Reducing Risk of Relevant Transfusion-Transmitted Infection

Recommendations for Reducing the
Risk of Transfusion-Transmitted
Babesiosis
Guidance for Industry

Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), 10903 New Hampshire Ave., Rm. 3128, Silver Spring, MD 209930002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, 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
May 2019

Contains Nonbinding Recommendations

Table of Contents
I.

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

II.

BACKGROUND ............................................................................................................... 1

III.

DISCUSSION .................................................................................................................... 2
A.
B.

Transfusion-Transmitted Infection ..................................................................... 2
Relevant Transfusion-Transmitted Infection ..................................................... 3

IV.

PUBLIC WORKSHOP AND ADVISORY COMMITTEE MEETINGS ON RISK
MITIGATION FOR TTB ................................................................................................ 5

V.

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

VI.

IMPLEMENTATION AND REPORTING CHANGES UNDER 21 CFR 601.12 ... 12
A.
B.
C.

VII.

Donation Testing, Donor History Questionnaire, Donor Deferral and
Requalification ...................................................................................................... 6
Product Management, Retrieval and Quarantine, Notification of Consignees
of Blood and Blood Components ......................................................................... 9
Product Disposition and Labeling ..................................................................... 10
Circular of Information ...................................................................................... 11
Donor History Questionnaire............................................................................. 12
Testing .................................................................................................................. 12
Circular of Information ...................................................................................... 13

REFERENCES ................................................................................................................ 14

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Recommendations for Reducing the Risk of TransfusionTransmitted Babesiosis
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, the Food and Drug Administration (FDA), are notifying you, blood establishments that
collect blood and blood components, that we have determined babesiosis to be a relevant
transfusion-transmitted infection (RTTI) under 21 CFR 630.3(h)(2). 1 Accordingly, we are
providing recommendations for donor screening, donation testing, donor deferral and product
management to reduce the risk of transfusion-transmitted babesiosis (TTB). The
recommendations contained in this guidance apply to the collection of blood and blood
components, except Source Plasma. 2
This guidance finalizes the draft guidance of the same title dated July 2018.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidance documents describe the Agency’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 Agency guidance means that something is
suggested or recommended, but not required.
II.

BACKGROUND

Human babesiosis is a tick-borne zoonosis caused by infections of humans with intraerythrocytic protozoa of the genus Babesia. Babesiosis can also be transmitted by transfusion of
blood and blood components (Refs. 1, 2) and by transplantation of solid organs (Ref. 3) collected
1

See Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use;
Final Rule (80 FR 29842, May 22, 2015). The rule became effective May 23, 2016.
2
Source Plasma is used for further manufacture of plasma-derived products. Pathogen inactivation and removal
methods that are currently used in the manufacturing process for plasma-derived products are sufficient to reduce
the risk of Babesia transmission.

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from an infected donor. Babesiosis is transmitted in many parts of the world but the highest
prevalence is reported in the United States (U.S.). The first documented human case of
babesiosis in the U.S. was identified in 1968 (Ref. 4). The vast majority of U.S. babesiosis cases
are caused by B. microti, the species that is prevalent in the Northeast and upper Midwest (Ref.
5). Less commonly, other Babesia species such as B. duncani (Refs. 6, 7) and related organisms
are implicated in transmission of Babesia in several western U.S. states, while transmission of
Babesia by “B. divergens-like” agents (Ref. 8) have been reported in multiple U.S. states.
Most cases of B. microti infections are asymptomatic and never diagnosed (Ref. 9). While the
duration of B. microti infections in healthy adults is not precisely known, in limited studies, the
parasitemic period is reported to last from 2 to 7 months (Ref. 10), but parasitemia may persist
for more than 2 years (Ref. 11). In a study of asymptomatic blood donors who were reactive for
B. microti using investigational nucleic acid tests (NAT) and antibody tests, follow-up testing
demonstrated DNA clearance in 86% (48 of 56 donors) after 1 year, and 95% (53 of 56 donors)
after 2 years (Ref. 10). Babesia transmission is generally seasonal and coincides with tick
activity (traditionally May-September) in affected states, but tick-borne (Refs. 12-17) and
transfusion-transmitted infections are reported throughout the year (Ref. 9). Transfusion of
blood and blood components collected from asymptomatic infected donors may result in TTB,
leading to potentially fatal clinical illness in blood transfusion recipients.
III.

DISCUSSION

FDA has determined, as discussed below, that babesiosis is a transfusion-transmitted infection
(TTI) under 21 CFR 630.3(l) and an RTTI under 21 CFR 630.3(h)(2). This determination is
based on the severity of the disease, confirmed transfusion-transmission by blood and blood
components, the availability of appropriate screening measures and donor screening tests and
significant incidence and prevalence affecting the potential donor population.
A.

Transfusion-Transmitted Infection

A transfusion-transmitted infection (21 CFR 630.3(l)) means a disease or agent:
(1) That could be fatal or life-threatening, could result in permanent impairment
of a body function or permanent damage to a body structure, or could
necessitate medical or surgical intervention to preclude permanent impairment
of body function or permanent damage to a body structure; and
(2) For which there may be a risk of transmission by blood or blood components,
or by a blood derivative product manufactured from blood or blood
components, because the disease or disease agent is potentially transmissible
by that blood, blood component, or blood derivative product.

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In this regard, FDA examined:
Severity of Disease
Clinical symptoms of babesiosis, caused by B. microti, range from asymptomatic or mild
to severe, and can result in death, particularly in certain high-risk populations. In the
majority of individuals who develop illness, clinical symptoms appear 1 to 4 weeks after
an infectious tick bite (Ref. 5). Common symptoms include fever, chills, body aches,
weakness, malaise and fatigue (Refs. 5, 9, 18, 19). Severe disease caused by B. microti
infection requiring hospitalization is generally seen in neonates, the elderly, asplenic
patients, and those receiving immunosuppressive drugs for cancer therapy (Refs. 5, 19,
20). The most common severe clinical manifestations include acute respiratory distress
syndrome and disseminated intravascular coagulopathy. Congestive heart failure, coma,
liver failure and renal failure are also reported (Refs. 5, 19, 20). In tick-borne cases,
fatality rates range from 6 to 9% among hospitalized patients and up to 21% in
immunosuppressed patients (Refs. 19, 20). In TTB cases, a fatality rate of about 20% has
been reported in the literature (Ref. 21).
Transfusion Transmission
Babesiosis can be transmitted by transfusion of blood and blood components, with the
first U.S. case of TTB reported in 1980 (Refs. 1, 2). Since then, more than 200 TTB
cases have been documented (Refs. 2, 22). While B. microti remains the major causative
agent, three TTB cases have been attributed to B. duncani (Ref. 2) and one possible case
to B. divergens in the U.S. (Ref. 23). Following transfusion of blood components
collected from an infected donor, symptoms in transfusion recipients have been observed
anywhere from 1 week to 9 weeks, and as long as 6 months after transfusion (Ref. 2).
In conclusion, FDA has determined that babesiosis is a TTI because it is a disease agent
that can be fatal or life-threatening and is transmissible by blood or blood components.
B.

Relevant Transfusion-Transmitted Infection

Having determined that babesiosis is a TTI, we outline, below, the criteria establishing
babesiosis as an RTTI under 21 CFR 630.3(h)(2)(i) and (ii).
An RTTI is a transfusion-transmitted infection not listed in 21 CFR 630.3(h)(1) when the
following conditions are met:
(1) Appropriate screening measures for the transfusion-transmitted infection have
been developed and/or an appropriate screening test has been licensed,
approved, or cleared for such use by the FDA and is available; and
(2) The disease or disease agent: (A) May have significant incidence and/or
prevalence to affect the potential donor population; or (B) May have been

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released accidentally or intentionally in a manner that could place potential
donors at risk of infection.
Availability of Appropriate Screening Measures or Screening Tests
Licensed Screening Tests: On March 6, 2018, FDA licensed two independent assays for
screening donors for B. microti: the Imugen Babesia microti Arrayed Fluorescent
Immunoassay (AFIA) for the detection of B. microti-specific antibodies and the Imugen
Babesia microti Nucleic Acid Test (NAT) for the detection of DNA of B. microti.
However, the manufacturer notified FDA of the permanent discontinuance of both donor
screening tests in November 2018. On January 24, 2019, FDA licensed the Grifols
Procleix Babesia Assay for the detection of RNA from Babesia species (B. microti, B.
duncani, B. divergens, and B. venatorum) in whole blood specimens for use in screening
donors of whole blood and blood components.
Pathogen Reduction: FDA has approved pathogen reduction devices that report effective
reduction of B. microti for indicated plasma or platelet components in the instructions for
use, which can be used as an alternative to testing or donor questions.
Donor History Questionnaire (DHQ): Upon implementing the recommendations in this
guidance, we do not find it necessary for blood establishments to continue to ask about a
history of babesiosis using the current question on the DHQ. Donors implicated in TTB
cases have been unaware of their infection status and hence have not reported a history of
babesiosis before donation (Ref. 24). When testing for Babesia begins according to the
recommendations in this guidance, we expect that some asymptomatic blood donors will
learn about their infection status when they are deferred. However, these donors might
still present to donate in a state where testing or pathogen reduction is not performed.
Accordingly, we are recommending a question on the DHQ, as follows:
•

If donations are not tested or pathogen reduced, we are recommending a question
to assess donors for a history of ever having a positive test result for Babesia,
obtained either from a medical diagnosis or reactive donor screening test. Such
donors are not eligible for donation, unless they are requalified by the
recommendations in this guidance.

•

If donations are tested, or if blood components from the donation are pathogen
reduced using an FDA-approved device effective against Babesia according to the
instructions for use, we are not recommending any Babesia-related questions.
However, if establishments choose to continue to ask a Babesia-related question,
donors with risk should be deferred according to the recommendations in this
guidance.

Significant Incidence and Prevalence
In 2011, babesiosis became a nationally notifiable disease. Between 2011 and 2017, an
average of 1,628 (range 937-2,100) babesiosis cases per year was observed in 26 states,

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excluding several Babesia-risk states because disease reporting was not required in those
states (Refs. 12-17). According to data from the Centers for Medicare and Medicaid
Services (CMS), babesiosis cases were reported among elderly Medicare beneficiaries in
all states and Washington, D.C., except for Wyoming (Refs. 25, 26). In aggregate, more
than 200 cases of TTB have been documented (Refs. 2, 22, 27). About 99% of the
clinical babesiosis cases reported and 95% of TTB cases reported are from Connecticut,
Massachusetts, Rhode Island, New York, New Jersey, Minnesota, Wisconsin, New
Hampshire, Maine, Maryland, Virginia, Vermont, Pennsylvania, Delaware, and
Washington, D.C. (Refs. 12-17, 25, 26).
TTB risk in other states is mostly attributed to infected donors who had lived or traveled
in Babesia-risk states or to distribution of blood components collected in areas affected
by Babesia to other states.
In summary, we have determined that babesiosis meets the criteria in 21 CFR 630.3(h)(2)
for an RTTI because of the availability of appropriate screening measures and screening
tests, and because of the sufficient incidence and prevalence of Babesia to affect the
potential donor population in the U.S.

IV.

PUBLIC WORKSHOP AND ADVISORY COMMITTEE MEETINGS ON RISK
MITIGATION FOR TTB

FDA solicited public input on how best to mitigate the risk of TTB in the U.S. and support the
development of donor screening tests for Babesia. On September 12, 2008, FDA convened a
public workshop entitled “Approaches to Reduce the Risk of Transfusion-Transmitted
Babesiosis in the United States” (Refs. 28, 29). The focus of this workshop was to discuss
various aspects of TTB in the U.S. including the status of detection technologies and possible
strategies to identify and defer blood donors who might have been exposed to Babesia parasites.
Experts emphasized the need for better understanding of the epidemiology of babesiosis in the
U.S. and efforts to develop highly sensitive and specific laboratory tests to identify Babesiainfected blood donors, especially tests to distinguish between current infections and resolved
infections. Discussions also focused on the biology, pathogenesis and epidemiology of
babesiosis. A detailed summary of this workshop has been published in Transfusion and the
meeting transcript is available on the FDA website (Refs. 28, 29).
On July 26, 2010, FDA discussed “Risk of Babesia Infection by Blood Transfusion and Potential
Strategies for Donor Testing” at a Blood Products Advisory Committee (BPAC or Committee)
meeting (Ref. 30). Based on the information available at that time, the Committee recommended
regional testing of blood donors for Babesia. The Committee did not provide advice on the
question of the most suitable technologies for donor screening for Babesia, noting that additional
information on the performance of different testing technologies was needed. A transcript of the
meeting and the presentations delivered at this BPAC meeting are available on the FDA website
(Refs. 30-34).

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On May 13, 2015, FDA again sought advice from the BPAC on strategies to test blood donors
for evidence of B. microti infection using licensed tests, when such tests become available (Ref.
25). In recent years, limited testing of blood donations using the available investigational tests
has provided additional information on the magnitude of B. microti prevalence in endemic areas
and on the relative value of NAT and antibody-based tests in identifying Babesia-exposed
donors with resolved infections as opposed to parasitemic donors. The sponsors of the
investigational B. microti tests presented the results of their clinical studies (Refs. 35, 36). The
Committee advised that the scientific data and FDA analysis support the concept of nationwide,
year-round testing of blood donations for Babesia risk by an antibody-based test. The
Committee also recommended unanimously that NAT-based testing should be performed on
blood donations in certain high-risk states, and the majority supported NAT testing in the nine
states considered endemic at that time (i.e., Connecticut, Maine, Massachusetts, Minnesota, New
Hampshire, New Jersey, New York, Rhode Island, and Wisconsin). The Committee
recommended including the bordering state of Pennsylvania in the year-round NAT-based
testing program. Additionally, the Committee supported a deferral period of at least 2 years for
donors with reactive test results, after which time, donor eligibility would be assessed based on
testing by both antibody and NAT-based testing. Since the meeting, Pennsylvania has been
identified as a B. microti endemic state.
FDA considered this BPAC recommendation for testing donations year-round by universal
antibody testing and regional NAT in states with the highest Babesia risk. Subsequently, we
performed an independent risk assessment that determined year-round antibody and NAT testing
in Babesia-risk states only is a preferred strategy that balances risk reduction with the scope of
testing. However, at the time of this writing, a licensed Babesia antibody test is not available for
blood donor screening. Consequently, we are recommending regional, year-round testing using
a licensed NAT for Babesia, or use of an FDA approved pathogen reduction device, in the
highest risk states. Consistent with BPAC’s advice, and based on the available published data on
Babesia DNA persistence in some screened blood donors beyond one year (Ref. 10), we are
recommending a 2-year deferral following a reactive donor NAT.

V.

RECOMMENDATIONS
A.

Donation Testing, Donor History Questionnaire, Donor Deferral and
Requalification

The recommendations in this guidance for regional testing for Babesia or pathogen
reduction of indicated blood components are based on the current epidemiological data
on Babesia and the risk of TTB, and the availability of FDA-licensed and approved
devices. FDA may modify these recommendations in the future based on scientific
evidence as it becomes available, for example, if we determine that regional NAT testing
alone does not adequately reduce the risk of TTB or if there is a need to expand the
recommendations to include additional Babesia-risk states as they are identified. In
addition, we may modify the recommendations in the future based on the availability of
licensed serology tests and approved pathogen reduction devices.

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1. We recommend that you update your donor history questionnaire, including
full-length and abbreviated donor history questionnaires, and accompanying
materials as necessary to incorporate the recommendations provided in this
document. You must update your standard operating procedures to reflect any
such changes (21 CFR 606.100(b)).
2. To comply with the requirements in 21 CFR 610.40(a)(3), you must test
donations as described in section V.A.3. of this document or implement
pathogen reduction technology for platelets and plasma using an FDAapproved pathogen reduction device effective against Babesia, according to
the manufacturer’s instructions for use. If an FDA-approved pathogen
reduction device becomes available for Whole Blood or red blood cells that
effectively inactivates Babesia, you may implement pathogen reduction
technology for such blood components.
3. You must test each donation for evidence of Babesia using a licensed NAT 3
when collected in Connecticut, Delaware, Maine, Maryland, Massachusetts,
Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode
Island, Vermont, Virginia, Wisconsin and Washington, D.C. (21 CFR
610.40(a)(3) and 610.40(b)). Testing must be performed year-round and in
accordance with the instructions for use of the device (21CFR 610.40 (a)(3)
and 606.65(e)).
a. You must defer donors with a reactive NAT result for Babesia for at
least 2 years from the date of the reactive donation (21 CFR 610.41(a)
and 21 CFR 630.35(a)). You must make reasonable attempts to notify
any donor whose blood tests reactive for Babesia of their deferral and
of their test results, within 8 weeks after determining that the donor is
deferred (21 CFR 630.40). Deferred donors must be counseled about
the possible medical significance of the results (21 CFR 630.40(b)).
b. When testing or pathogen reduction is performed, you may discontinue
asking donors questions about a history of babesiosis. 4 If you choose

3

Blood establishments that are participating in a clinical trial and testing for Babesia using an unlicensed NAT may
continue in the clinical trial but must implement the regulatory requirement to use a licensed donor screening test for
Babesia nucleic acid by 12 months of this guidance issuance date (21 CFR 610.40(b)).
4
To provide for appropriate donor screening and testing for this RTTI, the Director of the Center for Biologics
Evaluation and Research is providing an alternative procedure (testing, as described in section V. of this document)
under 21 CFR 640.120(b) to the provisions in 21 CFR 630.10 that require blood establishments to assess donors for
risk factors for babesiosis before collecting blood or blood components. Specifically, FDA is not recommending
assessing donors for risk factors for babesiosis, in particular, travel to or residence in an area endemic or at risk for
babesiosis. Assessing donors for travel to or residence within the United States and deferring donors for time spent
in areas endemic or at risk for babesiosis is not feasible because of the anticipated detrimental effect on the blood
supply. Approximately one-quarter of the U.S. population resides in the states identified at risk for babesiosis in this
guidance, and a large number of prospective blood donors may travel to the at-risk states.

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to ask a donor question about Babesia, you should follow the
recommendations in section V.A.4. of this document.
c. When testing or pathogen reduction is performed, donors who were
previously deferred for a history of babesiosis based on their responses
on the donor history questionnaire may be eligible to donate provided
they have not had a positive test result for Babesia in the last 2 years
obtained from either a medical diagnosis or a positive donor screening
test result and they meet all other donor eligibility criteria (21 CFR
630.35(b)).
4

In states that do not test donations for Babesia or pathogen reduce blood
components we recommend the following:
a. Revise your donor history questionnaire to ask prospective donors if
they have ever had a positive test result for Babesia, obtained from
either a medical diagnosis or a reactive donor screening test.
b. You must defer donors who report a history of a positive test result for
Babesia, obtained from either a medical diagnosis or a reactive donor
screening test result (21 CFR 630.10(h)). Such donors should be
indefinitely deferred or deferred for at least 2 years from the date of
the positive test and evaluated for requalification as described below in
section V.A.4.c. of this document.
c. A donor who was previously deferred for a history of babesiosis or is
deferred for a history of a positive test result for Babesia may be
eligible to donate under 21 CFR 630.35(b) provided the following
conditions are met:
i.

On the day of donation, the donor has not had a positive test
result for Babesia in the last 2 years and they meet all other
eligibility criteria.

ii.

The donation must be tested for Babesia by a licensed NAT
and found to be nonreactive at the time of blood collection
(21 CFR 610.40(a)(3)(ii)(A).
If the donor meets the criteria for requalification in section
V.A.4.c.i and ii., subsequent donations do not need to be tested
for Babesia provided the donor is assessed by the DHQ and has
not had a positive test for Babesia since the date of the last
negative test result that was the basis for requalification.

5. For donor counseling purposes, the responsible physician may perform
additional testing such as alternative Babesia NAT and/or diagnostic antibody

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tests that are not indicated for use in donor screening. The results of such
testing cannot be used to requalify a deferred donor with a reactive screening
test by a licensed NAT.
B.

Product Management, Retrieval and Quarantine, Notification of Consignees
of Blood and Blood Components
1. You may release donations that are nonreactive for Babesia by a licensed
donor screening test provided all other donation suitability requirements are
met (21 CFR 630.30).
2. You must not ship or use a donation that is reactive for Babesia, unless an
exception for shipment or use is applicable (21 CFR 610.40(h) and 21 CFR
630.30(b)(1)).
3. We recommend that you take the following actions when a donation tests
reactive for Babesia by a licensed donor NAT:
a. Identify all cellular blood components previously collected from that
donor in the 12 months prior to the date of the reactive index donation.
The responsible physician may also consider the disposition of in-date
cellular components (e.g., frozen RBC components) collected more
than 12 months prior to the reactive index donation, especially those
that were not tested; and
b. Quarantine the identified in-date cellular components held at your
establishment; and
c. Notify consignees of all identified cellular blood components collected
from the donor in the 12 months prior to the date of the reactive index
donation that have been distributed, and:
1. Retrieve the identified in-date cellular blood components.
2. If components were transfused, encourage consignees to have a
discussion with the recipient’s physician of record about a
possible risk of TTB, particularly if the involved component(s)
had not been tested or pathogen reduced.
The recommendation for consignee notification and retrieval does not
apply to previously distributed cellular blood components that were
pathogen reduced using an FDA-approved device according to its
instructions for use.
4. We recommend that you take the following actions when a donor later reports
a history of a positive test result for Babesia and should have been deferred
according to the recommendations in section V.A.4.b.

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a. Identify all cellular blood components previously collected from that
donor going back 12 months prior to the reported date of the positive
test result for Babesia; and
b. Quarantine the identified in-date cellular components held at your
establishment; and
c. Notify consignees of all identified cellular blood components collected
from the donor in the 12 months prior to the reported date of the
positive test for Babesia and retrieve the identified in-date cellular
blood components. This recommendation does not apply to previously
distributed cellular blood components that were pathogen reduced
using an FDA-approved device according to its instructions for use.
5. If you previously collected acellular blood components (i.e., frozen plasma
products) intended for transfusion or for further manufacturing from a donor
that tests reactive for Babesia by a licensed donor NAT or from a donor who
later reports a history of a positive test result for Babesia and should have
been deferred according to the recommendations in section V.A.4.b,
quarantine any in-date acellular blood components held at your establishment
collected from the donor in the 12 months prior to the date of the reactive
index donation or reported date of a positive test for Babesia.
Note: Based on the very low risk of TTB associated with frozen acellular blood
components, we are not recommending notification of consignees or product
retrieval if you distributed such products.
C.

Product Disposition and Labeling
1. We recommend that you destroy or relabel blood and blood components that
were collected from a donor who should have been deferred based on their
responses to the DHQ according to the recommendations in section V.A.4. of
this document. If you relabel the blood and blood components, they may be
released for research if labeled appropriately as described below.
You must label the unit as required under 21 CFR 606.121. You must use the
following statements to prominently relabel the blood and blood components
(21 CFR 606.121(c)):
a. “NOT FOR TRANSFUSION: Collected from a Donor with a History
of a Positive Test Result for Babesia”
AND
b. “Caution: For Laboratory Research Only”

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2.

We recommend that you destroy or relabel blood and blood components
that test reactive for Babesia by a licensed donor NAT. If you relabel the
blood and blood components, they may be released for research or for
further manufacture into non-injectable products or in vitro diagnostic
reagents when no other suitable sources are available, when written
approval by FDA is obtained and if labeled appropriately as described
below. (see 21 CFR 610.40(h)(2)(ii))
You must label the reactive unit as required under 21 CFR 606.121 and
with the “BIOHAZARD” legend (21 CFR 610.40(h)(2)(ii)(B)). You must
use the following statements to prominently relabel the blood components
(21 CFR 606.121(c)):
a. “NOT FOR TRANSFUSION: Collected from a Donor Determined to
be Reactive for Babesia”
AND
b. “Caution: For Laboratory Research Only”
OR
“Caution: For Further Manufacturing into In Vitro Diagnostic Reagents
for Which There Are No Alternative Sources”
OR
“Caution: For Further Manufacturing Use as a Component of a Medical
Device for Which There Are No Alternative Sources”

D.

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.
1. When testing is performed, you must update your circular of information (21
CFR 606.122(h)). We recommend the following statement:
“A licensed NAT for Babesia has been performed and found to be nonreactive.”
2. If a blood system distributes components from both tested and untested
donations, we recommend the following statement:
“A licensed NAT for Babesia has been performed and found to be nonreactive for
blood collected in states where testing is required by FDA.”

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VI.

IMPLEMENTATION AND REPORTING CHANGES UNDER 21 CFR 601.12

You may implement the recommendations as soon as feasible. FDA intends to begin requiring
compliance with the underlying regulatory requirements regarding relevant transfusiontransmitted infection screening, testing, and product management 12 months after the guidance
issuance date. Licensed blood establishments must report changes under 21 CFR 601.12, as
follows:
A.

Donor History Questionnaire

Licensed blood establishments that modify the donor history questionnaire (DHQ) must
report the change under 21 CFR 601.12 as follows:
1. If you implement testing of each donation for Babesia or pathogen reduction
consistent with the recommendations in section V.A.3. of this document, you
may remove the current question regarding a history of babesiosis from your
DHQ. Report this change in your next annual report, noting the date the
change was made (21 CFR 601.12(d)).
2. If you do not implement testing for Babesia or pathogen reduction, you should
revise your current DHQ consistent with the recommendations in section
V.A.4. of this document. Revising the existing question on babesiosis or
using a revised DHQ found acceptable to FDA is considered a minor change
and must be reported in your next annual report, noting the date that the
change was made (21 CFR 601.12(d)).
3. You must submit a Prior Approval Supplement if you wish to revise your
DHQ other than as recommended in section V.A.4. of this document, as this
constitutes a major change (21 CFR 601.12(b)(1)).
B.

Testing

Licensed blood establishments that implement testing for Babesia must report the change
under 21 CFR 601.12 as follows:
1. If you implement testing consistent with the recommendations in section
V.A.3. of this document, submit the change in an annual report under 21 CFR
601.12 (d), 5 noting the date that the testing was implemented.
2. You must submit a Prior Approval Supplement if you wish to implement a
testing strategy other than as recommended in section V.A.3. of this document
(21 CFR 601.12(b)(1)).
5

See 21 CFR 601.12 (a)(3).

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Contains Nonbinding Recommendations

Note: If you wish to implement a testing strategy that is more restrictive (e.g.,
testing in other states in addition to those required or nationwide testing) than
recommended in this document, you may submit the change as an annual report
under 21 CFR 601.12.
C.

Circular of Information

Licensed blood establishments that update their circular of information to include a test
statement recommended in this document must report this change under 21 CFR 601.12.
You may include this change in your supplement reporting implementation of testing or
you may include it in your next annual report.

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Contains Nonbinding Recommendations
VII.

REFERENCES

1. Jacoby, G.A., et al., Treatment of transfusion-transmitted babesiosis by exchange
transfusion. N Engl J Med, 1980. 303(19):1098-1100.
2. Herwaldt, B.L., et al., Transfusion-associated babesiosis in the United States: a description
of cases. Ann Intern Med, 2011. 155(8):509-519.
3. Brennan, M.B., et al., Transmission of Babesia microti Parasites by Solid Organ
Transplantation. Emerg Infect Dis, 2016. 22(11):1869-1876.
4. Western, K.A., et al., Babesiosis in a Massachusetts resident. N Engl J Med, 1970.
283(16):854-856.
5. Vannier, E. and P.J. Krause, Human babesiosis. N Engl J Med, 2012. 366(25): 2397-2407.
6. Persing, D.H., et al., Infection with a babesia-like organism in northern California. N Engl J
Med, 1995. 332(5):298-303.
7. Conrad, P.A., et al., Description of Babesia duncani n.sp. (Apicomplexa: Babesiidae) from
humans and its differentiation from other piroplasms. Int J Parasitol, 2006. 36(7):779-789.
8. Herwaldt, B.L., et al., Babesia divergens-like infection, Washington State. Emerg Infect Dis,
2004. 10(4):622-629.
9. Krause, P.J., et al., Increasing health burden of human babesiosis in endemic sites. Am J
Trop Med Hyg, 2003. 68(4):431-436.
10. Moritz, E.D., et al., Screening for Babesia microti in the U.S. Blood Supply. N Engl J Med,
2016. 375(23):2236-2245.
11. Krause, P.J., et al., Persistent parasitemia after acute babesiosis. N Engl J Med, 1998.
339(3):160-165.
12. MMWR Summary of Notifiable Diseases—United States, 2011. Centers for Disease Control
and Prevention, 60 (53):1-117. July 5, 2013.
13. MMWR Summary of Notifiable Diseases—United States, 2012. Centers for Disease Control
and Prevention, 61(53):1-121. September 19, 2014.
14. MMWR Summary of Notifiable Infectious Diseases and Conditions—United States, 2013.
Centers for Disease Control and Prevention, 62(53). October 23, 2015.
15. MMWR Summary of Notifiable Infectious Diseases and Conditions—United States, 2014.
Centers for Disease Control and Prevention, 63(54);1-23. October 14, 2016.
16. MMWR Notifiable Diseases and Mortality Tables. Centers for Disease Control and
Prevention, 66 (52). January 5, 2018.
17. MMWR Summary of Notifiable Infectious Diseases and Conditions—United States, 2015.
Centers for Disease Control and Prevention, 64(53);1-143. August 11, 2017.
18. Reubush, T.K., et al., Human babesiosis on Nantucket Island. Evidence for Self-Limited and
Subclinical Infections. N Engl J Med, 1977. 297(15):825-827.
19. White, D.J., et al., Human babesiosis in New York State: Review of 139 hospitalized cases
and analysis of prognostic factors. Arch Intern Med, 1998. 158(19):2149-2154.
20. Hatcher, J.C., et al., Severe babesiosis in Long Island: Review of 34 cases and their
complications. Clin Infect Dis, 2001. 32(8):1117-1125.
21. Levin, A.E., et. al., Transfusion-transmitted babesios: Is it time to screen the blood supply?
Curr Opin Hematol. 2016 November; 23(6):573-580.
22. Linden, J.V., et al., Transfusion-transmitted and community-acquired babesiosis in New
York, 2004 to 2015. Transfusion, 2018. 660-668.
23. Burgess, M.J., et al., Possible Transfusion-Transmitted Babesia divergens-like/MO-1
Infection in an Arkansas Patient. Clin Infect Dis, 2017. 64(11):1622-1625.
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Contains Nonbinding Recommendations
24. Tonnetti, L., et al., Transfusion-transmitted Babesia microti identified through
hemovigilance. Transfusion, 2009. 49(12):2557-2563.
25. Blood Products Advisory Committee Meeting. FDA. May 13, 2015. http://wayback.archiveit.org/7993/20170722221132/https://www.fda.gov/AdvisoryCommittees/CommitteesMeeting
Materials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm441228.
htm.
26. Menis, M., et al., Babesiosis Occurrence among the Elderly in the United States, as
Recorded in Large Medicare Databases during 2006-2013. PLoS One, 2015.
10(10):e0140332.
27. Biological Product Deviation Reports Annual Summaries. FDA.
https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/Biological
ProductDeviations/ucm129757.htm.
28. Approaches to Reduce Risk of Transfusion-Transmitted Babesiosis in the United States,
Public Workshop. (July 11, 2008, 73 FR 39972).
29. Gubernot, D.M., et al., Transfusion-transmitted babesiosis in the United States: Summary of
a workshop. Transfusion, 2009. 49(12):2759-2771.
30. Blood Products Advisory Committee Meeting. FDA. July 26, 2010. https://wayback.archiveit.org/7993/20170111180050/http://www.fda.gov/AdvisoryCommittees/CommitteesMeeting
Materials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm205013.
htm.
31. Kumar, S., Risk of Babesia Infection by Blood Transfusion and Potential Strategies for
Donor Testing: Introduction. BPAC meeting July 26, 2010.
32. Herwaldt, B., Epidemiology of Babesiosis, including Transfusion-Associated Infection
BPAC: Risk of Babesia Infection by Blood Transfusion and Potential Strategies for Donor
Testing. July 26, 2010.
33. Leiby, D., Experience with Testing Blood Donors for Babesia. BPAC: Risk of Babesia
Infection by Blood Transfusion and Potential Strategies for Donor Testing. July 26, 2010.
34. Walderhaug, M., et al., Transfusion Transmitted Babesiosis Risk Assessment. BPAC: Risk
of Babesia Infection by Blood Transfusion and Potential Strategies for Donor Testing. July
26, 2010.
35. Stramer, S., Investigational Blood Donor Screening for Babesia microti: Implications For
Blood Safety. BPAC: Strategies for Implementation of Serological and Nucleic Acid Testing
for Babesia microti in Blood Donors. May 13, 2015.
36. Levin, A.E., Screening with an investigational enzyme immunoassay for Babesia microti
evaluated in an IND study on U.S. blood donor populations. BPAC: Strategies for
Implementation of Serological and Nucleic Acid Testing for Babesia microti in Blood
Donors. May 13, 2015.

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