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Indication - Vaccine-preventable diseases
Measles IgG antibody
Facility level:
2. Laboratory
Assay formats
Immunoassay
Status history
First added in 2020
Purpose type
Aid to diagnosis
Purpose
To aid in the diagnosis of clinically suspected measles infection
Specimen types
Serum, Plasma, Dried blood spots, Oral fluid
WHO prequalified or recommended products
N/A
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
Codes
ICD11 code: 1F03

Summary of evidence evaluation

As an IgG response is part of the standard confirmation of a measles case, it is difficult to assess test accuracy; inevitably, the reference standard used will incorporate an IgG test in some cases. 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 measles. Evidence of the value of the IgG test could be better established by looking at the numbers of measles cases that were diagnosed by an IgG when other methods failed. The study from the Spanish outbreak indicates that a small number of cases were only identified by IgG testing following a negative IgM test. Some evidence exists showing that there are measles cases detected only by use of the IgG test, particularly showing reinfection or infection in the vaccinated population. 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 disease of public health concern, and it is important to detect outbreaks early. In clinical settings the measles IgG test is mostly used in combination with IgM or PCR tests to confirm cases. A single positive or negative result of measles IgG does not rule out the presence or absence of measles infection; so it is not diagnostic of measles on its own. The test is known to be useful in diagnosing some complications of measles, such as SSPE, and in determining immune status in specific groups, including transplant patients. It is also known to be a useful test for determining the immunity of a person pre- and post-vaccination, and thus could be used to study seroprevalence in a population. But the test was not submitted as a screening tool for immunization; moreover, the WHO representative confirmed that IgG is not recommended for seroprevalence. Nevertheless, the IgG test is part of the case definition for measles and forms part of the WHO algorithm for diagnosing the disease in an elimination setting. In part because of this, there is not much data on the test’s clinical accuracy or performance. And very few data were submitted on the test’s usefulness. SAGE IVD noted a definite need for more evidence on how the measles IgG test has made a difference to show that it is an essential test. Other limitations of the test include the fact that it requires paired sera and cannot be used as a POC test. It requires a laboratory with ambient environmental conditions and a regular power supply; it may also prove costly in LMICs and resource-constrained settings. SAGE IVD noted that the application listed an EIA format for the test, but highlighted the existence of avidity assays, which could also be useful in diagnosing acute measles.

SAGE IVD recommendation

SAGE IVD recommended conditionally including the measles IgG antibody 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 aid in the diagnosis of clinically suspected measles infection; pending the submission of further evidence to show that the test has utility in confirming cases when used with IgM.

Details of submission from 2020

Background

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 subacute sclerosing panencephalitis (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 IgG seroconversion testing is used to confirm IgM-positive tests in elimination settings where incidence of measles is low. Two serum samples must be collected: the first (acute) no later than 7 days from rash onset; and the second (convalescent) 10–28 days later. A significant rise in IgG levels indicates a positive result. Laboratory case confirmation for measles includes diagnostically significant titre change in IgG antibody level in acute or convalescent sera, or documented seroconversion (IgG negative to IgG positive).

Public health relevance

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 each 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 lab-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) states that measuring measles-specific IgG can be a useful additional serologic method for case classification when an equivocal result is obtained for IgM, or when a positive IgM result is questioned due to clinical or epidemiologic information that is inconsistent with a case of measles. A significant rise in IgG titre in convalescent sera from suspected cases confirms a positive IgM result. The 2018 WHO surveillance standards (3) also state that IgG rise in titre between acute and convalescent sera can be used as to aid measles diagnosis.

Evidence for diagnostic accuracy

No systematic reviews of measles IgG test clinical accuracy were available. One study by Dina et al. (14) compared three commercial assays in three different types of preselected subjects: clinical measles suspects, possible cases (IgM negative) and general population. All clinical suspects were found to be IgG positive by all methods, as were the possible cases.

Evidence for clinical usefulness and impact

Mosquera et al. (15) show the value of measles IgG combined with RT-PCR in further classifying IgM-negative cases detected during an outbreak.

Evidence for economic impact and/or cost–effectiveness

No data available.

Ethical issues, equity and human rights issues

None identified.
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. Dina J, Creveuil C, Gouarin S, Viron F, Hebert A, et al. Performance evaluation of the VIDAS® measles IgG assay and its diagnostic value for measuring IgG antibody avidity in measles virus infection. Viruses. 2016;8(8):234. doi:10.3390/v8080234. 15. 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.