# Presentation: 224408

## Issues Related to Implementation of Blood Donor Screening for Infection with Trypanosoma cruzi 

- Presentation to BPAC
- April 26, 2007
- Robert Duncan, PhD

## Issues

- FDA seeks the advice of the Committee related to use of a licensed test for antibodies to *T. cruzi*:
- Donor management
- Product management
- Design of research studies
- Strategies for selective screening
- Investigation of cross-reactivity of the licensed test with other pathogens

## Questions for the Advisory Committee

- Please comment on any scientific issues that FDA should further consider in developing its recommendations on implementation of blood donor screening for antibodies to *T. cruzi.*
- What suggestions does the committee have on the design of research studies to validate a strategy for selective screening of repeat donors?
- Please comment on the need for and design of studies to determine whether repeatedly reactive test results for antibodies to *T. cruzi* should be further investigated for cross-reactivity to *Leishmania, Plasmodium, Paracoccidioides braziliensis *or other agents when the donor lacks risk factors for *T. cruzi *infection or a test sample is found negative by other, more specific tests.

## Background 

*Trypanosoma cruzi: *causative agent of Chagas disease

**Small protozoan parasite**
**Chronic, asymptomatic infection**
**Difficult or impossible to treat, severe symptoms late in about 30% of cases**
**Endemic to portions of Mexico, Central America, and South America, 16-20 million people infected **
**Transmission: feces of an infected triatomine insect, congenital, organ transplant, transfusion, oral (breast milk), via conjunctiva, laboratory accident**
**Blood transfusion transmission is a recognized problem in endemic areas.  An infected unit is estimated to have a 12-20% probability of causing infection in the recipient (**_**WHO TRS**_** 905, 2002)**

## Background: Risk and Epidemiology in the US

**7 cases of transfusion transmission**
**	**** ****documented in US/Canada**
**5 cases of solid organ transplant transmission**
**Rare natural transmission of *****T. cruzi***** in the US**
**Seroprevalence in US donor population ranges from 0.01-0.2% with the higher rates in areas with large numbers of immigrants from Central and South America.**
**Increasing rates of immigration raises concern about the potential for increased transmission.**

- Triatomine bug

## Chagas Transmissions by Blood or Organ Donations: U.S./Canadian

- 1987:		California – Mexican blood donor
- 1989:		New York City – Bolivian blood donor
- 		Manitoba – Paraguayan blood donor
- 1993:		Houston – unknown blood donor
- 1999:		Miami – Chilean blood donor
- 2000:		Manitoba – German/Paraguayan blood donor
- 2001:		Three organ recipients – Central American 			organ donor
- 2002:		Rhode Island – Bolivian donor
- 2006:		Los Angeles – Heart donor traveled to Mexico
- 		Los Angeles – Heart donor born in El Salvador

## Background (Continued)

- September 1989- BPAC recommends donor screening for Chagas disease if a suitable test were available
- December 1995- BPAC does not endorse available FDA cleared diagnostic Chagas tests for blood screening with uncertainty about appropriate criteria for acceptance
- September 2002- FDA presents to BPAC regulatory pathway and criteria for evaluation of Chagas tests
- December 2006- FDA approves the first blood donor screening assay (the Ortho® *T. cruzi* ELISA Test System)
- No FDA licensed _supplemental_ test for *T. cruzi *antibodies is currently available

## Blood donor screening for Chagas disease

- Chagas screening with the Ortho ELISA initiated by ARC and BSI on January 29, 2007 other centers have followed.  Through March 27, 2007, ~1 million donors had been screened, resulting in detection of 198 repeatedly reactive.
- Retested on a more specific, unlicensed *T. cruzi *RIPA:* *131 non-reactive, 31 reactive, 36 pending.
- 0.02% RR, 99.984% specificity, 0.004% prevalence
- Voluntary industry recommendations: AABB issues recommendations for implementation to member establishments. (Bulletin #06-08, Dec. 2006)

## Issues for Implementation of Blood Donor Screening : Donor Management

- We are considering whether blood establishments should:
- Test donations for antibodies to *T. cruzi*
- Universal screening
- Potential for selective testing if appropriately validated* *
- Defer (indefinitely) and notify all donors repeatedly reactive by the licensed test

## Donor Management (Continued)

- Counseling:
- inform all repeatedly reactive donors about likelihood and medical significance of infection; referral for additional medical diagnostic testing may be useful
- Medical follow up for cross-reacting diseases
- Specific counseling of repeatedly reactive donors with no apparent exposure or negative results on more specific medical diagnostic tests for further medical follow up based on risk factors

## Issues for Implementation of Blood Donor Screening : Product Management

- We are considering whether blood establishments should:
- Index donations
- quarantine and label all repeatedly reactive donations
- Products from prior collections
- retrieve, quarantine and label
- Lookback (recipient tracing)
- notify consignees to enable notification of recipients of prior donations from repeatedly reactive donors

## Product Management (Continued)

- Autologous donations
- test when allogeneic use of these units is allowed or units are shipped to centers where allogeneic use is allowed.
- Repeatedly reactive units for autologous use must be labeled “Biohazard” (21 CFR 610.40)

## Product Management (Continued)

- Inventory testing
- perform local assessment of risk
- Label and Circular of Information
- update to include *T. cruzi *antibody testing
- Biological Product Deviation Report and fatality report
- report release of reactive units or any fatality related to a reactive unit

## Areas where research is needed?

- Possible targeted screening of repeat donors
- Necessity for continued universal screening?
- Validation of strategies for retesting selected repeat donors for *T. cruzi *antibodies
- Presentation to follow, outlining plans for a validation strategy

## Additional areas where research is needed?

- Possibility of cross-reactive antibodies of medical significance: indications from Ortho’s performance evaluation study
*Leishmania*
- Test reacts with samples from individuals with leishmaniasis (74/100 samples from area non-endemic for *T. cruzi*)
- Other pathogens
- Test can react with samples from individuals with malaria* *(1/100)
- Test may react with *Paracoccidioides* antibodies* *(2/5 from *T. cruzi* endemic area)

## Possible studies to evaluate cross-reactivity of Chagas blood screening tests

- Test a panel of serum/plasma samples from individuals well characterized as infected with *Leishmania *with licensed *T. cruzi* blood screening assay
- CDC repository
- Other US repositories of infected samples
- Acquire additional samples from  *Leishmania *endemic countries
- Prospectively follow up for leishmaniasis all donors repeatedly reactive on licensed *T. cruzi* blood screening assays
*Leishmania *serology
- Risk factors for exposure to *Leishmania*
- Other medical diagnoses
- Similar studies of *Plasmodium* or *Paracoccidioides *cross-reactivity could also be proposed

## Session Agenda

- Introduction and Issues Related to Implementation of Blood Donor Screening for antibodies for *T. cruzi *Infection
- Robert Duncan, Ph.D., DETTD, OBRR, FDA
- Introduction of Issues Related to the Potential Transmission of *T. cruzi* by Human Cells, Tissue and Cellular and Tissue-Based Products
- Melissa A. Greenwald, M.D., DHT, OCTGT, FDA
- Ortho *T. cruzi* ELISA Test System Experience
- Susan Stramer, Ph.D., American Red Cross
- Public Health Impact of Donor Screening for *T. cruzi* infection
- Susan Montgomery, M.D., CDC
- Potential Strategies for Targeted Testing for *T. cruzi* Infection in Repeat Donors
- Michael Busch, M.D./ Brian Custer, Ph.D., M.P.H.,  Blood Systems Research Institute
- Open Public Hearing, Questions and Discussion

## T. cruzi Blood Screening Question#1

- Please comment on any scientific issues that FDA should further consider in developing its recommendations on implementation of blood donor screening for antibodies to *T. cruzi.*

## T. cruzi Blood Screening Question#2

- What suggestions does the committee have on the design of research studies to validate a strategy for selective screening of repeat donors?

## T. cruzi Blood Screening Question#3

- Please comment on the need for and design of studies to determine whether repeatedly reactive test results for antibodies to *T. cruzi* should be further investigated for cross-reactivity to *Leishmania, Plasmodium, Paracoccidioides braziliensis *or other agents when the donor lacks risk factors for *T. cruzi *infection or a test sample is found negative by other, more specific tests.