Reducing Risk of Relevant Transfusion-Transmitted Infection

Use of Serological Tests to
Reduce the Risk of
Transmission of Trypanosoma
cruzi Infection in Blood and
Blood Components

Guidance for Industry
Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring,
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email [email protected], or
from the Internet at
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or email
address listed above.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
December 2017
OMB Control No. 0910-0681
Expiration Date: 6/30/2020
See additional PRA statement in Section VI of this guidance

Contains Nonbinding Recommendations

TABLE OF CONTENTS
I.

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 2
A.
B.
C.
D.

III.

RECOMMENDATIONS.................................................................................................. 6
A.
B.
C.

IV.

Blood Donor Testing for Chagas Disease in the United States ......................... 2
Donor Screening for History of Chagas Disease ................................................ 4
Further Testing of Donations Repeatedly Reactive with a Licensed Screening
Test for Antibodies to T. cruzi ............................................................................. 4
Donor Reentry ....................................................................................................... 5

Blood Donor Testing, Deferral, Further Testing and Notification................... 7
Reentry Algorithm for Donors Deferred on the Basis of Screening Test
Results for Antibodies to T. cruzi or Predonation Screening Question ........... 8
Product Managemen ........................................................................................... 10

IMPLEMENTATION .................................................................................................... 11
A.
B.

Donor Screening .................................................................................................. 11
Reentry of Deferred Donors ............................................................................... 12

V.

REFERENCES ................................................................................................................ 13

VI.

PAPERWORK REDUCTION ACT OF 1995 .............................................................. 15

APPENDIX: REENTRY ALGORITHM FOR DONORS DEFERRED ON THE BASIS
OF SCREENING TEST RESULTS FOR ANTIBODIES TO T. CRUZI OR
PREDONATION SCREENING QUESTION.................................................. 16

i

Contains Nonbinding Recommendations

Use of Serological Tests to Reduce the Risk of Transmission of
Trypanosoma cruzi Infection in Blood and Blood Components
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.

I.

INTRODUCTION

We, FDA, are providing you, blood collection establishments, with recommendations regarding
the use of serological tests to reduce the risk of transmission of Trypanosoma cruzi (T. cruzi)
infection in blood and blood components. These recommendations apply to the collection of
blood and blood components, except Source Plasma, for transfusion or for use in manufacturing
a product, including donations intended as a component of, or used to manufacture, a medical
device.
FDA previously issued the following guidance documents related to T. cruzi:
•

•

In 2010, we issued a document entitled “Guidance for Industry: Use of Serological Tests
to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and
Blood Components Intended for Transfusion” dated December 2010 (2010 Chagas
Guidance).
In 2016, we issued a draft document entitled “Amendment to ‘Guidance for Industry:
Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi
Infection in Whole Blood and Blood Components Intended for Transfusion’; Draft
Guidance for Industry” dated November 2016 (2016 Draft Chagas Guidance).

The 2016 Draft Chagas Guidance, if finalized, would have amended the 2010 Chagas Guidance
by: 1) expanding the scope of the guidance to include the collection of blood and blood
components for use in manufacturing a product, including donations intended as a component of,
or used to manufacture, a medical device, 2) removing the recommendation to ask donors about
a history of Chagas disease, and 3) providing a recommendation for a reentry algorithm for
certain donors deferred on the basis of screening test results for antibodies to T. cruzi or on the
basis of answering “yes” to the Chagas screening question. The 2016 Draft Chagas Guidance
also noted that FDA had licensed a supplemental test for antibodies to T. cruzi and further testing
of donations found repeatedly reactive to a screening test for T. cruzi is therefore required under
21 CFR 610.40(e).
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Contains Nonbinding Recommendations

This guidance supersedes the 2010 Chagas Guidance and finalizes the 2016 Draft Chagas
Guidance.
T. cruzi is a relevant transfusion-transmitted infection (RTTI) (21 CFR 630.3(h)(1)(vii)), and
therefore subject to the testing requirements in 21 CFR 610.40, the donor deferral practices in
21 CFR 610.41, and the donor notification requirements in 21 CFR 630.40. 1
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.

II.

BACKGROUND

Chagas disease is caused by the protozoan parasite T. cruzi. The disease is endemic in Mexico
and Central and South America. Natural infections are transmitted by infected blood sucking
insects (triatomine bugs). Several cases of natural transmission also have been reported in the
United States (U.S.), which were associated with documented infections in insect vectors and
reservoir hosts in the southern U.S. (Refs. 1 and 2). Vector-borne T. cruzi infections are mostly
mild in the acute phase and then persist throughout life, usually without symptoms. Acute
infection in patients with compromised immune systems can be very serious and sometimes
fatal. The lifetime risk of severe cardiac complications (cardiomegaly, heart failure and
arrhythmias) or intestinal disorders (megacolon, megaesophagus) in infected individuals
averages about 30% (range of 10% to 40%, depending on a variety of factors) and may occur
decades after the initial infection. Treatment options are limited, and are most effective early in
the infection. During the chronic phase of Chagas disease, most persons are asymptomatic and
unaware of their infection. During this phase, parasites have been identified on examination of
muscle (especially cardiac muscle), nerves, and the digestive tract. However, there has been
little investigation into the mechanisms that trigger mobilization of parasites that can be present
into the circulating blood during the chronic phase (Refs. 3 through 5).
Other known routes of transmission include oral, congenital (mother to unborn infant), organ
transplantation and blood transfusion. The presence of the pathogenic agent in U.S. donors has
increased due to immigration of infected individuals from endemic areas. Some experts estimate
that approximately 300,000 persons unknowingly infected with T. cruzi reside in the U.S. (Ref.
6). These individuals could serve as a potential source of transfusion-transmitted infection
should they become U.S. donors. In the U.S. and Canada, 10 cases of transfusion-transmitted T.
cruzi and 9 cases of infection from organ transplantation have been documented (Refs. 7 through
9).
A.

Blood Donor Testing for Chagas Disease in the United States

1

See Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use;
Final Rule (80 FR 29842, May 22, 2015), effective May 23, 2016.

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Contains Nonbinding Recommendations

The voluntary testing of U.S. blood donors for antibodies to T. cruzi was initiated in
January 2007, subsequent to FDA licensure of the first T. cruzi blood donor screening
test. 2 A second serological test for detection of antibodies to T. cruzi in donors was
licensed on April 30, 2010. 3
At the April 2009 Blood Products Advisory Committee (BPAC) meeting, FDA sought
advice from the committee regarding selective testing strategies for T. cruzi infection in
repeat blood donors. Issues discussed at the meeting included the epidemiology of
Chagas disease in the U.S., the experience with blood donor testing for T. cruzi
antibodies during the timeframe of January 2007 through November 2008 (i.e., since the
first test was approved and implemented), and the experience with asking donors
questions to assess their risk of having acquired Chagas disease. After discussing
potential testing strategies, the committee voted in favor of a selective testing strategy in
which one negative test would qualify a donor for all future donations without further
testing or the need to be asked questions regarding risk of a newly acquired infection
(Ref. 10). The committee’s recommendation was contingent upon the continuation of
studies to define the incidence of new infections in previously screened negative donors.
In the 2010 Chagas Guidance, FDA recommended one-time testing of each donor of
blood and blood components intended for transfusion using a licensed test for antibodies
to T. cruzi. The guidance stated that donors who test non-reactive are qualified to return
to donate without further testing of subsequent donations for antibodies to T. cruzi and
that each blood establishment should review its records to determine the history of testing
for T. cruzi in prospective donors to determine whether a donor should be tested.
Results of an incidence study were discussed at the August 2, 2011 BPAC meeting.
Based on the finding of zero incident cases of T. cruzi infection identified in over 4.2
million donors over 4 years, BPAC recommended that one-time donor testing should
continue (Ref. 11).
In 2015 (80 FR 29842), FDA defined T. cruzi as a RTTI (21 CFR 630.3(h)(1)(vii)) and,
as of May 23, 2016, blood establishments must test for T. cruzi consistent with the
requirements in 21 CFR 610.40, subject to the exceptions found in 21 CFR 610.40(c) and
(d). Additionally, consistent with 21 CFR 610.40(a)(2)(iii)(A), FDA recommends onetime testing of each donor blood and blood components using a licensed test for
antibodies to T. cruzi.
An online report of the AABB Chagas Biovigilance Network (http://www.aabb.org)
dated March 14, 2017, showed that between January 1, 2007 and December 31, 2016,
12,525 donors gave collections that were repeatedly reactive on a licensed screening test
for antibodies to T. cruzi. Of those collections, 2,207 (17.6%) were reported as
confirmed, 9,596 (76.6%) negative, 684 (5.5%) indeterminate, and 38 (0.3%) were
pending at the time the report was generated.
2
3

ORTHO T. cruzi ELISA Test System, Ortho-Clinical Diagnostics, Inc., Raritan, NJ.
ABBOTT PRISM Chagas, Abbott Diagnostics, Abbott Park, IL.

3

Contains Nonbinding Recommendations

B.

Donor Screening for History of Chagas Disease

FDA’s 2010 Chagas Guidance recommended asking the question “Have you ever had
Chagas disease?” to all donors at each donation, to identify donors with a history of
Chagas disease. It also recommended that donors who answer “no” to the question
should be tested with a licensed screening test for antibodies to T. cruzi, and donors who
answer “yes” to this question should be deferred indefinitely and notified of their
deferral. In a recent study, Steele, et al., identified 34 donors deferred because of a
history of Chagas disease as revealed by the question among approximately 76 million
qualified donors screened by the American Red Cross (ARC) between January 2000 and
August 2011 (Ref. 12). In comparison, ARC identified 488 donations positive by the
unlicensed supplemental Radioimmunoprecipitation Assay (RIPA) among approximately
21 million donations tested between January 2007 and August 2011. The 488 T. cruzi
RIPA positive donors had not responded in the affirmative to the Chagas history question
during the predonation screening process. This report also showed that only one of the
six donors who provided a follow-up sample, among the 34 donors deferred based on the
Chagas disease history question, had a repeatedly reactive result with a licensed
screening test. This donor was also T. cruzi RIPA positive on further testing. The
authors concluded that the Chagas question has no added value when all donors are tested
at least once.
Based on the low sensitivity and specificity of the donor question, the significant clinical
sensitivity of the two currently licensed screening tests (Refs. 13 and 14), the low (0.8%)
risk of transfusion-transmitted T. cruzi infection from a seropositive donor (Ref. 11), and
the observation that T. cruzi RIPA positive donors are likely not aware of their infection,
we are recommending that one-time testing alone, without donor questioning for history
of Chagas disease, is adequate and appropriate to identify donors at risk for transmission
of Chagas disease.
C.

Further Testing of Donations Repeatedly Reactive with a Licensed Screening
Test for Antibodies to T. cruzi

Consistent with 21 CFR 610.40(e), you must further test each donation found to be
reactive by a donor screening test using a licensed, approved or cleared supplemental test,
when available. 4 In November 2011, FDA licensed a supplemental test for antibodies to
T. cruzi. 5 This test is intended for use as an additional, more specific test for human
serum or plasma specimens found to be repeatedly reactive using a licensed screening
test for antibodies to T. cruzi.
A positive test result on the licensed supplemental test indicates that antibodies to T. cruzi
were detected, providing further confirmation of the repeatedly reactive licensed
screening test result. Conversely, scientific data support FDA’s current thinking that
donors whose blood samples are found to be repeatedly reactive on a licensed screening
4
5

See footnote 1.
ABBOTT ESA Chagas, Abbott Diagnostics, Abbott Park, IL.

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Contains Nonbinding Recommendations
test, but negative on a licensed supplemental test, may be considered for reentry as set
forth in section III.B of this document.
D.

Donor Reentry

The reentry of donors deferred on the basis of screening test results for antibodies to T.
cruzi was discussed at the July 31, 2014 BPAC meeting (Ref. 15).
FDA presented an analysis of donor follow-up studies used to develop a proposed donor
reentry algorithm and four alternative scenarios. In these follow-up studies, donors
whose collections were repeatedly reactive on a licensed screening test for antibodies to
T. cruzi and negative on a licensed supplemental test for antibodies to T. cruzi on their
initial donation were further evaluated to determine their eligibility for reentry as donors.
Follow-up testing was performed to assess their most likely T. cruzi infection status and
determine those who could safely be reentered.
Results of the follow-up studies showed that 117/238 (49.2%) of donors in the FDA
analysis had follow-up samples that were non-reactive with the two licensed screening
tests. Among the 117 donors with negative screening tests on follow-up, 115/117
(98.3%) had non-reactive results with the licensed supplemental test. Conversely, 2/117
(1.7%) of these donors had indeterminate results with the licensed supplemental test.
These studies showed that testing the follow-up samples with only the two licensed
screening tests did not identify all the donors with antibody reactivity to T. cruzi antigens.
FDA believes that it would not be safe to reenter a donor with any reactivity with a
licensed supplemental test given the higher analytical sensitivity of the currently licensed
supplemental test compared with the licensed screening tests and the consequent
uncertainty regarding the donor’s infectious status. FDA considers donors whose followup samples are tested with all three currently licensed tests and show no reactivity with
any of the three tests to be eligible for reentry, provided all other donor eligibility criteria
are met. A least burdensome approach to identifying potentially eligible donors would be
to perform sequential testing. The donors’ follow-up samples would be first tested with
the two licensed screening tests, which are run on automated instruments. Only
specimens which are non-reactive on both screening tests would be subsequently tested
with the manual licensed supplemental test.
Previously deferred donors who have had positive test results with either the unlicensed
T. cruzi RIPA test or with an investigational or licensed supplemental test for antibodies
to T. cruzi are not eligible for reentry and therefore should not be considered for reentry
using the recommended algorithm (see section III.B and Appendix of this document).
The T. cruzi RIPA test has a long history of use to identify individuals infected with T.
cruzi. In a study by ARC of T. cruzi RIPA positive donors, 74.5% (117/157), were born
in a T. cruzi endemic country (Ref. 10). Data from the licensed supplemental test clinical
trial showed high concordance, 98.7% (151/153), between T. cruzi RIPA positivity and
licensed supplemental test positivity among screening test repeatedly reactive donors
(Ref. 16). Similarly, previously deferred donors who have had an indeterminate test
5

Contains Nonbinding Recommendations
result with either the T. cruzi RIPA test or with an investigational or licensed
supplemental test are not eligible for reentry and therefore should not be considered for
reentry using the recommended algorithm. As noted in section II.A of this guidance,
these donors represent a small percentage (5.5%) of currently deferred donors and
because their infectious status is unclear due to low level antibody reactivity to T. cruzi
specific antigens, FDA considers them not eligible for reentry. 6 Only previously deferred
donors with negative test results on the unlicensed T. cruzi RIPA (if so tested) and the
investigational or licensed supplemental test for antibodies to T. cruzi (if so tested), and
deferred donors who have never been tested by T. cruzi RIPA or an investigational or
licensed supplemental test should be considered for reentry using the recommended
algorithm.
Deferred donors who previously answered “yes” to the predonation screening Chagas
question may also be considered for reentry using the recommended algorithm provided
that they have had no positive or indeterminate test results on the unlicensed T. cruzi
RIPA or on the investigational or licensed supplemental test for Chagas. 7
Donors who may be considered for reentry using the recommended algorithm may
provide a follow-up blood sample for testing after a minimum of 6 months since the time
of their last deferral. Although all T. cruzi positive U.S. blood donors identified since
testing was initiated January 2007 have shown evidence of a long term rather than recent
infection, the six-month time period prior to reentry testing would add a safeguard by
allowing time for maturation of an early antibody response in a donor with low level
antibodies at the index donation due to recent infection. Six months would also allow for
potential resolution of cross-reacting antibodies attributable to an unrelated acute medical
condition that may have produced the repeatedly reactive screening test result.
While the BPAC did not take a formal vote on the donor reentry algorithm proposed by
FDA at its July 31, 2014 BPAC meeting, the Committee discussed this approach and did
not express concerns about the adequacy of this plan as a reentry algorithm (Ref. 15).

III.

RECOMMENDATIONS

These recommendations apply to the collection of blood and blood components, except Source
Plasma, for transfusion or for use in manufacturing a product, including donations intended as a
component of, or used to manufacture, a medical device. 8

6

FDA may reconsider in the future the eligibility of donors with an indeterminate test result using the unlicensed T.
cruzi RIPA test, or an investigational or licensed supplemental test for antibodies to T. cruzi based on newly
acquired supporting scientific evidence that these donors are not infected.
7
If donors participated in follow-up studies prior to May 23, 2016, those with a positive or indeterminate test result
with an investigational or licensed supplemental test for antibodies to T. cruzi or with the unlicensed T. cruzi RIPA
test should not be considered eligible for reentry.
8
Blood establishments are not required to test donations of Source Plasma for evidence of infection due to T. cruzi
(21 CFR 610.40(a)(2)(ii)).

6

Contains Nonbinding Recommendations
We no longer recommend that the question “Have you ever had Chagas disease?” be asked to all
donors at each donation. The question may be removed from your donor history questionnaire.
Donors deferred previously on the basis of answering “yes” to the predonation screening
question “Have you ever had Chagas disease?” may be considered for reentry as described in
section III.B of this document.
A.

Blood Donor Testing, Deferral, Further Testing and Notification
1.

Donor Testing

You must test donations for evidence of T. cruzi using a licensed screening test
for antibodies to T. cruzi (21 CFR 610.40(a)(2)), subject to the exceptions found
in 21 CFR 610.40(c) and (d). We recommend one-time testing of each donor of
blood and blood components (21 CFR 610.40(a)(2)(iii)(A)). We also recommend
one-time testing of autologous donors of blood and blood components only when
the circumstances described in 21 CFR 610.40(d)(1) through (3) are applicable.
Each blood establishment should review its records 9 to determine the history of
testing for T. cruzi in prospective donors to determine whether a donor should be
tested.
Donors who test non-reactive are qualified to return for subsequent donations
without further testing of subsequent donations for antibodies to T. cruzi.
2.

Donor Deferral, Further Testing and Notification

Donors who test repeatedly reactive on a licensed screening test for T. cruzi
antibody must be deferred (21 CFR 610.41(a)).
You must further test each donation which tests repeatedly reactive using a
licensed screening test for antibodies to T. cruzi with a licensed, approved, or
cleared supplemental test for antibodies to T. cruzi (See 21 CFR 610.40(e)).
Further, you must make reasonable attempts to notify any donor that tests
repeatedly reactive for antibodies to T. cruzi of their deferral and of their test
results including the results of further testing required under 21 CFR 610.40(e)
within 8 weeks after determining that the donor is deferred (See 21 CFR 630.40).
Donors whose blood tests positive or indeterminate on the licensed supplemental
test should be deferred permanently and informed of the likelihood and medical
significance of infection with T. cruzi. Donors whose blood tests negative on a
licensed supplemental test may be considered for reentry using the recommended
algorithm and informed of the procedure to follow for reentry.

9

Blood establishments are required to maintain donor and processing records under 21 CFR 606.160.

7

Contains Nonbinding Recommendations
B.

Reentry Algorithm for Donors Deferred on the Basis of Screening Test
Results for Antibodies to T. cruzi or Predonation Screening Question

We consider the recommendations for donor reentry in this section to be an acceptable
requalification method or process, within the meaning of 21 CFR 610.41(b), for reentry
of donors deferred due to repeatedly reactive screening tests for antibodies to T. cruzi and
within the meaning of 21 CFR 630.35(b) 10 for donors deferred for previously answering
“yes” to the donor history question, “Have you ever had Chagas disease?”
1.

FDA recommends that donors with the following Chagas test results are
not eligible for reentry.11
a. Positive or indeterminate with an investigational or licensed
supplemental test for antibodies to T. cruzi.
OR
b. Positive or indeterminate with the unlicensed T. cruzi RIPA test.

2.

Donors deferred on the basis of screening test results for antibodies to T.
cruzi who had (at the time of donation that prompted the deferral) the
following Chagas test results may be considered for reentry provided that
they do not meet any of the ineligibility criteria described in item 1 of this
section: 11
a. Negative with an investigational or licensed supplemental test for
antibodies to T. cruzi.
OR
b. Negative with the unlicensed T. cruzi RIPA test.
OR
c. Not tested with an investigational or licensed supplemental test for
antibodies to T. cruzi, and not tested with the unlicensed T. cruzi RIPA
test.

3.

Donors deferred previously on the basis of answering “yes” to the
predonation screening question “Have you ever had Chagas disease?” may

10

See footnote 1.
Effective May 23, 2016, blood collection establishments must use a licensed supplemental test for T. cruzi in
accordance with 21 CFR 610.40(e).

11

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Contains Nonbinding Recommendations
also be considered for reentry provided that they do not meet any of the
ineligibility criteria described in item 1 of this section. 12, 13
4.

To reenter a donor who meets the criteria described in items 2 or 3 of this
section, we recommend that you do the following (see also algorithm in
the Appendix):
a. At least 6 months after the date of deferral, obtain a new blood sample
from the donor (no donation is made at this time) and perform followup testing as follows:
i. Test sample using two different licensed screening tests for
antibodies to T. cruzi.
One of the two screening tests should be the test that was
repeatedly reactive on the original donation.
AND
ii. If the follow-up sample is non-reactive with the two licensed
screening tests, then test the follow-up sample with a licensed
supplemental test for antibodies to T. cruzi.
b. Evaluate the results of the follow-up testing on the donor’s new
sample as follows:
i. If either one or both screening tests are repeatedly reactive, we
recommend that you defer the donor permanently.
ii. If the licensed supplemental test is either positive or
indeterminate, we recommend that you defer the donor
permanently.
iii. If the two licensed screening tests are non-reactive and the
licensed supplemental test is negative, you may reenter the
donor provided all other donor eligibility criteria are met at the
time of donation. Testing for T. cruzi is not required on future
blood donations from the reentered donor.

12

If donors participated in follow-up studies prior to May 23, 2016, those with a positive or indeterminate test result
with an investigational or licensed supplemental test for antibodies to T. cruzi or with the unlicensed T. cruzi RIPA
test should not be considered eligible for reentry.
13
We no longer recommend that donors be asked the question “Have you ever had Chagas disease?”

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Contains Nonbinding Recommendations
C.

Product Management
1.

Index Donations

You must not ship or use blood and blood components that test repeatedly
reactive for antibodies to T. cruzi unless an exception exists (21 CFR 610.40(h)
and 21 CFR 630.30(b)(1)). You must appropriately label such blood or blood
components as required under 21 CFR 606.121 and with the “BIOHAZARD”
legend (21 CFR 610.40(h)(2)(ii)(B). Blood and blood components determined to
be unsuitable for transfusion must be prominently labeled: “NOT FOR
TRANSFUSION,” and the label must state the reason the unit is considered
unsuitable. This requirement does not apply to blood and blood components
intended solely for further manufacture (21 CFR 606.121(f)).
2.

Lookback (Product Retrieval and Consignee Notification)

Within 3 calendar days after a donor tests repeatedly reactive by a licensed test for
T. cruzi antibody, you should:
a. Identify all in-date blood and blood components previously donated by
such a donor, going back either 10 years (or indefinitely where
electronic records are available), or else, in a previously tested donor,
12 months prior to the donor’s most recent negative test result with a
licensed test for T. cruzi antibody, whichever is the lesser period (the
lookback period). It is recognized that under the selective testing
recommended herein, most donors tested will not have a prior negative
test.
b. Quarantine all previously collected in-date blood and blood
components from that donor held at your establishment; and
c. Notify consignees of all previously collected in-date blood and blood
components from that donor to quarantine and return the blood and
blood components to you or to destroy them.
In addition, when you identify a donor who is repeatedly reactive by a licensed
screening test for T. cruzi and positive or indeterminate by a licensed or
investigational supplemental test, we recommend that you:
d. Notify consignees of all previously distributed blood and blood
components collected from that donor during the lookback period; and
e. If blood or blood components were transfused, encourage consignees
to notify the recipient’s physician of record of a possible increased risk
of T. cruzi infection.

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Contains Nonbinding Recommendations
f. Make such notifications within 12 weeks of obtaining the repeatedly
reactive test result.
3.

Autologous Donation

Although autologous use of blood does not increase a patient’s/donor’s risk of
illness from a pre-existing infection, FDA regulations under 21 CFR 610.40(d)
and (e) require testing of autologous blood donors under certain circumstances to
prevent inadvertent allogeneic exposures to unsuitable units. Additionally,
a. Establishments must provide the results of further testing under
21 CFR 610.40(e) to the autologous donor’s referring physician. (21
CFR 630.40(d)(1)(iii) and (d)(2)).
b. Each autologous donation must be labeled as required under
21 CFR 610.40(d)(4) and 21 CFR 606.121(i)(5), as appropriate.
Autologous donations that are repeatedly reactive by a licensed test for
T. cruzi antibody must bear a “BIOHAZARD” legend. See 21 CFR
610.40(d)(4).
4.

Circular of Information

Under 21 CFR 606.122(h), the circular of information must include the names and
results of all tests performed when necessary for safe and effective use. We
recommend the following statement for T. cruzi testing:
“All blood has been collected from donors who have tested negative by a
licensed test for antibodies to Trypanosoma cruzi either on the current
donation or at least one previous donation.”

IV.

IMPLEMENTATION
A.

Donor Screening

If you are a licensed establishment and you remove the “Have you ever had Chagas
disease?” question from your donor history questionnaire (DHQ), you must report this
change to FDA under 21 CFR 601.12, as follows: 14
1.

14

Revision of your own DHQ and accompanying materials: report in your
annual report consistent with 21 CFR 601.12(d), noting the date the
question was removed from your DHQ and accompanying materials.

See 21 CFR 601.12(a)(3).

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Contains Nonbinding Recommendations
2.

Revision of a previously FDA accepted DHQ and accompanying
materials: report in your annual report consistent with 21 CFR 601.12(d),
noting the date the question was removed from the accepted DHQ and
accompanying materials.

Unlicensed establishments are not required to report this change to FDA but are required
to maintain records under 21 CFR 606.160.
B.

Reentry of Deferred Donors

We consider the recommendations in section III.B of this document for donor reentry to
be an acceptable requalification method or process, within the meaning of 21 CFR
610.41(b), for reentry of donors deferred due to repeatedly reactive screening tests for
antibodies to T. cruzi and within the meaning of 21 CFR 630.35(b) 15 for donors deferred
for previously answering “yes” to the donor history question, “Have you ever had Chagas
disease?”
Licensed establishments implementing the recommendations for donor reentry in this
guidance must report this change to FDA as required under 21 CFR 601.12. Specifically,
licensed establishments must submit a statement of this change in an annual report under
21 CFR 601.12(d), indicating the date that the revised standard operating procedures
were implemented (see 21 CFR 601.12(a)(3)). Unlicensed establishments implementing
the recommendations for donor reentry in this guidance in their entirety and without
modification are not required to report this change to FDA.
Sections 610.41(b) and 630.35(b) require that a donor requalification method or process
used to requalify a donor be acceptable to FDA. Accordingly, before you implement an
alternative requalification method or process from that described in this guidance, FDA
must first find the alternative method or process to be acceptable for such purpose.
Licensed establishments intending to use an alternative requalification method must
submit a supplement for prior approval, as required under 21 CFR 601.12(b). Similarly,
before an unlicensed establishment implements an alternative requalification method or
process from that described in this guidance, FDA must first find the method or process
to be acceptable for such purpose (21CFR 610.41(b) and 630.35(b)).

15

See footnote 1.

12

Contains Nonbinding Recommendations
V.

REFERENCES

1.

Dorn P. L., et al., “Autochthonous transmission of Trypanosoma cruzi, Louisiana.”
Emerg Infect Dis 13(4): 605-607 (2007).

2.

Garcia, M. N., et al., “Case Report: Evidence of Autochthonous Chagas Disease in
Southeastern Texas.” Am J Trop Med Hyg 92(2): 325-330 (2015).

3.

Vago, A. R., et al., “PCR detection of Trypanosoma cruzi DNA in oesophageal tissues of
patients with chronic digestive Chagas’ disease.” Lancet 348: 891-892 (1996).

4.

Añez, N., et al., “Myocardial parasite persistence in chronic chagasic patients.” Am J
Trop Med Hyg 60(5): 726-732 (1999).

5.

Virreira, M., et al., “Trypanosoma cruzi: Typing of genotype (sub)lineages in megacolon
samples from bolivian patients.” Acta Tropica 100(3): 252-255 (2006).

6.

Manne-Goehler, J., et al. “Estimating the Burden of Chagas Disease in the United
States.” PLoS Negl Trop Dis 10(11): e0005033 (2016).

7.

Benjamin, R. J., et al., “Trypanosoma cruzi infection in North America and Spain:
evidence in support of transfusion transmission.” Transfusion 52: 1913-1921 (2012).

8.

Kirchhoff, L.V. “Epidemiology of American trypanosomiasis (Chagas disease).” Adv
Parasitol 75: 1-18 (2011).

9.

Huprikar, S., et al., “Donor-Derived Trypanosoma cruzi Infection in Solid Organ
Recipients in the United States, 2001–2011.” American Journal of Transplantation 13:
2418-2425 (2013).

10.

FDA Blood Products Advisory Committee “Potential Testing Strategies for T. cruzi
Infection in Blood Donors.” April 1, 2009. Available at https://wayback.archiveit.org/7993/20170111183035/http://www.fda.gov/AdvisoryCommittees/CommitteesMeet
ingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm2
76273.htm.

11.

FDA Blood Products Advisory Committee “T. cruzi Incidence Study in Blood Donors
and its Implications for One-time Testing of Blood Donors.” August 2, 2011. Available
at https://wayback.archiveit.org/7993/20170111183050/http://www.fda.gov/AdvisoryCommittees/CommitteesMeet
ingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm2
88494.htm.

12.

Steele, W. R., et al., “Donors deferred for self-reported Chagas disease history: does it
reduce risk?” Transfusion 54(8): 2092-2097 (2014).

13

Contains Nonbinding Recommendations
13.

Trypanosoma cruzi (T. cruzi) Whole Cell Lysate Antigen, ORTHO T. cruzi ELISA Test
System, Package Insert (2009). Available at
https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/L
icensedProductsBLAs/BloodDonorScreening/InfectiousDisease/ucm085846.htm.

14.

Trypanosoma cruzi (E. coli, Recombinant) Antigen, ABBOTT PRISM Chagas, Package
Insert (2010). Available at
https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/L
icensedProductsBLAs/BloodDonorScreening/InfectiousDisease/ucm210158.htm#.

15.

FDA Blood Products Advisory Committee “Reentry of blood donors deferred on the
basis of screening test results for antibodies to T. cruzi.” July 31, 2014. Available at
https://wayback.archiveit.org/7993/20170111180042/http://www.fda.gov/AdvisoryCommittees/CommitteesMeet
ingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm3
86681.htm.

16.

Trypanosoma cruzi (E. coli, Recombinant) Antigen, ABBOTT ESA Chagas, Package
Insert (2011). Available at
https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/L
icensedProductsBLAs/BloodDonorScreening/InfectiousDisease/ucm280719.htm.

14

Contains Nonbinding Recommendations
VI.

PAPERWORK REDUCTION ACT OF 1995

This guidance contains information collection provisions that are subject to review by the Office
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520). The collections of information that the establishment notify consignees of all
previously collected in-date blood and blood components to quarantine and return the blood and
blood components to establishments or to destroy them; notify consignees of all previously
distributed blood and blood components collected during the lookback period; encourage
consignees to notify the recipient’s physician of record of a possible increased risk of T. cruzi
infection; and provide the results of further testing to the autologous donor’s referring physician
do not create a new burden for respondents and are part of usual and customary business.
This guidance also refers to previously approved collections of information found in FDA
regulations. The collections of information in 21 CFR part 601 have been approved under OMB
control number 0910-0338; and the collections of information in 21 CFR parts 606, 610, and 630
have been approved under OMB control number 0910-0116 and 0910-0795. An agency may not
conduct or sponsor, and a person is not required to respond to, a collection of information unless
it displays a currently valid OMB control number. The OMB control number for this
information collection is 0910-0681 (expires 06/30/2020).

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Contains Nonbinding Recommendations
APPENDIX: Reentry Algorithm for Donors Deferred on the Basis of Screening Test
Results for Antibodies to T. cruzi or Predonation Screening Question
Deferred donors that meet the following conditions and do not meet the
ineligibility criteria described in this guidancea,b:
• Negative (at the time of the donation that prompted the deferral) with an
investigational or licensed supplemental test for antibodies to T. cruzi; or
• Negative (at the time of the donation that prompted the deferral) with the
unlicensed T. cruzi RIPA test; or
• Not tested (at the time of the donation that prompted the deferral) with an
investigational or licensed supplemental test for antibodies to T. cruzi or with the
unlicensed T. cruzi RIPA test; or
• Deferred on the basis of answering “yes” to the predonation Chagas questionc

Obtain a follow-up sample > 6
months since date of deferral

RR on either
test or RR on
both tests

Test follow-up sample with two
different licensed screening tests

Defer donor
Permanently

NR on both tests
POS or IND
Test follow-up sample with a
licensed supplemental test
NEG
Reenter donor provided all other
donor eligibility criteria are met.
Testing for T. cruzi antibodies is
not required on future blood
donations from the reentered
donor.
RR = repeatedly reactive; NR = non-reactive; POS = positive; NEG = negative; IND = indeterminate
a

Effective May 23, 2016, blood collection establishments must use a licensed supplemental test for T. cruzi
in accordance with 21 CFR 610.40(e).
b
FDA recommends that donors with the following Chagas test results are not eligible for reentry: (1) Positive or
indeterminate with an investigational or licensed supplemental test for antibodies to T. cruzi or (2) Positive or
indeterminate with the unlicensed T. cruzi RIPA test.
c
If donors participated in follow-up studies prior to May 23, 2016, those with a positive or indeterminate test result
with an investigational or licensed supplemental test for antibodies to T. cruzi or with the unlicensed T. cruzi RIPA
test should not be considered eligible for reentry.

16