Indication - Vaccine-preventable diseases
Measles nucleic acid test
First added in 2020
To diagnose clinically suspected measles infection
Oral fluid, Throat swab, Nasopharyngeal aspirates or swabs Urine
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
A positive RT-PCR result for measles is considered to confirm infection, and 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. Substantial evidence exists showing that significant numbers of measles cases are detected only by using RT-PCR, particularly among the vaccinated population. There was also evidence that RT-PCR has a greater ability to detect measles in samples taken in the first few days after the rash appears. Figures from the studies suggest that 4–16% of samples were IgM negative and PCR positive. 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. Measles IgM testing may be the gold standard for identifying cases, but it has limitations. In particular, detection of measles IgM depends on timing of specimen collection and may need to be complemented with a PCR test. Supplementary testing may also be needed to confirm measles IgM-positive tests in a low measles incidence context (to rule out false positives). Measles PCR is recommended in WHO guidelines, both for acute diagnosis in the early stages of disease and symptom onset, when IgM can still be negative, and to confirm IgM-positive cases in low-prevalence settings. Because the test has become part of the case definition, it is difficult to gather data on its accuracy. In this case, SAGE IVD looked for evidence that the PCR test makes a valuable contribution in terms of the number of cases detected by PCR, particularly where IgM is negative. And the studies submitted do provide sufficient evidence of this. But SAGE IVD noted that specialized equipment and highly skilled personnel are required to perform the PCR test and that it is more costly than either the measles IgM or IgG tests. As such, it may only be applicable where high-level PCR testing is available. In LMICs and resource-constrained settings, it may only be made available at a regional or central level. SAGE IVD noted that if more robust assays become available that can be performed close to POC, they could reduce the turnaround time for case confirmation and help to rapidly identify cases in an outbreak situation.
SAGE IVD recommendation
SAGE IVD recommended including the measles nucleic acid 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 a nucleic acid test 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 Optimal RT-PCR testing requires nasopharyngeal or throat swabs collected within the first 4 days of rash onset, or urine specimens collected within the first 7 days. A stand-alone positive RT-PCR result confirms measles infection if there was no measles vaccination 7–14 days prior to rash onset. If vaccination is evident, follow-up sequencing is recommended to determine wild vs vaccine type strain. If the RT-PCR test is negative and no other cause of symptoms is confirmed, serology follow-up testing is recommended to rule out measles infection. If optimal IgM collection of serum sample (4–28 days from rash onset) is available, a negative IgM test result confirms no infection. If the sample was collected within 3 days of rash onset and the result is negative, repeat testing (≥ 6 days) with IgM is advised if the case remains suspicious for measles. In elimination areas, where measles incidence is low, RT-PCR testing is recommended to confirm an IgM positive or equivocal test.
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 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) recommends using conventional or real-time RT-PCR to confirm cases, in combination with testing serologic or oral fluid specimens for virus-specific IgM. The manual recommends that this testing be performed in countries in coordination with the GMRLN. The 2018 WHO surveillance standards (3) for vaccine-preventable diseases also recommends RT-PCR to confirm measles case.
Evidence for diagnostic accuracy
No systematic reviews of measles RT-PCR test clinical accuracy were available. Three primary studies were reviewed: • Chuaa et al. (14) compared two platforms for measles RT-PCR and found these to be comparable. • Ma et al. (15) showed that RT-PCR has lower sensitivity for detecting measles at 0–3 days in vaccinated individuals. • Roy et al. (16) evaluated an in-house assay in three reference laboratories and found that their assay had 94% sensitivity for identifying five measles vaccine strains.
Evidence for clinical usefulness and impact
Four primary studies show the clinical value of RT-PCR for diagnosing measles: • Mosquera et al. (17) used RT-PCR in an outbreak in Spain and showed its value in addition to IgM testing as it identified additional cases. • Ma et al. (15) showed that RT-PCR used in China at 4–28 days post-rash was more sensitive (94.4%) than IgM (82.1%). • Cui et al. (18) used RT-PCR to supplement IgM testing in a pre-elimination setting and found that RT-PCR successfully identified additional cases among IgM-negative individuals. • Benamar et al. (19) similarly showed RT-PCR additionally identified 52% of IgM-negative cases in an outbreak as measles confirmed.
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. Chua KYL, Thapa K, Yapa CM, Somerville LK, Chen SCA, et al. What assay is optimal for the diagnosis of measles virus infection? An evaluation of the performance of a measles virus real-time reverse transcriptase PCR using the Cepheid SmartCycler® and antigen detection by immunofluorescence. J Clin Virol. 2015;70:46–52. doi:0.1016/j.jcv.2015.07.004. 15. 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. 16. Roy F, Mendoza L, Hiebert J, McNall RJ, Bankamp B, et al. Rapid identification of measles virus vaccine genotype by real-time PCR. J Clin Microbiol. 2016;55:735–743. doi:10.1128/JCM.01879-16. 17. 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. 18. Cui A, Mao N, Wang H, Xu S, Zhu Z, et al. Importance of real-time RT-PCR to supplement the laboratory diagnosis in the measles elimination program in China. PLoS One. 2018;13:11.e0208161. doi:10.1371/journal.pone.0208161. 19. Benamar T, Tajounte L, Alla A, Khebba F, Ahmed H, et al. Real-time PCR for measles virus detection on clinical specimens with negative IgM result in Morocco. PLoS One. 2016;11:1.e0147154. doi:10.1371/journal.pone.0147154.