Indication - Visceral leishmaniasis (kala-azar)
Recombinant K39 (rK39) antigen
First added in 2019
Changed in 2020
Aid to diagnosis
To aid in the diagnosis of clinically suspected visceral leishmaniasis
Serum, Capillary whole blood, Venous whole blood16
WHO prequalified or recommended products
WHO supporting documents
WHO Technical Report Series 949 https://apps.who.int/iris/handle/10665/44412; https://www.who.int/teams/control-of-neglected-tropical-diseases
ICD11 code: 1F54.0
Summary of evidence evaluation
Key supporting evidence is given in a Cochrane review of diagnostic test accuracy of the rK39 immunochromatographic test (ICT) that comprised 18 studies with a total of 3622 participants (4). The results were heterogeneous, but the overall sensitivity was 91.9% (95% confidence interval (95% CI) 84.8 ; 96.5), and the specificity was 92.4% (95% CI 85.6 ; 96.8). The sensitivity was lower in East Africa (85.3%; 95% CI 74.5 ; 93.2) than on the Indian subcontinent (97.0%; 95% CI 90.0 ; 99.5).
Summary of SAGE IVD deliberations
Visceral leishmaniasis is fatal in over 95% of cases if untreated. As the clinical features lack specificity, a confirmatory test is essential, to avoid unnecessary, costly treatment with toxic medications in uninfected people. Field studies show high diagnostic accuracy of the rK39 test in practice in various settings, although the performance on the Indian subcontinent is better than that in East Africa, where the sensitivity and negative predictive values are lower. The test can be performed by trained non-laboratory health staff, does not require a cold chain or specific instruments and is relatively inexpensive. Treatment for the disease is available and is included in the EML.
SAGE IVD recommendation
The SAGE IVD recommended inclusion on the EDL of the RDT for antibodies against Leishmania rK39 antigen for use in settings with no clinical laboratory facilities, noting the good accuracy and simplicity of the test when used according to WHO leishmaniasis control guidelines. The Group recommended, however, that regulatory approval of the available tests be included, with a statement on whether any of the tests has been prequalified and a summary of any studies of cost–effectiveness. The Group requested WHO to accelerate a submission for inclusion of a direct agglutination test for leishmaniasis and to commission a systematic review of rK28 assays that may show greater accuracy in East African countries. The group further recommended that the test purpose not be limited to detection of L. donovani so that its use could be broadened to include L. infantum.
Details of submission from 2020
Disease condition and impact on patients: Visceral leishmaniasis, also known as kala-azar, is fatal in over 95% of cases if untreated. It is characterized by irregular episodes of fever, weight loss, enlargement of the spleen and liver and anaemia. Does the test meet a medical need? The test is used for serological confirmation of primary visceral leishmaniasis. As the signs and symptoms are non-specific, the diagnosis is confirmed from standard clinical criteria and a positive rK39 test. The rK39 test detects antibodies against a recombinant antigen, rK39, derived from L. chagasi that is present in serum and blood of patients. The target antibodies bind to the recombinant antigen on the test strip, yielding a visual positive result. The test can be used in the field, and results are available within 20–30 min. The rK39 test is highly sensitive and specific in endemic countries in South-East Asia but has shown less sensitivity and specificity in East African countries, where a negative test does not totally rule out visceral leishmaniasis if clinical suspicion is strong. As antibodies remain in the body for many years, even after the patient is cured, this test cannot differentiate between present and past infection. How the test is used: Patients with probable visceral leishmaniasis (> 2 weeks of fever, splenomegaly and/or weight loss) in endemic areas or with a history of travel to an endemic area are tested. Each test is for single use (1, 2).
Public health relevance
Prevalence: The leishmaniases are caused by protozoan Leishmania parasites of more than 20 species, which are transmitted by the bite of infected female phlebotomine sand flies. The three main forms of leishmaniasis are visceral (the most serious form of the disease), cutaneous (the most common) and mucocutaneous (the most destructive). An estimated 700 000 to 1 million new cases and 20 000–30 000 deaths occur annually. Visceral leishmaniasis is endemic in all six WHO regions. Most cases occur in Brazil, East Africa and South-East Asia. An estimated 50 000–90 000 new cases occur worldwide each year. In 2015, more than 90% of new cases reported to WHO occurred in seven countries: Brazil, Ethiopia, India, Kenya, Somalia, South Sudan and Sudan. The disease affects some of the poorest people and is associated with malnutrition, population displacement, poor housing, a weak immune system and lack of financial resources. Leishmaniasis is also linked to environmental changes such as deforestation, building of dams, irrigation schemes, urbanization and climate change. Socioeconomic impact: The economic impact of the disease on affected populations and communities is huge. For example, in Bihar, India, 83% of households in communities with high rates of the disease were in the poorest 40% of wealth distribution. The evidence is most complete for visceral leishmaniasis, as studies in many countries show that, even when diagnosis and medicines are provided free of charge, 25–75% of households of victims experience some form of financial catastrophe.
WHO or other clinical guidelines relevant to the test
The WHO document on use of visceral leishmaniasis RDTs (1) is intended for training but serves as guidance.
Evidence for clinical usefulness and impact
The WHO document on use of visceral leishmaniasis RDTs (1) states that, when used according to the manufacturer’s instructions, the rK39 RDT is highly effective in detecting visceral leishmaniasis. In a comprehensive scientific review of published studies, its sensitivity was estimated to be 93.9% (87.7–97.1%). Its sensitivity was higher and more consistent in studies in South Asia, with a specificity of 90.6% (66.8–97.9%) in a clinical setting with febrile patients as negative controls.
Evidence for economic impact and/or cost–effectiveness
The rK39 RDT does not require a specialized set-up or specialized laboratory technicians. It is mainly for field use in primary care settings; a health care worker can use it after a proper demonstration and training. It is highly cost–effective for diagnosing primary visceral leishmaniasis in endemic areas, with high sensitivity and specificity.
Ethical issues, equity and human rights issues
Consent is required to obtain a serum sample. The availability of rK39 RDT in primary care settings and the field has greatly improved access to diagnosis and treatment of fatal visceral leishmaniasis, significantly reducing inequity.
1. The use of visceral leishmaniasis rapid diagnostic tests. Geneva: World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases; 2008 (http:// apps.who.int/iris/bitstream/handle/10665/44012/9789241597357_eng.pdf?sequence=1&is Allowed=y, accessed April 2019). 2. Visceral leishmaniasis rapid diagnostic test performance (Diagnostics Evaluation Series No.4). Geneva: World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases; 2011 (http://www.who.int/tdr/publications/documents/vl-rdt- evaluation.pdf, accessed April 2019). 3. Matlashewski G, Ravi Das VN, Pandey K, Singh D, Das S, Ghosh AK, et al. Diagnosis of visceral leishmaniasis in Bihar India: comparison of the rK39 rapid diagnostic test on whole blood versus serum. PLoS Negl Trop Dis. 2013;7(5):e2233. 4. Boelaert M, Verdonck K, Menten J, Sunyoto T, van Griensven J, Chappuis F, et al. Rapid tests for the diagnosis of visceral leishmaniasis in patients with suspected disease. Cochrane Database Syst Rev. 2014;(6):CD009135.