Indication - Neglected tropical diseases
Dengue virus IgM antibody
First added in 2019
Changed in 2020
Aid to diagnosis, Surveillance
To aid in the diagnosis of dengue fever (always in combination with NS1) and for population surveys
Serum, Venous whole blood
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 1D2Z
Summary of evidence evaluation
Several studies of use of IgM ELISA and RDTs have been conducted, but no systematic review has been done to determine any risk of bias or the applicability of the findings. The studies show that the sensitivity and specificity of these tests is variable and low, and they are not accurate enough to be used on their own. Several studies have evaluated the combination of NS1 and IgM, as separate tests or in a purpose-made dual RDT, which appears to increase sensitivity without compromising specificity, but no systematic review of studies of this test combination has been reported.
Summary of SAGE IVD deliberations
Dengue fever is the most rapidly spreading mosquito-borne viral disease in the world. Antibody and antigen tests are essential for detection, case management, surveillance and confirmation of outbreaks. Detection of antigens can be used to diagnose an early infection, while viraemia present during the acute phase requires use of DENV-1-4 real-time RT-PCR plus IgM ELISA or NS1 antigen ELISA.
SAGE IVD recommendation
The SAGE IVD recommended inclusion on the EDL of the EIA or RDT for DENV IgM only if used in combination with the EIA or RDT for DENV NS1 antigen (see below) in a specified algorithm. The Group noted that the tests for DENV IgM cross-react with other flaviviruses, and seroconversion cannot be measured owing to the high rate of attrition in the countries in which dengue is endemic. They noted that guidelines for DENV testing would become available shortly. The Group recommended that the test be prequalified to ensure that the most appropriate tests are available.
Details of submission from 2020
Disease condition and impact on patients: Dengue fever occurs in a broad spectrum of clinical presentations, often with unpredictable clinical evolution and outcome. While most patients recover after a self-limiting, non-severe clinical course, a small proportion progress to severe disease, characterized mainly by plasma leakage with or without haemorrhage. Intravenous rehydration is the therapy of choice and can reduce the case fatality rate to < 1% of severe cases. The characteristics of patients with dengue that progresses from non-severe to severe are difficult to define. This is an important concern, as appropriate treatment may prevent more severe clinical illness. Does the test address a medical need? Efficient, accurate diagnosis of dengue is of primary importance for clinical care (for early detection of severe cases, case confirmation and differential diagnosis from other infectious diseases), surveillance, outbreak control, pathogenesis, academic research, vaccine development and clinical trials. In relation to the EDL, antibody and antigen tests are essential for case management and surveillance. During the early stages of the disease, detection of antigens can be used to diagnose an infection, while, at the end of the acute phase of infection, serology is the method of choice. The choice of the assay for diagnosis depends on the time of sample collection and the purpose of testing (1). As for other Aedes-borne arboviruses, viraemia is present during the acute phase, and 90% of cases of primary and secondary dengue fever can be identified accurately from a single serum specimen collected during the first 10 days of illness, with DENV-1-4 real-time RT-PCR plus IgM ELISA or NS1 antigen ELISA (2, 3). Purpose of testing: In surveillance, testing is used to alert health authorities to the possible emergence of an outbreak. Testing is usually done with high- throughput immunoassays for IgM antibodies. While they are not ideal markers of active infection (which can persist for 5–6 months), they can be used as the basis for an outbreak alert when an increase in IgM-positive cases is reported or unusually high IgM titres are observed. EIA can be used to identify the cause of an outbreak. The tests must be highly sensitive and specific for detecting DENV directly, by isolation of the virus or its nucleic acid or antigen in the acute phase of infection. Infection can also be diagnosed retrospectively from seroconversion of IgM or a fourfold rise in IgG between samples collected in the acute and convalescent stages > 14 days apart. A combination of IgM and either NAAT or antigen detection tests extends the window of detection of acute infection and was effective in a retrospective study of DENV infections. In surveys, EIA can be used to assess the extent of an outbreak, inform control strategies and identify hotspots. High-throughput, ideally highly specific, tests that can be used in various populations are required. In research, the tests are used to assess the impact of control interventions and increase understanding of the pathogen and its pathogenesis. How the test is used: The DENV IVD can be used at three levels of a health system: primary care centres, district centres and reference centres. A single test is sufficient if a sample is taken within the defined time. As dengue fever is easily confused with other illnesses, particularly in non-epidemic situations, the DENV IVD can also be used for differential diagnosis.
Public health relevance
Prevalence: Dengue fever is the most rapidly spreading mosquito-borne viral disease in the world. Its incidence has increased by 30 times in the past 50 years, and it is spreading to other countries; during the current decade, it has spread from urban to rural settings. An estimated 50 million cases of dengue infection occur annually among the 2.5 billion people who live in countries endemic for the disease. World Health Assembly resolution WHA55.17 in 2002 urged WHO and its Member States to make a greater commitment to controlling dengue fever. World Health Assembly resolution WHA58.3 on revision of the IHR gives dengue fever as an example of a disease that may constitute a public health emergency of international concern (PHEIC), with implications for health security due to disruption and rapid epidemic spread beyond national borders. Socioeconomic impact The estimated global cost of the prevention and control of dengue fever is at almost US$ 9 billion per year (4), and WHO has estimated that more than 3 billion DALYs are lost due to dengue fever.
WHO or other clinical guidelines relevant to the test
Evidence for clinical usefulness and impact
Evidence for economic impact and/or cost–effectiveness
If only a subset of patients is tested during an outbreak or for confirmation in endemic periods, the impact on overall budgets will be small.
Ethical issues, equity and human rights issues
Consent is required to obtain a serum sample. Dengue fever predominantly affects populations living in poverty, and access to high-quality diagnostics can reduce the burden and improve equity.
1. Peeling R, Murtagh M, Olliaro P. Epidemic preparedness: why is there a need to accelerate the development of diagnostics? Lancet Infect Dis. 2019;19(5):e172–8. 2. Hunsperger EA, Muñoz-Jordán J, Beltran M, Colón C, Carrión J, Vazquez J, et al. Performance of dengue diagnostic tests in a single-specimen diagnostic algorithm. J Infect Dis. 2016;214(6): 836–44. 3. Peeling RW, Olliaro P. Reimagining the future of the diagnosis of viral infections. J Infect Dis. 2016;214:828–9. 4. Shepard DS, Undurraga EA, Halasa YA, Stanaway JD. The global economic burden of dengue: a systematic analysis. Lancet Infect Dis. 2016;16(8):935–41.