1

Reviewer’s Questionnaire for Evaluation of Submissions for EDL v3

Based on the Criteria for Selection of Essential Diagnostics for the EDL

Diagnostic test: Trypanosoma cruzi IgG

Test purpose: Chronic Chagas disease

ID number: PreSubmission_ID106_FullSubmission_ID68

The selection process for essential diagnostics for the EDL will include consideration of a

number of factors, including:

1. The public health and clinical need for the category of tests as determined for example,

by disease burden and whether the proposed category of IVDs can help to bridge

any existing gap in access to diagnostics that has been identified.

Draft questions:

1. Does the disease addressed by the test cause:

☒ a high burden of morbidity (human suffering)

☒ mortality

☒ cost on the populations and societies where it occurs

2. How strong is the evidence provided to support this?

☐ weak

☒ strong

Please complete the sub-questions below on evidence provided:

a. Disease prevalence data?

☒ yes

☐ no

b. Information on the disease impact on the quality of life of its sufferers?

☐ yes

☒ no

Comment: Some of the references provided use DALYs as an outcome but no

specific publications were included on the impact of Chagas disease on the quality of

life of patients (or families). There are a number of studies evaluating the disease

impact on quality of life that could have been cited e.g.:

• Santos-Filho et al. Quality of life and associated factors in patients with

chronic Chagas disease. Trop Med Int Health 2018;23(11):1213-1222. doi:

10.1111/tmi.13144. Epub 2018 Sep 19.

• Costa et al. The prognostic value of health-related quality of life in patients

with Chagas heart disease. Qual Life Res 2019;28(1):67-72. doi:

10.1007/s11136-018-1980-7.

• Suman et al. Evaluating respiratory musculature, quality of life, anxiety, and

depression among patients with indeterminate chronic Chagas disease and

2

symptoms of pulmonary hypertension. Rev Soc Bras Med Trop

2017;50(2):194-198. doi: 10.1590/0037-8682-0198-2016.

• Cavalcanti et al. Manifestations and strategies of coping with Chagas Disease

that interfere in the quality of life of the individual: a systematic review. Cien

Saude Colet 2019;24(4):1405-1416. doi: 10.1590/1413-

81232018243.11842017. Epub 2019 May 2.

c. Information on the disease impact on the quality of life of the families of sufferers

and the communities in which they live? E.g. patients with high care needs, orphans,

spread of infection

☐ yes

☒ no (see comment above)

d. Impact assessments on health care resources and budgets?

☒ yes

☐ no

References provided:

Burden: “Chagas is the most important parasitic disease in the Americas, affecting around 8–10

million people” (Rassi et al, 2012). 38,000 new cases every year; 8,700 of them due to congenital

transmission (PAHO/WHO Guidelines for the diagnosis and treatment of Chagas disease, 2018 and

Carlier et al, 2019)

Mortality: 12,000 deaths annually (PAHO/WHO Guidelines for the diagnosis and treatment of Chagas

disease, 2018)

Cost: “The global annual burden of Chagas disease is calculated to be more than USD 7 billion per

year, considering healthcare costs and DALYs from infected individuals” (Lee et al, 2013).

The applicants also provide data from non-endemic countries (e.g. USA, Spain).

A recent publication uses the estimates from the Global Burden Disease report to summarize the

data associated with Chagas disease (Wilson et al. The importance of vector control for the control

and elimination of vector-borne diseases. PLoS Negl Trop Dis 2020;14(1):e0007831):

Estimated cases worldwide in 2017 (thousands [95% CI]) – prevalence

Estimated global all-age DALYs in 2017 (thousands [95% CI])

Estimated all-age deaths worldwide in 2017 (thousands [95% CI])

Reference

6,197.0 (5,248.5–7,243.9) 232 (210–261) 7.9 (7.5–8.6) Global Burden of Disease 2017

3. Is any information provided showing the degree of access to diagnostic testing for the

addressed disease in the primary care setting?

☐ yes

☒ no

Comment: no specific data are provided on the degree of access to diagnostic testing for

Chagas disease in the primary care setting. The current gold standard for T. cruzi chronic

infection requires performance of two laboratory-based diagnostic tests (e.g. ELISA, IFA,

IHA), which limits the capacity to diagnose Chagas disease in primary care in endemic

countries. A study conducted in Spain showed that screening Latin American migrants at

primary health care centres in Europe is cost-effective (Requena-Mendez et al 2017).

3

Does the submitted test category help to increase access in any way? E.g. reduced skill

required, lower cost, improved performance vs alternative options

☐ yes

☒ no

Comment: The application is for Trypanosoma cruzi IgG tests in general and does not specify

the assay format (test category). There are several immunoassay formats available: ELISA,

IHA, IFA, ICT, CMIA. Those require different skills, have different costs and performance.

Most of the evidence provided in the application focuses on one of the assay formats:

chemiluminescent microparticle immunoassay (CMIA). This format has an improved

performance compared with other formats but its complexity and cost may limit is use in

Chagas disease endemic countries: “Because access to the CMIA is restricted at this time,

the panel judged that the recommendation to implement this test [CMIA] before others

could have a negative impact on equity in all of the scenarios presented” (PAHO/WHO

guidelines for the diagnosis and treatment of Chagas disease, 2018). Nevertheless, the same

panel recommended the use of this assay format to screen blood in blood banks: “Use of the

ELISA test (highly sensitive kits) or CMIA is recommended to screen Chagas disease in

hemotherapy services.”

Note: Answers to the questions above will have been assessed as part of the screening application and will

have been deemed acceptable. Nevertheless, information provided on these matters in the full application may

be commented upon in your assessment.

2. Availability of validated commercial diagnostic tests as indicated by sound and adequate data

on quality, safety, performance, and regulatory status.

Draft questions:

1. How many commercially available IVDs are included in the application for this category?

1

a. Does the submission include a list?

☐ yes

☒ no A list was provided in the preliminary submission (Elecsys Chagas (Roche),

Liaison XL Murex Chagas (Diasorin), Architect Chagas […] Wiener Lab Chagatest

ELISA recombinante v4.0 (Wiener Lab Group), …). The table “Commercial products in

the submitted test category” in Annex 1 only includes information about the Roche

Elecsys Chagas test. The applicant refers to the PAHO/WHO guidelines and other

references (Afonso et al 2012) for “details of competitors”.

Does the application consider IVDs of all technologies 1that are available for the

analyte2 of interest?

☐ yes

☒ no Although there are several assay formats for T. cruzi IgG available (e.g. ELISA,

IFA, RDT) the application focuses in one of them: CMIA and a single product in

particular: Elecsys Chagas (Roche). No performance data on the CMIA tests available

through other suppliers or different assay formats are provided.

1 Technologies: It may be that, within the IVD category, there are tests that use different technologies to measure or detect the same analyte e.g. an RDT or and EIA for HIV antibody 2 Analyte: Marker that the IVDs in the category measures or detects

4

2. Which national regulatory bodies have approved these tests for market access e.g. CE IVD,

US FDA, SFDA, WHO-PQ, others?

According to the information provided, the Roche Elecsys Chagas is CE marked for

“diagnostic use and for testing of blood donations […], for use of cadaveric blood

specimens), and it is available in “countries accepting CE mark and (the) product has gone

through local registration in Latin America.”

The applicant could have provided information about the registration and regulatory status

of other CMIA tests and other T. cruzi IgG detection platforms. For example Alinity s Chagas

and RTHO T. cruzi ELISA Test System are FDA approved as donor screening tests to detect

antibodies to T. cruzi in plasma and serum samples. And the Chagas Detect Plus Rapid Test

(Inbios, USA) is FDA approved as a rapid immunochromatographic strip assay to support

Chagas disease diagnosis.

3. Have package inserts been provided showing studies demonstrating quality, safety, and

performance of regulatory approved IVDs in this category?

Quality: ☒ yes ☐ no

Safety: ☒ yes ☐ no

Performance: ☒ yes ☐ no

a. If so, what is your assessment of the strength of the study data described in the

package inserts?

Most of the performance data in the insert was published in the manuscript: Flores-

Chavez et al. Evaluation of the Elecsys Chagas Assay for Detection of Trypanosoma

cruzi-Specific Antibodies in a Multicenter Study in Europe and Latin America. J Clin

Microbiol 2018;25;56(5). pii: e01446-17. doi: 10.1128/JCM.01446-17

(https://jcm.asm.org/content/56/5/e01446-17.long)

4. Have any independently published studies been provided, showing IVDs’ performances

compared to a recognised gold standard? How strong are these studies?

☐ yes ☒ no Comment: as indicated in the manuscript, the Flores-Chavez et al study was

funded by Roche Diagnostics (Penzberg, Germany), but it is well designed and uses the

recognized gold standard.

a. If no gold standard exists, what is your assessment of the characterisation of the

studies’ specimens?

5. Where relevant, have studies to demonstrate ease of use by trained lay providers been

provided?

☐ yes ☐ no Comment: not relevant for CMIA tests

What is your assessment of these studies?

5

6. Where relevant, have studies been provided to show the IVD’s robustness3 in variable

environmental conditions e.g. temperature and humidity?

☐ yes ☒ no

3. Clinical effectiveness4 based on published peer reviewed data, safety and comparative cost-

effectiveness.

Draft questions:

1. Has the applicant provided strong peer reviewed clinical studies that demonstrate the

clinical utility 5and effectiveness of IVDs in this category?

clinical utility: ☐ yes ☒ no

effectiveness: ☐ yes ☒ no

2. Are you satisfied that these studies are properly designed and sufficiently powered

statistically to support their conclusions?

☐ yes ☐ no Comment: NA

3. Has the applicant provided cost effectiveness, health economics or budget impact studies

demonstrating the value of IVDs in this category?

cost effectiveness: ☒ yes ☐ no

health economics: ☒ yes ☒ no

budget impact studies: ☐ yes ☒ no

How strong are these studies in terms of design and statistical power? (See Note above)

☐ weak

☒ strong Comment: The studies included in the application assess the impact of improving

the access to T. cruzi infection diagnosis in endemic and non-endemic countries. These

studies model the “the impact and economic outcomes (costs, cost-effectiveness, cost-

benefit) of identifying and treating different percentages of Chagas patients” (Bartsch SM,

2018) and “an economic evaluation of systematic Chagas disease screening of the Latin

American population attending primary care centres in Europe “ (Requena-Mendez et al,

2017). Both studies conclude that screening/identifying T. cruzi infected patients is cost-

effective. Full references:

• Bartsch et al. The economic value of identifying and treating Chagas disease patients

earlier and the impact on Trypanosoma cruzi transmission. PLoS Negl Trop Dis

2018;12(11): e0006809. https://doi.org/10.1371/journal.pntd.0006809

• Requena-Méndez et al. Cost-effectiveness of Chagas disease screening in Latin

American migrants at primary health-care centres in Europe: a Markov model

analysis. Lancet Glob Health 2017;5(4):e439-e447. doi: 10.1016/S2214-

109X(17)30073-6. Epub 2017 Feb 28.

4. Has the applicant provided pricing information for commercially available IVDs in this

category? ☐ yes ☒ no

3 Robustness: An IVD’s capacity to remain unaffected by small variations in method parameters, which

provides an indication of its reliability during normal usage 4 Clinical effectiveness: The degree to which a particular health care intervention does more good than harm. It is measured by the number of lives saved, or by improvements of objective parameters of a morbid condition 5 Clinical utility: The likelihood of improved outcomes from use of diagnostic tests in the IVD category

6

a. Is the pricing information given inclusive of instrument and service costs where

relevant? ☐ yes ☐ no Comment: NA

b. In your experience, based on the pricing information provided, how accessible are

IVDs in this category to LMIC settings?

accessible: ☐ yes ☒ no

not accessible: ☒ yes ☐ no

Please provide examples to support your conclusions.

Comment: the answers above are based on the recommendation on the use of CMIA

to diagnose chronic T. cruzi infection included in the PAHO/WHO Guidelines for the

diagnosis and treatment of Chagas disease (2018): “Because access to the CMIA is

restricted at this time, the panel judged that the recommendation to implement this

test [CMIA] before others could have a negative impact on equity in all of the

scenarios presented”. However, the same guidelines recommended the use of this

assay format to screen blood in blood banks: “Use of the ELISA test (highly sensitive

kits) or CMIA is recommended to screen Chagas disease in hemotherapy services.”

5. In your experience, do you consider the cost of tests in this category (cost per test includes

reagents, any amortised instrument capital expenditure and service contracts) to justify the

clinical benefits. Please provide examples to support your conclusions.

☐ yes ☒ no

Examples

Comment: See recommendation from PAHO/WHO above on the use of CMIA. Other assay

formats (e.g. ELISA, IHA, IFA or RDT) may be more affordable.

4. Appropriateness of the IVD category for use at specified levels of the laboratory or health

care system.

Answer questions 1 and 2 for each IVD technology in the category. A table may help with reaching

your recommendation, the characteristics of each IVD represented by one row of the table

1.

a. What specimen type is required?

b. What skill level and training is required for specimen collection? E.g. Phlebotomist

c. Do specimens need to be processed in any way prior to analysis? E.g. centrifugation,

microscope slide staining, etc. ☐ yes ☐ no

i. If so, for how long and at what temperature is the specimen stable before

being processed (00:00:00 hours, min, seconds format)

ii. At what temperature is the processed specimen stored before testing

(please specify if Celsius or Fahrenheit)

d. How long does it take to get a result? E.g. can a result be obtained during a

consultation i.e. < 10 minutes, or while the patient is at the facility i.e. 2 – 3 hours or

7

specimens are tested in a batch using the IVD i.e. days?

e. Where relevant to the IVD has ease of and effective use by trained lay providers

been demonstrated?

☐ yes ☐ no

f. What equipment, if any, is required to perform this type of test?

g. Do instruments need to be calibrated, maintained, or serviced on a regular basis?

☐ yes ☐ no

h. How robust is the IVD?

i. What is the impact of an unreliable power supply, or can the IVD operate without a

power supply?

What is the minimal skill level and training required for personnel to perform this

test?

☐ Unskilled

☐ Skilled

☐ Highly trained

8

Assay #

Assay format*

Specimen How long and at what

temperature is the specimen

stable

Specimen storage temperature

Process before analysis

Time to result

Equipment required

Power supply

required

Skill level personnel

1 CMIA Serum or plasma (phlebotomist required)

For living patients and donor specimens obtained while the donor’s heart is still beating: Stable for 7 days at 20–25°C, 14 days at 2–8°C, 12 months at ‑20°C (± 5°C). The samples may be frozen 6 times. For cadaveric specimens: Stable for 3 days at 20–25°C, 7 days at 2–8°C. The samples may be frozen 3 times.

Centrifugation <20 min Yes Yes Skilled (lab techs)

2 ELISA Serum or plasma (phlebotomist required)

Centrifugation Hours (processed in batches)

Yes, plate reader

Yes Skilled (lab techs)

3 IHA Serum or plasma (phlebotomist required)

Centrifugation Hours (processed in batches)

No No Skilled (lab techs)

4 IFA Serum or plasma (phlebotomist required)

Centrifugation Hours (processed in batches)

Yes Yes Skilled (lab techs)

5 ICT/RDT Serum, plasma or blood

Centrifugation required if serum is used

<20 min (processed individually)

No No Unskilled if blood is used

*Information on one of the CMIA products available (Roche Elecsys Chagas) provided by the applicant. The information on the other assay formats

has been summarized by the reviewer.

9

2. Considering a 4-tier laboratory system, with the following levels:

i. Primary care

ii. District hospitals/laboratories

iii. Regional hospitals/laboratories and

iv. National hospitals/Reference laboratories

in your judgement, which level would be best suited to handle the required complexity of

the relevant IVD?? Please include your answer in the table based on the likely availability of

the following at district, regional and national laboratory level:

a. Infrastructure requirements e.g. instrument size and complexity, biosafety

requirements

b. Specimen types

c. Testing volumes expected (sample throughput required)

d. Complexity of specimen handling e.g. biosafety level required, centrifugation or

complex protocols requiring highly skilled laboratory technicians

e. Availability of infrastructure for transporting specimens

f. Result turn-around times required

g. Reagent shipping, storage and operating conditions required

h. Where relevant, instrument operating conditions required

i. Required qualifications, training and skill levels needed for test performance and

result interpretation e.g. non-laboratory personnel for a simple rapid test, trained

laboratory technician to perform routine testing, medically trained personnel for

result interpretation, Ph.D. level scientist required for highly complex and variable

methodologies

j. Quality management requirements based on complexity of facilities & support

required to perform the test

Proposed answer table:

Primary care District hospitals/lab

Regional hospitals/lab

National hospitals/ Reference lab

Infrastructure requirements Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

Specimen types Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

Testing volumes expected Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

Complexity of specimen handling Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

Infrastructure for transporting specimens

Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

Result turn-around times required

Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

Reagent shipping, storage and operating conditions required

Assay 5 (those may be required for ICT/RDTs)

Assays 2, 3 and 5

Assays 1–5 Assays 1–5

10

Instrument operating conditions required

Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

Required qualifications, training and skill levels

Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

Quality management requirements

Assay 5 Assays 2, 3 and 5

Assays 1–5 Assays 1–5

5. What is your recommendation to SAGE IVD? Please summarise the key points you considered

in reaching your conclusion.

Trypanosoma cruzi IgG serological tests are required to diagnose chronic Chagas disease in endemic

and non-endemic countries. The current PAHO/WHO guidelines and most of the national

programmes require more than one test to be conducted to confirm T. cruzi infection in suspected

patients (see use case 1 below). There are different assay formats for T. cruzi IgG (e.g. ELISA, ICT,

HAI, CMI; see section Assay Formats & Specimen Types), so the SAGE working group may need to

evaluate the different tests available and decide which ones should be included in the EDL. Including

one single type/assay format in the EDL would not allow diagnosing T. cruzi infection.

Recommendations:

• Include Trypanosoma cruzi IgG serological tests for chronic Chagas disease diagnosis to

the EDL.

• According to the current PAHO/WHO guidelines, the following assay formats, not

captured in the actual application, may be included for this use case: ELISA, ELISA-r, HAI

and IFAT.

• Similarly, following the PAHO/WHO guidelines:

o CMIA may be added to the section “IVDs for blood screening laboratories”

o ICT/RDTs may be added as screening tools for T. cruzi infection.

Use cases (test purpose in the EDL table).

There are a number of use cases in which T. cruzi IgG tests are used to diagnose Chagas disease.

1. Diagnosing patients with suspected chronic T. cruzi infection

It is estimated that there are 6 to 8 million people with chronic T. cruzi infection.

According to the WHO/PAHO guidelines the chronic stage of the disease is diagnosed based on

clinical assessment, serology and epidemiological history. The definitive diagnosis of T. cruzi

infection depends on the positive result of at least two different serologic tests that detect specific

IgG antibodies in patient sera. Thus the diagnostic algorithm requires at least two tests. A third test

is required to confirm the status of the patient if the results of the first two tests are discordant. The

tests usually considered in the diagnostic algorithms in endemic countries are: ELISA, ELISA-r,

indirect immunofluorescence and indirect hemagglutination.

The classic diagnostic algorithm for chronic T. cruzi infection in endemic countries is:

ASSAY RESULTS

First test: ELISA crude antigens

Positive Negative Negative Positive

Second test: ELISA-r or IHA or IFA

Positive Negative Positive Negative

11

Status 1 T. cruzi infected patient

Non-infected Undetermined

Third test: different test than first and second

NA NA Positive Negative

Status 2 NA NA T. cruzi infected patient

Non-infected

Other assay formats such as CMIA and ICT are also now been considered and they may be part of the

diagnostic algorithm (see details below).

Special groups:

Sensitivity is prioritized in certain groups:

1a: Pregnant women: the results of the test will trigger further testing in infants born to T. cruzi

infected mothers. In some countries, a single test with high sensitivity (e.g. ELISA using crude lysates

of the parasite as antigen) is used to screen pregnant women.

1b: Organ donors: as for blood donors, high sensitivity is also needed in tests screening for T. cruzi in

organ donors, before transplanting their organs.

2. Diagnosing patients with suspected acute T. cruzi infection transmitted congenitally or otherwise

In the acute phase, diagnostic methods are focused on finding T. cruzi in blood samples by direct

parasitological and molecular (e.g. PCR) methods. However serological tests are also part of the

diagnostic algorithm. In general, the use of serological testing in those cases is associated to delays

in diagnosis (several months in congenital Chagas disease and several weeks in other forms of acute

Chagas disease).

2a: congenital Chagas disease: the same diagnostic algorithm as for chronic T. cruzi infection is

applied 8 to 12 months after birth in infants born to T. cruzi infected mothers if the tests at birth

(parasitology, PCR) were negative or were not performed.

2b: other forms of acute Chagas disease (e.g. oral infection, reactivation): seroconversion of

serological tests (at least 21 days apart) is used to diagnose T. cruzi infection in these cases.

3. Screening Chagas disease in population studies

An accurate, easy-to-use test is required to conduct population studies on the prevalence of Chagas

disease (chronic infection).

4. Screening Chagas disease in hemotherapy services

A highly sensitive, high throughput test is required to identify T. cruzi infected blood donations and

avoid transmission via blood transfusion. The tests to screen for T. cruzi infection in blood banks are

already included in the Second WHO Model List of Essential In Vitro Diagnostics:

https://www.who.int/medical_devices/publications/EDL_2_0_Standalone_11_2019_v2.pdf?ua=1

12

The current submission should focus on the use of T. cruzi IgG serological tests for chronic Chagas

disease diagnosis (use case 1 above), including the diagnosis of congenital Chagas disease using

serological tests 8 to 12 months after birth (included in use case 2 above).

Assay formats & specimen types

There are a number of assay formats used mainly to detect T. cruzi IgG in serum and plasma. Some

immunochromatographic test (ICT) can also use whole (capillary) blood. All of them should be

considered in the application for the EDL as they have different characteristics and their combination

is required for Chagas disease diagnosis (see WHO guidelines,

http://iris.paho.org/xmlui/bitstream/handle/123456789/49653/9789275120439_eng.pdf). A list of

commercially available assays is available in the Annex 6 of these guidelines. Briefly:

(1) ELISA: There are two types of ELISA tests, those using crude antigens (e.g. Bios Chile ELISA Chagas

III, Chile) and those using recombinant antigens (ELISA-r, e.g. BioELISA Chagas, Spain). Crude antigen

ELISAs are considered more sensitive than recombinant antigens. The current WHO guidelines

require combining these two types of ELISAs (or different techniques) to confirm the T. cruzi

infection in suspected patients (see use-cases above).

(2) Indirect haemagglutination assay (IHA) (e.g. Chagas test, Wiener)

(3) Indirect immunofluorescence assay (IFA) (e.g. IF Immunocruzi, Biolab-Mérieux)

(4) Chemiluminescent microparticle immunoassay (CMIA): These tests (e.g. Roche Elecsys Chagas,

Architect Abbot) require complex laboratory equipment and are not usually available in Chagas

endemic countries/areas. CMI tests can be used as part of the Chagas disease diagnostic algorithm

but the current WHO/PAHO guidelines do not recommend their use as standalone tests for chronic

T. cruzi infection diagnosis

(http://iris.paho.org/xmlui/bitstream/handle/123456789/49653/9789275120439_eng.pdf).

The WHO/PAHO guidelines recommend using CMIAs to screen blood banks for T. cruzi infection,

which is a different use case.

(5) Immunochromatographic test (ICT): A number of ICTs (commonly referred as RDTs) have been

developed in recent years (e.g. Chagas Detect Inbios, Onsite Chagas CTK). These tests are easier to

use (e.g. no lab equipment, blood as sample) and can be deployed in endemic regions. The current

WHO/PAHO guidelines do not recommend their use as standalone tests for chronic T. cruzi infection

13

but new evidences indicate their potential use, e.g. meta-analysis:

https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0007271 and field studies:

https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0007877.

The WHO/PAHO guidelines recommend using ICTs to evaluate the prevalence of Chagas disease in

population studies, which is a different use case.

Another interesting (although slightly outdated) WHO reference:

https://www.who.int/diagnostics_laboratory/publications/anti_t_cruzi_assays.pdf

14

Disease Diagnostic test Test purpose Assay format Specimen type

WHO prequalified or recommended products

WHO supporting documents

Chagas disease

T. cruzi antibody (immunoglobulin G) (IgG)

Chronic Chagas disease diagnosis (chronic T. cruzi infection) Including diagnosis of T. cruzi infection in infants born to infected mothers 8–12 months after birth

ELISA (crude antigens) Serum or plasma

Guidelines for the diagnosis and treatment of Chagas disease (2018) http://iris.paho.org/xmlui/bitstream/handle/123456789/49653/9789275120439_eng.pdf recommend their use as part of the “diagnostic gold standard, i.e., the combining of two positive serological tests (ELISA, hemagglutination inhibition assay [HAI], or indirect immunofluorescence [IIF]), and potentially a third test if the results are conflicting, in order to make a definitive diagnosis.”

ELISA-r (recombinant antigens)

Serum or plasma

Indirect hemagglutination assay (IHA)

Serum or plasma

Indirect immunofluorescence assay (IFA)

Serum or plasma

Chemiluminescent microparticle immunoassay (CMIA)

Serum or plasma

The use of CMIA alone for patients with suspected chronic T. cruzi infection is not recommended by the PAHO/WHO guidelines. However “CMIA is recommended to screen Chagas disease in hemotherapy services” – a different use case. Guidelines for the diagnosis and treatment of Chagas disease (2018) http://iris.paho.org/xmlui/bitstrea

15

m/handle/123456789/49653/9789275120439_eng.pdf

Immunochromato-graphic test (ICT)

Serum, plasma, blood (including capillary)

The use of ICT/RDT to diagnose chronic T. cruzi infection is not supported by PAHO/WHO guidelines. In those guidelines, ICT are “recommended for population studies on the prevalence of Chagas disease”, a different use case (Guidelines for the diagnosis and treatment of Chagas disease, 2018 http://iris.paho.org/xmlui/bitstream/handle/123456789/49653/9789275120439_eng.pdf ) However there is increasing evidence on the potential use of RDT/ICTs to diagnose chronic T. cruzi infection: - meta-analysis: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0007271 - field studies: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0007877

16

6. Please list the items that require further clarification from the originator of this submission.

The submission lacks of details and analysis in some sections. The different test purposes (use cases)

are not clearly presented and the PAHO/WHO recommendations in the different scenarios are not

presented. The submission focuses on one of the assay formats available to detect T. cruzi IgG

(chemiluminescent microparticle immunoassay [CMIA]), and in particular the product developed by

the originator of the submission (see table in Annex 1).