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1、Risk of Babesia Infection by Blood Transfusion and Potential Strategies for Donor Testing: IntroductionSanjai Kumar, PhDDivision of Emerging and Transfusion-Transmitted DiseasesOffice of Blood Research and ReviewCBER, FDABlood Products Advisory Committee MeetingJuly 26, 20101；.Issue for BPACBased on

2、 a risk analysis, do the available data support development of a regionally selective donor testing strategy to reduce the risk of transfusion-transmitted babesiosis. Please comment on the suitability of donor screening either by a nucleic acid-based test, an antibody test, or both, given the curren

3、t technology limitations.2；.Background I Babesiosis, a tick-borne zoonosis, is caused by infection with intraerythrocytic protozoans of genus Babesia that belong to phylum Apicomplexea. The most prevalent species in U.S. is Babesia microti. The other reported species are B. duncani (formerly called

4、WA1-type Babesia) and related organisms (CA1-type Babesia) and “B. divergens-like” agents such as MO1. 3；.Life Cycle of Babesia microtiWhite-tailed deer(Host to ticks)White-footed mouse(Reservoir host)4；.Background IIEndemic transmission is reported mostly in Northeastern, Mid-Atlantic and Upper Mid

5、western states including Connecticut, Rhode Island, New York, Massachusetts, New York, New Jersey, New York, Wisconsin and Minnesota Several other states without recognized prevalence areas also reported babesiosis cases due to infections acquired during travel to endemic areas5；.Clinical illness ra

6、nges from asymptomatic to mild to life-threatening severe disease. Neonates, immuno-compromised and asplenic persons and elderly are at the highest risk of severe disease. Highest number of clinical cases and transfusion-transmitted cases of babesiosis are reported in the U.S. Currently, babesiosis

7、is not a reportable disease in all states, and is not a nationally notifiable disease.Background III6；.Geographical distribution of babesiosis beneficiary claims in different states in 2008(n =1543; CMS dataset)428211207128908080504037211615131212 100 100 50 49 25 24 124 States4 States 2 States6 Sta

8、tes7；.Transfusion-Transmitted Babesiosis (TTB) in the U.S. - ITTB first reported in 1979Since then, more than 100 cases and 11 deaths reportedThe majority TTB cases caused by B. microtiA few non-B. microti cases of TTB8；.Transfusion-Transmitted Babesiosis (TTB) in the U.S. - II TTB a particular conc

9、ern in neonates- In 2007, three infections in neonates at a Rhode Island hospital from a single donor - In 2009, three infections at a Virginia hospital from a single donorWhile under-reported, B. microti is one of the most frequently reported transfusion-transmitted infectious agents.9；.FDA Fatalit

10、y Reports Suggest Increased Risk of TTB Since 2005Fiscal YearNo. of ReportsFY981FY99- FY050FY06- FY089FY10110；.Babesia Transmission is Regional while TTB Risk is SystemicMost TTB is acquired in the same region where blood is collected and used, howeverTTB has occurred in non-prevalence areas from do

11、nors who had traveled to a recognized endemic area Among 9 fatalities, 4 implicated donors and 5 recipients did not live in an endemic area 17 ab-positive implicated donors, 11 were from endemic areas while 4 were from non-endemic areas Donors who normally reside in endemic areas may donate elsewher

12、eBlood products are often shipped between widely separated regions across the U.S.11；.Transfusion-transmitted babesiosis cases in the U.S. between 2004-2008 (n =63; CDC data based on state of donation)11111111124461513442 States1 State14 States 10 10 52 years. The minimal infectious dose in TTB is n

13、ot known, nor is the level of parasite burden in asymptomatic carriers.There is no recommendation to treat persons with asymptomatic Babesia infections. Both clinical cases and TTB cases are underreported.23；.Current Test Technologies and their Limitations for Screening Donors for Babesia Infections

14、 - I Microscopy (Wright or Giemsa stains of thick and thin blood films) lacks the sensitivity to detect low-grade parasitemias Inoculation of blood samples in sensitive animal models (hamster or mouse for B. microti; gerbils for B. divergens) is impractical24；.Current Test Technologies and their Lim

15、itations for Screening Donors for Babesia Infections - II A laboratory-developed nucleic acid test (NAT) and antibody tests have been used to diagnose Babesia infections. Both NAT and antibody-based tests have limitations for use in donor screening. Lack of sufficient genomic/proteomic cross-reactiv

16、ity between B. microti and non-B. microti species25；.NAT as Donor Screening Test for Babesia - I Several versions of laboratory-developed PCR tests are available. Sensitivity of PCR has been demonstrated as equal to or superior to blood-film microscopy Parasitemia may be very low during the early ph

17、ase of acute infection (window period) and in asymptomatic infections (chronic phase)26；.NAT as Donor Screening Test for Babesia - II As a result, a few infected red cells may be potentially present in a unit of donated blood. Thus, to be effective, a NAT-based test must be highly sensitive. The lim

18、it of detection of NAT for Plasmodium falciparum (another intraerythrocytic parasite) is 20 parasites per ml of blood.27；.NAT as Donor Screening Test for Babesia - IIITechnologies such as use of large volume of blood sample for DNA/RNA preparation, or concentration of infected red cells before testi

19、ng would improve the assay sensitivity In addition, use of multiple copy gene(s) as target for NAT may also improve the assay sensitivity28；.Detection of Anti-babesial Antibodies as Evidence of Exposure - I IFA, ELISA and Western blot have been used for diagnosis and epidemiological studies. IFA is

20、highly sensitive for acute babesiosis cases. However, IFA is not adapted for high through-put donor screening. Similarly, the available Western blot is not suitable for high through-put donor screening. 29；.Detection of Anti-babesial Antibodies as Evidence Exposure - II Parasite-antigen lysate, reco

21、mbinant protein and peptide-based ELISA tests have been used. ELISA tests developed and used so far have had poor specificity.30；.Detection of Anti-babesial Antibodies as Evidence of Exposure - III Anti-Babesia antibody positivity in the U.S. ranged between 0.3% to 17.8% suggesting either low assay

22、specificities or very high rates of asymptomatic infections. IgG titers may persist for months or years and cannot distinguish current from past infections. Antibody testing would then cause deferral of recovered donors who would not transmit babesiosis.31；.Detection of Anti-babesial Antibodies as E

23、vidence of Exposure - IV Novel antibody-based tests for Babesia are needed To be effective for donor screening, these tests should be - Highly sensitive (able to detect early window period cases and asymptomatic chronic infections) and specific (low false-positive reactions) - Adapted for high throu

24、gh-put donor screening platform32；.FDAs Strategy to Mitigate TTB Risk Identification of Babesia risk in individual states based on clinical cases of babesiosis, TTB cases, and based on FDA risk assessment model Evaluation of the current laboratory methods for their value as donor screening testsA tw

25、o-phase strategy to donor testing for BabesiaNeed for highly sensitive and specific nucleic acid and antibody based tests to screen donors for Babesia 33；.BPAC AgendaEpidemiology of Babesiosis, Including Transfusion-Associated Infection, Barbara Herwaldt, M.D., CDC Experience With Testing Blood Donors for Babesia, David Leiby, Ph.D., Americ