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Issues Related to the Potential Transmission of Trypanosoma cruzi by Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps) Melissa A. Greenwald,

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Presentation on theme: "Issues Related to the Potential Transmission of Trypanosoma cruzi by Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps) Melissa A. Greenwald,"— Presentation transcript:

1 Issues Related to the Potential Transmission of Trypanosoma cruzi by Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps) Melissa A. Greenwald, M.D. Office of Cellular, Tissue and Gene Therapies (OCTGT); CBER Blood Products Advisory Committee 26 April 2007

2 Overview Question for the CommitteeQuestion for the Committee BackgroundBackground About HCT/PsAbout HCT/Ps About Chagas’ diseaseAbout Chagas’ disease Results of Literature ReviewResults of Literature Review Final CommentsFinal Comments

3 Question for Committee Please comment on the current scientific data as it relates to the potential for transmission of Chagas’ disease by HCT/Ps.Please comment on the current scientific data as it relates to the potential for transmission of Chagas’ disease by HCT/Ps.

4 Background What is an HCT/P? HCT/Ps are regulated by OCTGTHCT/Ps are regulated by OCTGT HCT/Ps encompass a wide variety of productsHCT/Ps encompass a wide variety of products 21 CFR 1217.3(d) defines HCT/Ps as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient21 CFR 1217.3(d) defines HCT/Ps as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient

5 Examples of HCT/Ps Musculoskeletal tissuesMusculoskeletal tissues SkinSkin Dura MaterDura Mater Cardiovascular tissuesCardiovascular tissues Ocular tissuesOcular tissues Reproductive cells and tissuesReproductive cells and tissues Hematopoietic stem/progenitor cells derived from peripheral and cord blood Other cellular therapies Gene therapies Tissue/device and other combination products

6 Not HCT/Ps Vascularized human organs for transplantation (HRSA oversight);Vascularized human organs for transplantation (HRSA oversight); Whole blood or blood components or blood derivative products;Whole blood or blood components or blood derivative products; Secreted or extracted human products, such as milk, collagen, and cell factorsSecreted or extracted human products, such as milk, collagen, and cell factors

7 Not HCT/Ps (continued…) Minimally manipulated bone marrow for homologous use and not combined with a drug or a device;Minimally manipulated bone marrow for homologous use and not combined with a drug or a device; Ancillary products used in the manufacture of HCT/P;Ancillary products used in the manufacture of HCT/P; Cells, tissues, and organs derived from animals other than humans; andCells, tissues, and organs derived from animals other than humans; and In vitro diagnostic productsIn vitro diagnostic products

8 HCT/P Donor Screening & Testing Donor screeningDonor screening medical history interview,medical history interview, physical assessment/examination, andphysical assessment/examination, and medical record reviewmedical record review Donor testingDonor testing FDA-licensed, cleared or approved donor screening testsFDA-licensed, cleared or approved donor screening tests Specifically labeled for cadaveric donors, if applicable and availableSpecifically labeled for cadaveric donors, if applicable and available

9 RCDADs—diseases for which all HCT/P donors are currently screened and/or tested Human immunodeficiency virus (HIV), types 1 and 2;Human immunodeficiency virus (HIV), types 1 and 2; Hepatitis B virus (HBV);Hepatitis B virus (HBV); Hepatitis C virus (HCV);Hepatitis C virus (HCV); Human transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease (CJD); andHuman transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease (CJD); and Treponema pallidum (syphilis)Treponema pallidum (syphilis) RCDADs are Relevant Communicable Disease Agents or Diseases

10 “New” RCDADs We have recently issued (final) guidance describing the following to be RCDADs for all HCT/PsWe have recently issued (final) guidance describing the following to be RCDADs for all HCT/Ps West Nile VirusWest Nile Virus SepsisSepsis Vaccinia (the virus used in smallpox vaccine)Vaccinia (the virus used in smallpox vaccine) Today’s discussion will focus on the current scientific data as it relates to the potential for transmission of Chagas’ disease by HCT/Ps and thus, the possible need to test HCT/P donors for T. cruziToday’s discussion will focus on the current scientific data as it relates to the potential for transmission of Chagas’ disease by HCT/Ps and thus, the possible need to test HCT/P donors for T. cruzi

11 Background, continued Chagas’ disease http://www.canr.msu.edu/vanburen/fbenny.htm

12 Transmission of T. cruzi In addition to transmission by a vector, published literature indicates the following other means of T. cruzi transmissionIn addition to transmission by a vector, published literature indicates the following other means of T. cruzi transmission Vertical (congenitally/mother to infant)Vertical (congenitally/mother to infant) Oral (breast milk or contaminated food)Oral (breast milk or contaminated food) Entrance via conjunctiva from hand contaminationEntrance via conjunctiva from hand contamination Blood transfusionBlood transfusion Organ transplantationOrgan transplantation

13 T. Cruzi lifecycle in humans Trypomastigotes in blood Invade tissue/cell Convert to amastigote form and replicate Trypomastigotes released into bloodstream to circulate or invade other host cells Tulane.edu

14 Tissue Transmission of T. cruzi No reports of tissue transmissionNo reports of tissue transmission Association between the tissue transplant and the development of symptoms may not be recognizedAssociation between the tissue transplant and the development of symptoms may not be recognized long time between exposure and symptom development in immunocompetent individualslong time between exposure and symptom development in immunocompetent individuals acute phase usually asymptomaticacute phase usually asymptomatic chronic (indeterminate) phase asymptomaticchronic (indeterminate) phase asymptomatic

15 Tissue Transmission of T. cruzi (continued…) May be difficult to recognize a tissue transplant-transmitted infection in an endemic area where there is vector exposureMay be difficult to recognize a tissue transplant-transmitted infection in an endemic area where there is vector exposure Tissue allografts generally undergo some processing—some methods may remove or inactivate T. cruziTissue allografts generally undergo some processing—some methods may remove or inactivate T. cruzi Some cellular products are cryopreserved; some tissues are frozen—parasite may survive 2-3 weeks at refrigerator or freezer temperatures, survival beyond that time period is unknownSome cellular products are cryopreserved; some tissues are frozen—parasite may survive 2-3 weeks at refrigerator or freezer temperatures, survival beyond that time period is unknown

16 Tissue distribution of T. cruzi in infected individuals Information is scantInformation is scant Acute phaseAcute phase Parasites found in skin lesions at site of transmissionParasites found in skin lesions at site of transmission Spread through the bloodstreamSpread through the bloodstream Lodge in various tissues, particularly skeletal muscleLodge in various tissues, particularly skeletal muscle

17 Tissue Distribution of T. cruzi in infected individuals (continued…) Chronic asymptomatic phaseChronic asymptomatic phase muscle (especially cardiac muscle)muscle (especially cardiac muscle) nervenerve digestive tractdigestive tract Little investigation of distribution within other tissues during this phase (tendency to look at tissues that have known clinical manifestations)Little investigation of distribution within other tissues during this phase (tendency to look at tissues that have known clinical manifestations) Parasites have been demonstrated in the affected tissues of individuals who die with cardiomyopathy, megaesophagus, or megacolonParasites have been demonstrated in the affected tissues of individuals who die with cardiomyopathy, megaesophagus, or megacolon

18 Review of T. cruzi literature provided to the committee http://www.ctegd.uga.edu/misc_pages/parasites.html

19 Mouse Studies Mice inoculated with T. cruzi demonstrated parasites in skeletal muscle, heart, bladder, peripheral nerve, liver, spleen, adrenal gland, brain, and adipose tissueMice inoculated with T. cruzi demonstrated parasites in skeletal muscle, heart, bladder, peripheral nerve, liver, spleen, adrenal gland, brain, and adipose tissue Parasite load decreased 100-fold over 10 months, still demonstrated visible parasites in skeletal muscle and bladderParasite load decreased 100-fold over 10 months, still demonstrated visible parasites in skeletal muscle and bladder Mice subcutaneously inoculated with T. cruzi demonstrated PCR positivity for T. cruzi DNA in ocular tissue and surrounding structuresMice subcutaneously inoculated with T. cruzi demonstrated PCR positivity for T. cruzi DNA in ocular tissue and surrounding structures

20 Mouse Studies (continued…) Experimentally infected mice demonstrated pseudocysts filled with amastigotes in <1% of evaluated tissue sections; but IHC methods demonstrated T. cruzi antigens in 11% of inflammatory infiltrates (visualization of amastigotes may be insensitive)Experimentally infected mice demonstrated pseudocysts filled with amastigotes in <1% of evaluated tissue sections; but IHC methods demonstrated T. cruzi antigens in 11% of inflammatory infiltrates (visualization of amastigotes may be insensitive) Experimentally infected mice demonstrated T. cruzi in sternum chondroblasts, osteoblasts, macrophages and fibroblasts (osteocyte and chondrocyte invasion was rare)Experimentally infected mice demonstrated T. cruzi in sternum chondroblasts, osteoblasts, macrophages and fibroblasts (osteocyte and chondrocyte invasion was rare)

21 Human Placenta Study Human placentas (collected post- partum) were perfused and inoculated with a bolus containing T. cruzi trypomastigotesHuman placentas (collected post- partum) were perfused and inoculated with a bolus containing T. cruzi trypomastigotes Specimens collected immediately following perfusion; after 24 and 48 hours of incubationSpecimens collected immediately following perfusion; after 24 and 48 hours of incubation T. cruzi DNA was identified in cells within all postinoculation placental tissue specimensT. cruzi DNA was identified in cells within all postinoculation placental tissue specimens

22 Clinical data Individuals with chronic Chagas’ disease who underwent endomyocardial biopsy demonstratedIndividuals with chronic Chagas’ disease who underwent endomyocardial biopsy demonstrated T. cruzi antigenic deposits by immunohistochemical techniquesT. cruzi antigenic deposits by immunohistochemical techniques T. cruzi DNA by PCRT. cruzi DNA by PCR Histopathology evaluation—necrosis, inflammatory infiltrates, and fibrosisHistopathology evaluation—necrosis, inflammatory infiltrates, and fibrosis

23 Clinical Data (continued…) Study demonstrated a correlation between the presence of T. cruzi antigen and the severity of myocardial inflammatory processStudy demonstrated a correlation between the presence of T. cruzi antigen and the severity of myocardial inflammatory process T. cruzi DNA by PCR has been demonstrated in esophageal tissues of persons who died of esophageal Chagas’ diseaseT. cruzi DNA by PCR has been demonstrated in esophageal tissues of persons who died of esophageal Chagas’ disease

24 Final Comments Science Daily.com Credits: WHO/TDR/Stammers

25 How do HCT/Ps transmit infection? Infectious disease transmission by HCT/Ps is complex—much is unknownInfectious disease transmission by HCT/Ps is complex—much is unknown In cases of known transmission of other infectious disease agents (e.g., HIV, HBV, and HCV), it has been difficult to determine whether transmission occurs because ofIn cases of known transmission of other infectious disease agents (e.g., HIV, HBV, and HCV), it has been difficult to determine whether transmission occurs because of agent in the tissue, oragent in the tissue, or agent in blood that is in the tissueagent in blood that is in the tissue

26 How do HCT/Ps transmit infection? (continued…) Infectious dose of T. cruzi is not clearly defined in the literature, generally believed to be lowInfectious dose of T. cruzi is not clearly defined in the literature, generally believed to be low What activates the organism to mobilize from the intracellular amastigote stage into bloodborne trypomastigotes is also unknown, but has been demonstrated to occur in persons who were infected via organ transplantationWhat activates the organism to mobilize from the intracellular amastigote stage into bloodborne trypomastigotes is also unknown, but has been demonstrated to occur in persons who were infected via organ transplantation

27 Summary T. cruzi is found in blood and various tissuesT. cruzi is found in blood and various tissues Much is unknown about potential transmission from tissue allograftsMuch is unknown about potential transmission from tissue allografts Necessary to make public health decisions based on best available informationNecessary to make public health decisions based on best available information

28 References Anez N, et al. Myocardial Parasite Persistence in Chronic Chagasic Patients. Am J Trop Med, 1999;60(5):726-732Anez N, et al. Myocardial Parasite Persistence in Chronic Chagasic Patients. Am J Trop Med, 1999;60(5):726-732 Bellotti, et al. In vivo detection of Trypanosoma cruzi antigens in hearts of patients with chronic Chagas’ heart disease. American Heart Journal, 1996 Feb;131(2):301-307Bellotti, et al. In vivo detection of Trypanosoma cruzi antigens in hearts of patients with chronic Chagas’ heart disease. American Heart Journal, 1996 Feb;131(2):301-307 Buckner FS, et al. Detection of Live Trypanosoma cruzi of Infected Mice by Using Histochemical Stain for β-Galactosidase. Infection and Immunity, 1999 Jan;67(1):403-409Buckner FS, et al. Detection of Live Trypanosoma cruzi of Infected Mice by Using Histochemical Stain for β-Galactosidase. Infection and Immunity, 1999 Jan;67(1):403-409

29 References, cont. Herrera L, et al. Cornea as a tissue reservoir of Trypanosoma cruzi. Parasitol Res, 2006 NovHerrera L, et al. Cornea as a tissue reservoir of Trypanosoma cruzi. Parasitol Res, 2006 Nov Morocoima A, et al. Trypanosoma cruzi: experimental parasitism of bone and cartilage. Parasitol Res, 2006;99:663-668Morocoima A, et al. Trypanosoma cruzi: experimental parasitism of bone and cartilage. Parasitol Res, 2006;99:663-668 Shippey SH, et al. Use of the placental perfusion model to evaluate transplacental passage of Trypanosoma cruzi. Am J Ob Gyn, 2005;192:586-591Shippey SH, et al. Use of the placental perfusion model to evaluate transplacental passage of Trypanosoma cruzi. Am J Ob Gyn, 2005;192:586-591

30 References, cont. Vago AR, et al. PCR detection of Trypanosoma cruzi in oesophageal tissues of patients with chronic digestive Chagas’ disease. Lancet, 1996 Sep;348:891-892Vago AR, et al. PCR detection of Trypanosoma cruzi in oesophageal tissues of patients with chronic digestive Chagas’ disease. Lancet, 1996 Sep;348:891-892 Younes-Chennoufi AB, et al. Persistence of Trypanosoma cruzi in the inflammatory lesions of chronically infected mice. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1988;82:77-83Younes-Chennoufi AB, et al. Persistence of Trypanosoma cruzi in the inflammatory lesions of chronically infected mice. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1988;82:77-83


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