected. While the symptoms may not be severe for that particular person, if they come into contact with others, particularly women in early pregnancy, the outcome can be severe for the fetus and child. Outbreaks can occur in countries where vaccination programmes are not routine, with severe consequences. A rise in vaccine hesitancy means they can also occur in HICs where the disease has previously been eradicated. Steps such as quarantining infected individuals and testing and vaccinating unvaccinated family members (or those who have not been previously exposed) is critical; no medications or treatments can prevent the disease other than vaccination or exposure. IVDs are critical to manage and control the spread of the disease. In an elimination setting, where every single case of rubella must be identified, sensitive, specific, high-quality standardized tests are required to support swift public health interventions. How the test is used The test supports a final diagnosis on its own to detect active disease or recent exposure. Given the high incidence of rubella, and the fact that several countries have not eliminated it (despite having an elimination goal), laboratory investigation by IgM testing for potential rubella cases and CRS is essential, with a huge positive public health impact. Laboratory confirmation of a suspect rubella case heavily relies on specific IgM serology.
Public health relevance
Prevalence and socioeconomic impact WHO recommends that all countries that have not yet introduced rubella vaccines should consider doing so using existing, well-established measles immunization programmes. To date, four WHO regions have established goals to eliminate this preventable cause of birth defects. In 2015, the WHO Region of the Americas became the first in the world to be declared free of endemic rubella. The number of countries using rubella vaccines in their national programme continues to steadily increase. By December 2018, 168 out of 194 countries had introduced rubella vaccines and global coverage was estimated at 69%. Reported rubella cases declined 97%, from 670 894 cases in 102 countries in 2000 to 14 621 cases in 151 countries in 2018 (5, 6). CRS rates are highest in the WHO African and South-East Asia regions, where vaccination coverage is lowest. In April 2012, the Measles Initiative – now known as the Measles & Rubella Initiative – launched its Global Measles and Rubella Strategic Plan for 2012–2020 (7). The plan articulates a series of global goals, which include achieving measles and rubella elimination in at least five WHO regions. Based on the 2018 Global Vaccine Action Plan Assessment Report by SAGE Immunization, rubella control is lagging (8), with 26 countries still to introduce the vaccine, while two regions (Africa and Eastern Mediterranean) have not yet set rubella elimination or control targets. SAGE Immunization recommends incorporating rubella vaccination into immunization programmes as quickly as possible to ensure additional gains in controlling rubella.
WHO or other clinical guidelines relevant to the test
WHO rubella surveillance standards (9) define a laboratory-confirmed case of rubella as a suspected case of rubella that has been confirmed by an IgM positive result by EIA; a significant rise in serum rubella IgG titre; or rubella PCR positive. These standards also recommend using rubella IgM testing in elimination settings to confirm cases). WHO recommends collecting specimens on first contact with the case without waiting for the ideal window, to avoid loss to follow-up. The follow-up serum sample for IgM testing should be collected after day 5 post-rash onset for rubella IgM retesting. Samples should still be collected on first contact with the case. However, IgM detection by EIA for rubella is more sensitive when collected 6–28 days after the onset of rash. A second serum sample may be required for additional testing under the following circumstances: • Detection of virus-specific RNA by RT-PCR is either unavailable or the results were inconclusive. • The first serum specimen was collected ≤ 3 days after rash onset and is negative for measles IgM, or is negative in serum collected ≤ 5 days for rubella IgM by EIA. • Repeat testing of the initial serum specimen fails to resolve an equivocal result for IgM. WHO offers governments and communities technical support to improve routine immunization programmes and hold targeted vaccination campaigns. The WHO GMRLN supports the diagnosis of rubella and CRS cases and the tracking of rubella virus spread. EIAs are the most commonly used and widely available diagnostic test for rubella IgM and IgG antibodies; they are sensitive and relatively easy to perform.
Evidence for diagnostic accuracy
No systematic reviews of IgM test clinical accuracy were found. One primary study (10) comparing three immunoassays, based on 57 samples from individuals with recent rubella and 220 samples from those without infection, showed sensitivities of the assays to range from 84.2% to 96.5%, and the specificities to range from 96.8% to 99.9%.
Evidence for clinical usefulness and impact
Despite much progress in tackling rubella, it remains an important pathogen and public health concern around the world. For example, the rubella epidemic in Japan, with more than 11 000 rubella cases and at least 13 CRS cases in the first 6 months of 2013, highlights the fact that a partial vaccination strategy can lead to major outbreaks (3). In the Japanese outbreak, 70% of the rubella cases were among males aged 20–39 years, indicating the weakness of the commonly used strategy to only give the rubella vaccine to adolescent girls. In 2012, Poland and Romania also experienced rubella outbreaks that predominantly affected males as a result of a vaccination strategy that initially focused on vaccination of females. For this reason, a global commitment to rubella control, elimination and eventual eradication must be in place. Rubella virus is a candidate for global elimination because humans are the only known host, safe and highly effective vaccines (> 95% following a single dose) exist, accurate diagnostic assays exist and sustained interruption of endemic transmission has been demonstrated in the Americas since 2009. Data from different African countries (11) and WHO surveillance data on vaccine preventable diseases suggest that rubella virus is common. They also point to a large number of susceptible women of childbearing age, highlighting the potential risk of acquiring CRS. Diagnostic tests will have a high impact on intervention with vaccines and patient outcomes. A French survey (12) found that the proportion of 18–32-year-olds susceptible to both measles and rubella infections remained high in France even after promotion campaigns about vaccination during and after the major 2009–2011 epidemic, further suggesting the importance of diagnostic intervention for follow-up. An Australian serological test survey (13) before and after a vaccination campaign found that susceptibility to rubella varied considerably between age groups and by sex. Before the vaccination campaign, 40% of children aged 10–12 years were susceptible to rubella; they were too old to have received rubella vaccine in infancy and too young to have received an adolescent dose. These differences disappeared after the campaign, when only 6% of preschool and 5% of primary school-aged children remained susceptible, suggesting the importance of diagnostic tools. IgM assays can detect rubella active infection during an outbreak to support patient management, particularly of pregnant women and CRS cases.
Evidence for economic impact and/or cost–effectiveness
A cost analysis for IVDs is not available, but cost–effectiveness of the vaccine can translate to IVD value as treatment for CRS is very costly.
Ethical issues, equity and human rights issues
1. Disease and epidemiology. In: EMRO/Rubella . Cairo: WHO Regional Office of the Eastern Mediterranean; 2020 (http://www.emro.who.int/health-topics/rubella/disease-and-epidemiology.html, accessed 11 March 2020). 2. More about measles, rubella and congenital rubella syndrome (CRS) worldwide. In: CDC/Global Health . Atlanta: US Centers for Disease Control and Prevention; 2020 (https://www.cdc.gov/globalhealth/measles/facts.htm, accessed 11 March 2020). 3. Lambert N, Strebel P, Orenstein W, Icenogle J, Poland GA. Rubella. Lancet. 2015;385(9984):2297–2307. doi:10.1016/S0140-6736(14)60539-0. 4. Njau J, Janta D, Stanescu A, Pallas SS, Pistol A, et al. Assessment of economic burden of concurrent measles and rubella outbreaks, Romania, 2011–2012. Emerg Infect Dis. 2019;25(6):1101–1109. doi:10.3201/eid2506.180339. 5. Rubella. In: WHO/Newsroom . Geneva: World Health Organization; 2020 (https://www.who.int/news-room/fact-sheets/detail/rubella, accessed 11 March 2020). 6. Lanzieri T, Redd S, Abernathy E, Icenogle J. Chapter 14: Rubella. In: Roush SW, Baldy LM, Kirkconnell Hall MA, editors. Manual for the surveillance of vaccine-preventable diseases. Atlanta: US Centers for Disease Control and Prevention; 2020. 7. Measles & Rubella Initiative . Washington DC: American Red Cross; 2020 (https://measlesrubellainitiative.org/, accessed 11 March 2020). 8. Immunization today and in the next decade: 2018 assessment report of the Global Vaccine Action Plan. Geneva: World Health Organization; 2018 (WHO/IVB/18.11). 9. Rubella. In: Surveillance standards for vaccine-preventable diseases, 2nd edition. Geneva: World Health Organization; 2018. 10. Dimech W, Panagiotopoulos L, Marler J, Laven N, Leeson S, et al. Evaluation of three immunoassays used for detection of anti-rubella virus immunoglobulin M antibodies. Clin Diagn Lab Immunol. 2005;12(9):1104–1108. doi:10.1128/CDLI.12.9.1104-1108.2005. 11. Mirambo MM, Majigo M, Aboud S, Groß U, Mshana SE. Serological makers of rubella infection in Africa in the pre vaccination era: a systematic review. BMC Res Notes. 2015;8:716. doi:10.1186/s13104-015-1711. 12. Antona D, Morel P, Jacquot C, Fonteneau L, Dina J, et al. Measles and rubella seroprevalence in a population of young adult blood donors, France 2013. Epidemiol Infect. 2019;147:e109. doi:10.1017/S0950268819000050. 13. Gilbert GL, Escott RG, Gidding HF, Turnbull FM, Heath TC, et al. Impact of the Australian measles control campaign on immunity to measles and rubella. Epidemiol Infect. 2001;127(2):297–303. doi:10.1017/s0950268801005830.