GFI Babesiosis

Recommendations for Reducing the Risk
of Transfusion-Transmitted Babesiosis
Draft Guidance for Industry
This guidance document is for comment purposes only.

Submit one set of either electronic or written comments on this draft guidance by the date
provided in the Federal Register notice announcing the availability of the draft guidance.
Submit electronic comments to https://www.regulations.gov. Submit written comments to the
Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852. You should identify all comments with the docket number listed in
the notice of availability that publishes in the Federal Register.
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 [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
July 2018

Contains Nonbinding Recommendations
Draft—Not for Implementation

Table of Contents
I.

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

II.

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

III.

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

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

IV.

MITIGATING THE RISK OF TRANSFUSION-TRANSMITTED BABESIOSIS .. 5

V.

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

VI.

IMPLEMENTATION AND REPORTING ................................................................. 10
A.
B.
C.

VII.

Donation Testing, Donor History Questionnaire, Donor Deferral and
Requalification ...................................................................................................... 6
Product Management ........................................................................................... 8
Donor History Questionnaire............................................................................. 10
Testing .................................................................................................................. 11
Circular of Information ...................................................................................... 11

TESTING PRIOR TO PUBLICATION OF THE FINAL GUIDANCE ................... 11

VIII. REFERENCES ................................................................................................................ 13
APPENDIX .................................................................................................................................. 16

i

Contains Nonbinding Recommendations
Draft—Not for Implementation

Recommendations for Reducing the Risk of TransfusionTransmitted Babesiosis
Draft Guidance for Industry
This draft guidance, when finalized, will represent 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 and we are providing you
with FDA’s assessment. 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
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
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
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 transmission of babesiosis.

1

Contains Nonbinding Recommendations
Draft—Not for Implementation
babesiosis in the U.S. was identified in 1968 (Ref. 4). The majority of U.S. babesiosis cases are
caused by B. microti, the species that is prevalent in the Northeast and upper Midwest (Ref. 5).
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.
The vast majority of B. microti infections are asymptomatic and never diagnosed (Ref. 9). While
the precise duration of B. microti infections in healthy adults is not clearly 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). Although Babesia transmission is seasonal and
coincides with tick activity (traditionally May-September), both tick-borne (Refs. 12-17) and
transfusion-transmitted infections are reported year-round (Refs. 5, 10). There are insufficient
data regarding the proportion of Babesia infections that persist as asymptomatic, chronic
infections. In one study on Block Island, Rhode Island one third of Babesia infections were
asymptomatic (Ref. 9), although the sample size was too small to draw firm conclusions.
Transfusion of blood and blood components collected from asymptomatic 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(1) 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(1)) 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.

2

Contains Nonbinding Recommendations
Draft—Not for Implementation
In this regard, FDA examined:
Severity of Disease
Clinical symptoms of babesiosis, caused by B. microti, range from asymptomatic to mild
to severe, and can result in death 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). 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). Common
symptoms include malaise, fatigue, fever, chills, headache, myalgia, anorexia, arthralgia
and nausea (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 tickborne 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
There is demonstrated evidence that babesiosis is transmitted by transfusion of blood and
blood components (Refs. 1, 2). The first U.S. case of TTB was reported in 1980 (Ref. 1).
Since then, more than 200 cases of transfusion-associated infections have been
documented (Refs. 2, 22); about 25% of all cases were recorded during the period of
2010-2016. While B. microti remains the major causative agent of TTB, three cases of
transfusion-transmitted infections attributed to B. duncani (Ref. 2) and one possible case
caused by a B. divergens-like parasite were reported in the U.S. (Ref. 23).
Therefore, 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).

3

Contains Nonbinding Recommendations
Draft—Not for Implementation
A relevant transfusion-transmitted infection means:
A transfusion-transmitted infection not listed in 21 CFR 630.3(h)(1) when the
following conditions are met:
(i) 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
(ii) The disease or disease agent: (A) May have significant incidence and/or
prevalence to affect the potential donor population; or (B) May have been
released accidentally or intentionally in a manner that could place potential
donors at risk of infection.
Availability of Appropriate Screening Measures or Screening Tests
Donor History Questionnaire: Currently, prospective donors are asked if they have ever
had babesiosis as part of the medical history interview. We do not find it necessary to
continue to ask about a history of babesiosis when donations will be tested. Health
history questions generally cannot prevent TTB because the donors implicated in these
cases are typically unaware of their infection status and hence do not report a history of
babesiosis (Ref. 24). As states begin testing for B. microti per our recommendations in
this guidance, we expect that some asymptomatic blood donors will learn about their
infection status when they are deferred, but the possibility exists that they might still
present to donate blood in another state that does not perform testing. To address this
concern, we have added a recommendation to assess donor history for a positive test
result for babesiosis when donations will not be tested for B. microti.
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. These
assays are intended to be used as donor screening tests on Whole Blood (NAT assay) or
in plasma (AFIA test) samples from individual human donors, including volunteer donors
of Whole Blood and blood components as well as living organ and tissue donors. Further
discussion of the value of NAT and antibody-based tests for screening blood donors for
B. microti is provided in the Appendix of this document.
Significant Incidence and Prevalence
In 2011, national surveillance for babesiosis began in 25 jurisdictions in 24 states and
New York City (Refs. 12-17). Between 2011 and 2017, an average of 1628 (range 9372100) babesiosis cases per year was observed in 26 states which excluded several
Babesia-risk states because disease reporting was not required in those states (Refs. 1217). According to data from the Centers for Medicare and Medicaid Services, babesiosis
cases were reported among elderly Medicare beneficiaries in all states and Washington,
4

Contains Nonbinding Recommendations
Draft—Not for Implementation
D.C., except for Wyoming (Refs. 25, 26). About 99% of the clinical babesiosis 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, 26).
As stated in section III.A. of this document, the first U.S. case of TTB was reported in
1980 (Ref. 1). Since then more than 200 cases of transfusion-associated infections have
been documented by the Centers for Disease Control and Prevention (CDC) and FDA
(Refs. 2, 27). According to the CDC, between 1979-2009, 19 states reported TTB cases
with 87% occurring in the seven highest B. microti endemic states (Ref. 2). TTB risk
outside of the endemic states is mostly attributed to travel to endemic areas and
movement of blood components from endemic states to non-endemic states. About 95%
of TTB cases are reported from Connecticut, Massachusetts, Rhode Island, New York,
New Jersey, Minnesota, Wisconsin, New Hampshire, Maine, Maryland, Virginia,
Vermont, Pennsylvania, Delaware, and Washington, D.C. (Ref. 25).
Therefore, 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.

MITIGATING THE RISK OF TRANSFUSION-TRANSMITTED BABESIOSIS

FDA has 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 complete
transcript of the meeting and the presentations delivered at this BPAC meeting are available on
the FDA website (Refs. 30-34).

5

Contains Nonbinding Recommendations
Draft—Not for Implementation
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 versus
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 Babesiarisk by an antibody-based test. The Committee also unanimously recommended 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 (Connecticut, Maine,
Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Rhode Island, and
Wisconsin). The Committee also recommended including the bordering state of Pennsylvania in
the year-round NAT-based testing program. Since the meeting, Pennsylvania has been identified
as a B. microti endemic state. Additionally, the Committee supported a deferral period of at least
2 years for donors with reactive test results, after which time, donor eligibility may be assessed
based on testing by both antibody and NAT-based testing.
FDA has considered the BPAC discussion and determined that limiting donation testing to states
with Babesia risk, but requiring both NAT and antibody testing year-round in those states, is a
preferred strategy that balances risk reduction with the scope of testing (see the Appendix of this
document for discussion and scientific rationale for this strategy).
V.

RECOMMENDATIONS
A.

Donation Testing, Donor History Questionnaire, Donor Deferral and
Requalification
1. We recommend that you update your donor history questionnaire, including fulllength 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. You must test each donation for evidence of B. microti infection using a licensed
NAT and licensed antibody test 3 when collected in Connecticut, Delaware,
Maine, Maryland, Minnesota, Massachusetts, New Hampshire, New Jersey, New

3

When this guidance is finalized, blood establishments must use licensed donor screening tests for B. microti (21
CFR 610.40(b)). Blood establishments that are participating in a clinical trial and testing for B. microti using an
unlicensed test may continue in the clinical trial but must also begin to test for B. microti using FDA licensed tests
(21 CFR 610.40(b)).

6

Contains Nonbinding Recommendations
Draft—Not for Implementation
York, Pennsylvania, Rhode Island, Vermont, Virginia, Wisconsin and
Washington, D.C. Testing must be performed year-round (21 CFR
610.40(a)(3)(ii)(A) and 610.40(b)).
a. You must defer donors with a reactive screening test (NAT or antibody
test) for B. microti (21 CFR 610.41(a)) for at least 2 years (21 CFR
630.35(a)). You must make reasonable attempts to notify any donor
whose blood tests reactive for B. microti 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 is performed, you may discontinue asking donors about a
history of babesiosis. 4
c. 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 and they meet all other donor eligibility criteria (21 CFR
630.35(b)). The donation must be tested for B. microti by both a licensed
NAT and a licensed antibody test (21 CFR 610.40(a)(3) and 610.40(b)).
3. In states that do not test donations for B. microti, we recommend the
following:
a. Update your donor history questionnaire to assess prospective donors for a
positive test result for Babesia, obtained from either a medical diagnosis,
or a reactive donor screening test result.
b. You must indefinitely defer donors who report a history of a positive test
result for Babesia (21 CFR 630.10(h)).
c. A deferred donor 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.

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 high-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 high-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 even more individuals may travel to the at-risk states.

7

Contains Nonbinding Recommendations
Draft—Not for Implementation
ii. The donation must be tested for B. microti by both a licensed NAT and
a licensed antibody test (21 CFR 610.40(a)(3)(ii)(A).
The donor’s eligibility should be assessed at each subsequent donation by
the donor history questionnaire (see section V.A.3.a. of this document).
The donor’s history of Babesia should be assessed for the time period after
the date of the donor’s last negative test result for B. microti.
B.

Product Management
1. You may release donations that are nonreactive for B. microti by both a licensed
nucleic acid test and antibody test provided all other donation suitability
requirements are met (21 CFR 630.30).
2. If a donation tests reactive for B. microti by a licensed nucleic acid test or
antibody test, you must not ship or use the donation, unless an exception for
shipment or use is applicable (21 CFR 610.40(h) and 21 CFR 630.30(b)(1)).
3. Within 3 calendar days after a donation tests reactive for B. microti by a licensed
NAT or antibody test, you should:
a. Identify and quarantine all in-date blood and blood components held at your
establishment from the donor that were not tested for B. microti and were
collected from that donor in the 2 years prior to the donation that was reactive
for B. microti; and
b. Notify consignees and retrieve and quarantine all distributed in-date blood and
blood components collected in the 2 years prior to the donation that was
reactive for B. microti; and
c. If previously distributed blood components collected in the 2 years prior to the
donation that was reactive for B. microti were transfused, encourage
consignees to have a discussion with the recipient’s physician of record about
possible TTB.
When there is information indicating risk of Babesia infection from blood
components collected from a donor who was found to have a reactive NAT or
antibody test for B. microti, in addition to the recommendations provided in
section V.B.3.a. of this document, we recommend that the responsible physician
determine any additional actions that should be taken on previously distributed
products and the extent of additional consignee notification and recipient
notification.

8

Contains Nonbinding Recommendations
Draft—Not for Implementation
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 according to the
recommendations in section V.A.3. 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
Babesiosis”
and
b. “Caution: For Laboratory Research Only”
2. We recommend that you destroy or relabel blood and blood components that test
reactive for B. microti. 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, if
labeled appropriately as described below.
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 microti”
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

9

Contains Nonbinding Recommendations
Draft—Not for Implementation
“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. When testing is
performed, you must update your circular of information to state that licensed tests for
nucleic acid and antibodies to B. microti were used to screen donors and that the results
of testing were nonreactive (21 CFR 606.122(h)). We recommend the following
statement:
“Blood donations found to be nonreactive by a licensed nucleic acid test and a
licensed antibody test for Babesia microti”
VI.

IMPLEMENTATION AND REPORTING

We propose that once the guidance is finalized, licensed blood establishments report
implementation of the recommendations:
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 B. microti consistent with the
recommendations in section V.A.2. 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 B. microti, you should update your current
DHQ consistent with the recommendations in section V.A.3. of this document.
Adding an additional question to your DHQ 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 update your DHQ
other than as recommended in section V.A.3. of this document. (21 CFR
601.12(b)(1)).

10

Contains Nonbinding Recommendations
Draft—Not for Implementation
B.

Testing

Licensed blood establishments that implement testing for B. microti must report the
change under 21 CFR 601.12 as follows:
Submit a supplement to your biologics license application adding testing for B. microti.
Include the name, address and FDA registration number of the product testing laboratory
and the effective date on which testing will be initiated in your supplement.
1. If testing will be performed by a laboratory that is FDA-registered and approved
to perform donor/blood product testing, but does not currently perform testing for
your blood establishment, submit the supplement as a Supplement-Changes Being
Effected (21 CFR 601.12(c)(5)).
2. If the laboratory is not registered with the FDA, submit the supplement as a Prior
Approval Supplement (21 CFR 601.12(b)). The testing laboratory must register
(21 CFR 607.20(a)) and be inspected by FDA prior to performing testing on blood
donation samples.
3. If testing will be performed by either your own FDA-registered laboratory or your
current contract outside testing laboratory approved for use by the FDA, submit
this change in your next annual report (21 CFR 601.12(d)).
C.

Circular of Information

Licensed blood establishments that implement testing for B. microti must update their
circular of information to include the test statement recommended in this document in
accordance with 21 CFR 606.122(h). You may include this change in your supplement
reporting implementation of testing or you may include it in your next annual report
under 21 CFR 601.12(d).
Note: Unlicensed blood establishments are not required to report implementation of the
recommendations in this document to FDA.
VII.

TESTING PRIOR TO PUBLICATION OF THE FINAL GUIDANCE

We understand that some blood establishments may wish to implement testing for B. microti
prior to publication of the final guidance. Such establishments must use the test consistent with
the test kit’s manufacturer’s instructions (21 CFR 606.65(e)). In addition, licensed blood

11

Contains Nonbinding Recommendations
Draft—Not for Implementation
establishments must report the change to FDA under 21 CFR 601.12. 5 Blood establishments that
also wish to revise their DHQ to remove the question regarding a history of Babesia must submit
a prior approval supplement prior to implementation (21 CFR 601.12(b)(1)).

5

See “Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended
for Transfusion or for Further Manufacture; Guidance for Industry” dated December 2014.

12

Contains Nonbinding Recommendations
Draft—Not for Implementation
VIII. 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.

13

Contains Nonbinding Recommendations
Draft—Not for Implementation
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.
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.
37. Ruebush, T.K., 2nd, et al., Development and persistence of antibody in persons infected with
Babesia microti. Am J Trop Med Hyg, 1981. 30(1):291-292.
38. Leiby, D.A., et al., A longitudinal study of Babesia microti infection in seropositive blood
donors. Transfusion, 2014. 54(9):2217-2225.

14

Contains Nonbinding Recommendations
Draft—Not for Implementation
39. Moritz, E.D., et al., Description of 15 DNA-positive and antibody-negative "window-period"
blood donations identified during prospective screening for Babesia microti. Transfusion,
2017. 57:1781-1786.
40. Johnson, S.T., et al., Seroprevalence of Babesia microti in blood donors from Babesiaendemic areas of the northeastern United States: 2000 through 2007. Transfusion, 2009.
49(12): 2574-2582.
41. Leiby, D.A., et al., Demonstrable parasitemia among Connecticut blood donors with
antibodies to Babesia microti. Transfusion, 2005. 45(11):1804-1810.
42. Levin, A.E., et al., Determination of Babesia microti seroprevalence in blood donor
populations using an investigational enzyme immunoassay. Transfusion, 2014. 54(9):22372244.

15

Contains Nonbinding Recommendations
Draft—Not for Implementation
APPENDIX
SCIENTIFIC RATIONALE AND FURTHER EXPLANATION FOR THE
RECOMMENDATIONS AND ADDITIONAL CONSIDERATIONS

Detection and Persistence of Antibodies to B. microti
Antibodies are a reliable marker of exposure to B. microti. Detectable antibodies emerge during
acute infections, persist in chronic infections. and indicate potential presence of parasites in the
host. However, antibodies to B. microti also may persist for an extended period after resolution
of parasitemia. The question of how long antibodies persist after B. microti infection is poorly
understood. While the B. microti-specific antibodies may persist for several years, in limited
studies, clearance of parasitemia is often associated with decline in antibody titers. Ruebush et
al., determined the development and persistence of B. microti antibodies in 16 patients who
developed IFA titers of 1:1024 or 1:4096 between the first 3 to 4 weeks after onset of clinical
symptoms. The antibody titers began to decline in the next 2 to 3 months and ranged between
1:16 to 1:256 at 5-7 months after onset of illness and were maintained at that level for up to 13
months (Ref. 37). In another prospective study, B. microti-infected individuals were followed
for up to 27 months to detect the episodes of illness and evidence of parasitemia and seroconversion. In 12 patients who were monitored for babesial DNA and persistence of antibody,
the circulating DNA lasted for 3 months or more after the initial diagnosis which also paralleled
the rise and decline of antibody titers. At 12 months after the initial diagnoses, antibody levels
either returned to baseline or dropped from a peak reciprocal titer of 1:1400 to 1:200 (Ref. 11).
In another longitudinal study, investigators assessed the course of B. microti infection in seropositive donors; 6 donors had become sero-negative within 6-9 months of being parasitemic. On
the other hand, 3 donors remained sero-positive over three years of follow up, despite having
received anti-babesial treatment (Ref. 38). Lastly, in a comprehensive long-term follow up
study, 62.1% (139/224) of all donor samples were negative for anti-B. microti antibody at 20
months and 94.6% (212/224) of all donor samples were antibody negative by 40 months after
index samples were tested (Ref. 39). These results suggest that, while the antibody response to
B. microti may persist for several years in a subset of individuals, generally there is a sharp
decline in antibody titers after the initial infection. The prolonged antibody levels in some B.
microti exposed individuals may be due to protracted asymptomatic infections, reinfections or
recrudescence.
Nucleic Acid-based Assays for Detection of B. microti
Whereas antibodies are a reliable marker of exposure to B. microti, the presence of nucleic acid
indicates an active infection. However, due to the intraerythrocytic nature of Babesia parasites
and the sensitivity limitations of nucleic acid tests (NAT), it is difficult to ascertain the ability to
transmit B. microti infections by sero-positive, but PCR-negative blood units. Studies in
Babesia-endemic areas have shown the presence of antibody positive donors year round (Refs.
10, 40); in a longitudinal study of 83 sero-positive blood donors, 21% had evidence of
parasitemia as determined by a PCR test, microscopy or hamster inoculation (Ref. 38). In a
smaller study, of B. microti antibody positive blood donors from Connecticut, 10 of 19 (53%)

16

Contains Nonbinding Recommendations
Draft—Not for Implementation
seropositive donors were also PCR positive (Ref. 41). NAT has been effective in detecting early
infections (window period: WP) when antibody levels are below detection limit. In one study of
prospective blood donors using the investigational NAT and antibody assays, 15 of 220,479
donations (about 1 in 15,000 donations) were NAT positive but antibody negative (Ref. 39) in
index sample testing. Twelve of 13 WP donors seroconverted in follow up testing while one
donor failed to seroconvert.
The scientific rationale and further explanation for the recommendations in section V. of this
document are as follows:
•

Due to the intra-erythrocytic nature of Babesia parasites, and the likelihood of low-grade
parasitemia during the early phase of acute infection (window period), and low-grade,
asymptomatic infections in chronic carriers, a NAT alone may not be effective to detect
all infected donors (Ref. 5). On the other hand, antibody-based tests may be highly
effective in detecting acute and chronic low-grade infections. However, antibody-based
tests have limitations in detecting the early phase of infections prior to seroconversion
(i.e., window period), lack of seroconversion or low antibody response in some donors,
and inability to distinguish between active and previously resolved infections (Refs. 10,
38). Therefore, a combination of NAT and antibody-based tests was considered the most
suitable option to detect Babesia infection during all phases of infection cycle.

•

Although tick-borne B. microti transmission in endemic areas is seasonal and occurs
primarily during the months of May-September (Refs. 12-17, 26), both clinical and TTB
cases are reported in all months of the year (Refs. 10, 12-17). Likewise, results of
investigational testing (Refs. 10, 42) and epidemiological (Refs. 40, 41) studies in
endemic areas have reported the presence of sero-positive and parasitemic donors yearround. Therefore, year-round NAT and antibody testing has been recommended to detect
asymptomatic chronic infections outside the main transmission season in Babesia-risk
states.

•

Due to donor travel to and from endemic areas and interstate commerce of blood and
blood products, TTB risk is not limited to endemic areas only but extends nationwide
(Refs. 2, 26). For example, although a vast majority of clinical cases and TTB cases are
reported within the 7 highest endemic states (Refs. 2, 12-17), clinical babesiosis have
been reported in 49 states (Ref. 26) and TTB cases have been reported in 22 states (Refs.
2). Therefore, to minimize the TTB risk, FDA is recommending that donor testing
should not be limited only to endemic states, but should also be expanded to include the
high-risk states, particularly in those states that are adjoining to those states where
endemic B. microti transmission is reported.

•

The May 13, 2015 BPAC recommended that antibody testing should be year-round and
nationwide. The Committee also recommended that year-round NAT should be
implemented in 9 endemic states and Pennsylvania. However, FDA’s recommendation
that the B. microti testing should be implemented in the 14 high risk states and
Washington, D.C. is based on the following scientific rationale:

17

Contains Nonbinding Recommendations
Draft—Not for Implementation
About 99% of clinical babesiosis cases (Refs. 12-17, 26) and 95% of TTB cases
(Ref. 25) are reported from these 14 states - Connecticut, Massachusetts, Rhode
Island, New York, New Jersey, Minnesota, Wisconsin, New Hampshire, Maine,
Maryland, Virginia, Vermont, Pennsylvania, Delaware and Washington, D.C. Of
these, endemic B. microti transmission is reported in following 10 states Connecticut, Massachusetts, Rhode Island, New York, New Jersey, Minnesota,
Wisconsin, New Hampshire, Maine and Pennsylvania. The states of Maryland,
Virginia, Delaware, Vermont and Washington, D.C. are included because of the
combination of estimated high babesiosis risk and proximity to an endemic state.
About 26% of the U.S. population resides in these 14 states and Washington, D.C.
The FDA benefit-risk assessment model has indicated that NAT and antibody
testing in the 14 states and Washington, D.C. would lead to 84.9% TTB risk
reduction (Positive Predictive Value 43.9%) versus 96% risk reduction (Positive
Predictive Value 19.3%) by nationwide testing. As shown in Table 1 of this
document, although an incremental increase in TTB risk reduction is achieved
with nationwide testing, the positive predictive value (the probability that donors
with reactive testing results actually have babesiosis) decreases significantly
under this testing scenario. The model estimated that nationwide testing could
result in the discard of over 1,700 additional otherwise-suitable donations per year
(compared to the selective testing strategy), the deferral of the falsely positive
donors, and the loss of future donations from the deferred donors, all of which
pose a risk to the blood supply. Alternatively, under the benefit-risk assessment
model, the positive predictive value improves significantly when testing is
performed only in the highest risk states.
In summary, FDA is adopting a selective testing strategy for B. microti in the 14
highest risk states and Washington, D.C. after considering the benefits and risks
of the selective testing strategy under the model, as explained in the paragraph
above, and the fact that approximately 99% of the clinical babesiosis cases and
95% of the TTB cases are reported in these states. However, FDA will continue
to monitor the epidemiology of babesiosis, cases of TTB in the U.S., and other
scientific information as it becomes available. If, based upon the available
scientific information, the risk of transmission of babesiosis by blood and blood
components changes significantly, we may update these recommendations as
warranted.
•

We have followed the Committee recommendation for a two-year deferral for Babesiareactive blood donors in states that perform routine donation testing. Such donors may
present for donation after a two-year deferral period when testing by NAT and antibody
will be performed.

•

Donors of Source Plasma are exempt from Babesia questioning and testing for Babesia
microti. This recommendation is consistent with the regulation that donors of Source
Plasma are excluded from deferral due to malaria risk under 21 CFR 630.15(b)(8).
18

Contains Nonbinding Recommendations
Draft—Not for Implementation
Similar to Plasmodium parasites, Babesia parasites are also intra-erythrocytic in nature
and subjected to killing during the manufacturing process.
Definitions:
Babesiosis – An infectious disease caused by the intraerythrocytic parasitic protozoans of
the genus Babesia. For additional information regarding babesiosis and its associated
symptoms, visit the CDC website at https://www.cdc.gov/parasites/babesiosis/.
Babesia-endemic state – Any state where tick-borne transmission of babesiosis is reported
to take place, as determined by the CDC or in the published literature.
Babesia-risk state – Any Babesia endemic state, a state that is adjoining an endemic state,
or a state where a high number of clinical or transfusion-transmitted cases of babesiosis are
reported.

Table 1.

Summary of Benefits and Risks Under Nucleic Acid and Antibody Testing
Under the Nationwide and the 14 Testing Scenarios by the FDA Risk Model
(Ref. 25)

Testing Scenario

Percent TTB Risk
Reduction

No Donor Testing

0

14 States + DC
CT, MA, RI, NY, NJ, MD, NH, ME, DC,
VA, MN, VT, PA, DE, WI
50 States + DC

Positive Predictive
Value

84.9

96.0

19

Units From
Positive Donors
Interdicted

False Positive
Donor Test
Results