Indication - Chagas disease
Trypanosoma cruzi IgG antibody
First added in 2020
Surveillance, Screening, Aid to diagnosis
For surveillance of T. cruzi infection; To screen girls, women of childbearing age and pregnant women without previous treatment for T. cruzi infection; To screen children and other at-risk populations; To aid in the diagnosis of chronic T. cruzi infection (Chagas disease); (only in settings where laboratory-based methods are not available)
Capillary whole blood, Venous whole blood, Serum
WHO prequalified or recommended products
WHO supporting documents
Guidelines for the diagnosis and treatment of Chagas disease (2018) https://www.who.int/publications/i/item/9789275120439 https://www.who.int/health-topics/chagas-disease#tab=tab_1
ICD11 code: 1F53.Z
Summary of evidence evaluation
Several recent systematic reviews have identified and pooled studies of the accuracy of immunologically based tests which show that they have high levels of performance, suitable for use across different settings. Estimates of sensitivity for ELISA, ICT and CMIA are 97% (CI: 96–98%), 94% (CI: 91–96%) and 99% (CI: 97–100%), respectively. Estimates of specificity for ELISA, ICT and CMIA are 98% (CI: 97–99%), 97% (CI: 96–98%) and 98% (CI: 91–99%), respectively. PAHO guidelines have carefully considered the consequences of test errors in different circumstances and make clear recommendations as to which tests are preferable in different 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
The T. cruzi IgG test has the potential to significantly increase access to diagnosis and, consequently, treatment in endemic countries. Automated tests have improved performance compared with other formats, but their complexity and costs could limit their use in countries where Chagas disease is endemic. In these cases, RDTs can be used. SAGE IVD members highlighted the debate surrounding the need for one or two positive tests to diagnose T. cruzi infection; the group also noted that while current WHO/PAHO guidelines do not recommend using RDTs as stand-alone tests, new evidence indicates their potential use as diagnostic tools in endemic countries. Further evidence is being generated to confirm this finding. SAGE IVD sought advice from WHO’s Neglected Tropical Diseases team on the potential use of the T. cruzi test in primary care settings. The submission did not include enough details about the different T. cruzi IgG detection assays available. Many different immunoassay formats exist (e.g. ELISA, ELISA-r, immunofluorescence assay , IHA, CMIA and ICT/RDT) which are used for different purposes, mainly chronic Chagas disease diagnosis and T. cruzi infection surveillance. The diagnostic algorithms and immunoassays used vary with the different purposes, populations targeted and regions.
SAGE IVD recommendation
SAGE IVD recommended including the Trypanosoma cruzi IgG antibody test category in the third EDL 3: • as a disease-specific IVD for use in community settings and health facilities without laboratories, and as a disease-specific IVD for use in clinical laboratories (EDL 3, Sections I.b and II.b, Neglected tropical diseases); • using an immunoassay format or an RDT (only in settings where laboratory-based methods are not available); • for surveillance of Trypanosoma cruzi infection; • to screen girls, women of childbearing age and pregnant women without previous treatment for Trypanosoma cruzi infection; • to screen children and other at-risk populations; and • to aid in the diagnosis (RDT) or to diagnose (immunoassay) chronic Trypanosoma cruzi infection (Chagas disease). The group noted that an immunoassay to screen for T. cruzi in blood donations is already listed in the EDL 2, as a disease-specific IVD for blood screening laboratories (Section II.c); but highlighted the potential value of this test category for screening organ donors too. It recommended reviewing Section II.c of the EDL to include donated organs as well as blood.
Details of submission from 2020
Disease condition and impact on patients Chagas disease, or American trypanosomiasis, is a parasitic, vector-borne disease caused by T. cruzi. In addition to vector transmission it can also be transmitted through food, congenital infection, blood transfusion, organ transplants and in the laboratory. More than 70 million people are estimated to be at risk of contracting Chagas disease, with around 38 000 new cases and 12 000 deaths each year. The disease affects around 8–10 million people in the Americas (1), where it is endemic. Vector control programmes have successfully reduced vector transmission of T. cruzi in these regions (2); but the disease has spread to other countries through migration and international travel and is now also present in Europe and the western Pacific region (3). An estimated 15% of patients with chronic Chagas disease develop severe clinical manifestations and related complications, such as vascular accidents, intestinal complications and death (mainly due to arrhythmias and heart failure) (4). WHO estimates that 1 125 000 women of fertile age are infected with T. cruzi in Latin America, with 8668 congenital infections each year. A further 40 000 infected women of childbearing age are estimated to live in the USA, where 60–315 congenital infections are expected to occur each year. In Latin America, the mean maternal–fetal transmission rate in chronic Chagas disease is estimated to be 4.7%, with the number of babies that would require testing each year an estimated 158 000–214 000 (mostly in Argentina, Brazil, Bolivia and Mexico). Does the test meet a medical need? WHO has recognized Chagas disease as a neglected tropical disease (NTD) since 2015. Early diagnosis and treatment are known to prevent congenital transmission and reduce the likelihood of disease progression. But Chagas disease remains underdiagnosed (5). How the test is used Diagnosis is usually made by serology (two positive serological tests), peripheral blood microscopy or PCR. A positive serology is indicative of either active T. cruzi infection or past exposure. Serologically positive asymptomatic patients can transmit the parasite to the vector insect and directly to other individuals via blood components, organ donation or through congenital infection. The Chagas serological assays to be used for screening and diagnosis must be both highly sensitive and specific. This can be achieved by using a combination of antigens to develop tests, which maintains the high sensitivity without compromising the specificity. An adequate performance of such tests can be reached by using recombinant antigens that cover all stages of the parasite life cycle, for example, flagellar calcium-binding protein, flagellar repetitive antigen and cruzipain for the determination of antibodies to T. cruzi (6).
Public health relevance
Prevalence and socioeconomic impact The global annual burden of Chagas disease is calculated at more than US$ 7 billion per year, considering health care costs and DALYs from infected individuals. The acute phase of Chagas infection lasts 2 months; without curative treatment, all patients enter a chronic phase (either as carriers or as symptomatic individuals).
WHO or other clinical guidelines relevant to the test
Pan American Health Organization (PAHO) guidelines for diagnosing and treating Chagas disease (2) provide recommendations on the use of various technologies for different test purposes. They make a strong recommendation for using ELISA and immunochromatographic test (ICT) for population studies on prevalence of Chagas disease. They also make a conditional recommendation on using ELISA, haemagglutination inhibition assay (HIA) or indirect immunofluorescence (IIF) test for diagnosing patients with suspected Chagas disease, in an algorithm with two initial tests with differing antigens, followed by a third test in case of conflicting results. In 2010, WHO published a report evaluating 19 anti-T. cruzi assays, including 11 EIAs, seven agglutination assays and one rapid test (7). The evaluations focused on operational characteristics such as sensitivity, specificity on a WHO serum/plasma evaluation panel, ease of use and suitability to small laboratories with limited facilities. The information is intended to support programme managers and users to decide which tests are best suited to their particular situation.
Evidence for diagnostic accuracy
Various formats of IgG immunoassays have been evaluated for the diagnosis of chronic Chagas. Sensitivity and specificity vary greatly based on the antigens used to develop IgG assays. Traditional HIAs, IIFs and ELISAs prepared with whole parasite lysates offer quantitative or semi-quantitative results. These, however, may cross-react with Leishmania spp. and Trypanosoma rangeli. IHA tests have sensitivities ranging from 96% to 98%, while IIF has a greater sensitivity of 99%, but is operationally more demanding. ELISAs have good sensitivity and specificity (8). Newer-generation ELISAs, CMIAs and RDTs (i.e. ICTs and ELISAs with POC applicability) offer qualitative results. They have improved specificity but may have lower sensitivity. In a study from Colombia, Díaz et al. (9) compared commercially available whole-parasite lysate and recombinant antigen ELISA assays and found 99–100% sensitivity and 98–100% specificity. WHO guidelines (2) evaluated the accuracy of ELISA, CMIA and ICT tests, and noted no substantial differences in terms of sensitivity.
Evidence for clinical usefulness and impact
Given the lack of evidence linking diagnostics to patient outcomes, clinical utility has been extrapolated from diagnostic accuracy studies (undetected, therefore untreated patients vs effect of trypanocidal treatment) (2). In different evaluations, the diagnostic sensitivities of the various methods did not vary substantially. When used as a single test without secondary confirmation, all methods showed some incorrect classification of patients (false negatives or false positives) (2). This is why PAHO guidelines recommend using two serological assays with different technologies for initial diagnosis. In resource-limited settings where a single ELISA test is used for initial diagnosis, PAHO recommends confirming a positive result with an additional test (2).
Evidence for economic impact and/or cost–effectiveness
Bartsch et al. (10) evaluated the economic impact and outcomes of identifying and treating different proportions of patients in the acute and indeterminate disease states in a 2000-person village in Yucatán, Mexico. The authors concluded that managing as few as 5% of Chagas cases annually (acute and indeterminate stages) reduces transmission and provides economic and health benefits. The PAHO guidelines (2) conclude that the ELISA method is more resource effective than ICT and CMIA. But the diagnostic accuracy of ELISA commercial assays varies significantly.
Ethical issues, equity and human rights issues
None identified. Testing reduces inequity by providing diagnosis. Easier-to-use methods such as ELISA or ICT are more likely to have a positive impact on equity.
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