Indication - Vaccine-preventable diseases
Measles IgM antibody
First added in 2020
To diagnose clinically suspected measles infection
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: 1F03
Summary of evidence evaluation
IgM is part of the standard diagnosis of measles; it is often part of the reference standard; and it is recommended in WHO guidelines. There are no studies comparing the results of this test against an independent reference standard (given that it is effectively part of the case definition). The test is embedded in WHO protocols for testing for measles. Many clinical cases are confirmed by a positive IgM. Evidence supporting the inclusion of IgM is largely based on experience that it confirms a measles diagnosis in most cases outside elimination settings. 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
Measles is a highly infectious disease of public health concern, and eradication requires concerted effort to identify outbreaks and stop chains of transmission. Despite being a common and severe condition, there is currently no test category listed for measles in the EDL. Detection of measles IgM is part of the case definition within WHO guidelines and is already established as the gold standard method for diagnosing acute measles. It is especially critical for confirming cases in an outbreak context. SAGE IVD noted that in all settings the test should be reserved for people with clinically suspected measles and is not appropriate as a screening tool for asymptomatic patients. The reviews submitted show that the test has good clinical accuracy and performance. SAGE IVD members acknowledged that the test is available in some RDT formats; but this application is only considering an EIA format for use in clinical laboratories. To that end, the group noted that the test is technically easy to perform by laboratory technicians with basic training. But it does require a laboratory with ambient environmental conditions and a regular power supply; moreover, it may be costly in LMICs and resource-constrained settings (although it is still cheap compared with PCR tests).
SAGE IVD recommendation
SAGE IVD recommended including the measles IgM test category in the third EDL: • as a disease-specific IVD for use in clinical laboratories (EDL 3, Section II.b, Vaccine-preventable diseases); • using an immunoassay format; • to diagnose clinically suspected measles infection.
Details of submission from 2020
Disease condition and impact on patients Measles, an acute illness caused by a virus in the family Paramyxoviridae, genus Morbillivirus, is one of the most highly infectious diseases known to humankind. Symptoms include fever (as high as 38 °C) and malaise, cough, coryza and conjunctivitis, followed by a maculopapular rash (1). Measles is generally a mild or moderately severe illness but can, if not diagnosed or treated, result in complications such as pneumonia, encephalitis and death. A rare long-term sequela of measles virus infection is SSPE, which is a fatal disease of the CNS that generally develops 7–10 years after infection (1, 2). Measles case fatality rates vary from 0.1% in HICs to 15% in LMICs (2). Does the test meet a medical need? Accurate diagnostic tests for measles infection are essential to confirm cases and outbreaks. A single laboratory-confirmed measles case should trigger an aggressive public health investigation and response in an elimination setting (3). How the test is used IgM testing requires the collection of serum samples, ideally between 4 and 28 days from rash onset. In elimination settings, or if the patient was vaccinated for measles within the past 6 weeks, confirmation of an IgM-positive or equivocal test is required, by repeat IgM testing (10–28 days after first test); seroconversion testing with IgG (where the first, acute, sample is collected no later than seven days from rash onset and the second, convalescent, sample is collected 10–28 days later); RT-PCR testing; or through clinical evidence or an epidemiological link. If samples are collected at the ideal times, an IgM-negative result rules out infection. If the sample was collected within 3 days of rash onset, IgM-negative results are confirmed with RT-PCR, and repeat IgM testing (≥ 6 days after onset of rash) is advised if the case remains suspicious for measles. Laboratory case confirmation for measles can yield the following test results: • Detection of anti-measles IgM antibody by EIA. This is the gold standard. • Diagnostically significant titre change in IgG antibody level in acute or convalescent sera, or documented seroconversion (IgG negative to IgG positive), positive RT-PCR or viral isolation in cell culture.
Public health relevance
Prevalence Significant gains towards measles elimination have been made with a highly effective measles vaccine. Countries in all six WHO regions have adopted measles elimination goals, and four WHO regions endorsed the Global Vaccine Action Plan to eliminate measles by 2015. Not all of the plan’s goals were accomplished, but measles was successfully eliminated through comprehensive vaccination and surveillance in 61 Member States in the Region of the Americas, and the European and Western Pacific regions (2). Still, in many parts of the world, the disease remains endemic. In 2015, there were 254 928 cases reported and an estimated 134 200 measles deaths globally (1). In 2019, the greatest number of cases were reported from the Indian subcontinent, where annual incidence rates exceeded 50 per million population. Other areas of Africa, Asia, Europe, Central and South America, and the Pacific also have large annual numbers of measles cases (4). Vaccine hesitancy remains an obstacle to measles elimination and has been identified by WHO as one of the major threats to global health in 2019. International travel also allows measles importation from endemic countries and has contributed to a resurgence of the disease in high-income countries and countries previously thought to be free of the disease (4). For example, in the USA, even though measles was officially eliminated in 2000, occasional outbreaks (three or more linked cases) are still reported to the CDC every year, often imported from overseas and spreading among communities with low rates of immunization (4). Socioeconomic impact Measles outbreaks can place a heavy economic burden on local and state public health institutions. USA outbreaks in 2011 cost an estimated US$ 2.7–5.3 million (5); 2015 outbreaks cost between US$ 0.25 million and US$ 1.35 million (6). Estimates from the 2013 outbreak in New York City cost the city’s Department of Health and Mental Hygiene US$ 400 000 (7). And in 2016, it was estimated that each case of measles cost the public sector US$ 20 000 (8). Outside the USA, total costs associated with measles in the Netherlands from 2013 to 2014 were estimated at US$ 4.7 million (9); in Italy outbreaks in 2002 and 2003 cost between €17.6 million and €22 million, respectively (10). Total societal costs from outbreaks in Romania in 2011 were estimated at US$ 5.5 million (11). In addition, a study of 3207 laboratory-confirmed measles cases reported by Public Health England from January 2012 to June 2013 resulted in an estimated loss of 44.2 QALYs (12).
WHO or other clinical guidelines relevant to the test
The 2018 WHO manual for laboratory-based surveillance of measles, rubella, and congenital rubella syndrome (13) recommends routine testing of all suspected cases of measles or rubella for both measles and rubella IgM, as well as initial testing of all samples for measles IgM. Detection of measles IgM in a single serum specimen is the standard method for rapid laboratory confirmation of measles. The 2018 WHO surveillance standards for vaccine-preventable diseases (3) also recommend using measles IgM for laboratory confirmation and stipulate that results of IgM should be reported within 4 days of the specimen’s arrival to the laboratory.
Evidence for diagnostic accuracy
No systematic reviews of IgM test clinical accuracy were available. Four primary studies (14–17) were reviewed. All studies concluded that use of IgM alone does not reach 100% sensitivity for diagnosis of acute cases. The sensitivity and specificity ranges reached in these studies were: • Bolotin et al. (14): 79.2% and 65.7%, respectively (21 299 tests in elimination setting of Canada). • Tipples et al. (15): 87.9–96.7% and 94.6–98.7%, respectively. • Ma et al. (16): 56.53% sensitivity on 0–3 day post-rash but 82.06% on days 4–28 post-rash. • Ratnam et al. (17): similar conclusions on higher sensitivity in convalescent sera and in sera collected at 6–14 days. In their evaluation of 308 positive and 454 negative samples, indirect ELISAs had lower sensitivity (82.8–88.6%) and specificity (86.6–99.6%) than commercially available IgM capture ELISAs (sensitivity 92.2%, specificity 86.6%). WHO evaluations of assays used in the Global Measles and Rubella Laboratory Network (GMRLN)noted that “confidence in the accuracy of laboratory classification provided by routine IgM testing is very high”, but also noted that the assays have inherent limitations that should be considered while interpreting results (13).
Evidence for clinical usefulness and impact
The clinical utility of measles diagnostic tests relates to the ability of the tests to confirm or rule out suspected cases, and one confirmed case results in extensive outbreak control strategies. A study in outbreak setting by Mosquera et al. (18) used various methods to diagnose measles infection and concluded that IgM testing supplemented by PCR or virus isolation identifies maximum patients.
Evidence for economic impact and/or cost–effectiveness
No data available.
Ethical issues, equity and human rights issues
1. Gastanaduy PA, Redd SB, Clemmons NS, Lee AD, Hickman CJ, et al. Chapter 7: Measles. 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; 2014. 2. Orenstein WA, Cairns L, Hinman A, Nkowane B, Olivé JM, et al. Measles and rubella global strategic plan 2012–2020 midterm review report: background and summary. Vaccine. 2018;36(Suppl 1):A35–A42. doi:10.1016/j.vaccine.2017.10.065. 3. Surveillance standards for vaccine-preventable diseases, 2nd edition. Geneva: World Health Organization; 2018. 4. O’Donnell S, Davies F, Vardhan M, Nee P. Could this be measles? Emerg Med J. 2019;36:310–314. doi:10.1136/emermed-2019-208490. 5. Ortega-Sanchez IR, Vijayaraghavan SM, Barskey AE, Wallace GS. The economic burden of sixteen measles outbreaks on United States public health departments in 2011. Vaccine. 2014;32(11):1311–1317. doi:10.1016/j.vaccine.2013.10.012. 6. Ozawa S, Portnoy A, Getaneh H, Clark S, Knoll M, et al. Modeling the economic burden of adult vaccine-preventable diseases in the United States. Health Aff. 2016;11:2124–2213. doi:10.1377/hlthaff.2016.0462. 7. Rosen JB, Arciuolo RJ, Khawja AM, Fu J, Giancotti FR, et al. Public health consequences of a 2013 measles outbreak in New York City. JAMA Pediatr. 2018;172(9):811–817. doi:10.1001/jamapediatrics.2018.1024. 8. Lo NC, Hotez PJ. Public health and economic consequences of vaccine hesitancy for measles in the United States. JAMA Pediatr. 2017;171(9):887–892. doi:10.1001/jamapediatrics.2017.1695. 9. Suijkerbuijk AWM, Woudenberg T, Hahné SJM, Lochlainn LN, de Melker HE, et al. Economic costs of measles outbreak in the Netherlands, 2013–2014. Emerg Infect Dis. 2015;21(11):2067–2069. doi:10.3201/eid2111.150410. 10. Filia A, Brenna A, Panà A, Cavallaro GM, Massari M, et al. Health burden and economic impact of measles-related hospitalizations in Italy in 2002–2003. BMC Public Health. 2007;7:169. doi:10.1186/1471-2458-7-169. 11. Njau J, Janta D, Stanescu A, Pallas SS, Pistol A, Khetsuriani N, 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. 12. Thorrington D, Ramsay M, van Hoek AJ, Edmunds WJ, Vivancos R, et al. The effect of measles on health-related quality of life: a patient based survey. PloS One. 2014;9(9):e105153. doi:10.1371/journal.pone.0105153. 13. Manual for the laboratory-based surveillance of measles, rubella, and congenital rubella syndrome, 3rd edition. Geneva: World Health Organization; 2018. 14. Bolotin S, Lim G, Dang V, Crowcroft N, Gubbay J, et al. The utility of measles and rubella IgM serology in an elimination setting, Ontario, Canada, 2009–2014. PLoS One. 2017;12(8):e0181172. doi:10.1371/journal.pone.0181172. 15. Tipples GA, Hamkar R, Mohktari-Azad T, Gray M, Parkyn G, et al. Assessment of immunoglobulin M enzyme immunoassays for diagnosis of measles. J Clin Microbiol. 2003;41(10):4790–4792. doi:10.1128/jcm.41.10.4790-4792.2003. 16. Ma R, Lu L, Suo L, Zhangzhu J, Chen M, et al. Evaluation of the adequacy of measles laboratory diagnostic tests in the era of accelerating measles elimination in Beijing, China. Vaccine. 2019;37(29):3804–3809. doi:10.1016/j.vaccine.2019.05.058. 17. Ratnam S, Tipples G, Head C, Fauvel M, Fearon M, et al. Performance of indirect immunoglobulin M (IgM) serology tests and IgM capture assays for laboratory diagnosis of measles. J Clin Microbiol. 2000;38:99–104. 18. Mosquera MM, de Ory F, Gallardo V, Cuenca L, Morales M, et al. Evaluation of diagnostic markers for measles virus infection in the context of an outbreak in Spain. J Clin Microbiol. 2005;43(10):5117–5121. doi:10.1128/JCM.43.10.5117-5121.2005.