BB Ch26 - Xenozoonoses

Question 1

1. Why has an interest in xenotransplantation been in development?

Answer 1

Because of the great scarcity of human organ and tissue donors

Question 2

2. What is allotransplantation?

Answer 2

Transplantation of organs, tissues, or cells between genetically dissimilar individuals of the same species

Question 3

3. What is a recognized risk of allotransplantation that will also be of concern in xenotransplantation?

Answer 3

Risk of transmission of infections from donor organs, tissues, or cells to the recipient

Question 4

4. What is xenotransplantation?

Answer 4

Transplantation of organs, tissues, or cells between species. For example, baboon bone marrow transplanted into a human patient

Question 5

5. What is the term for potential novel infections emerging from xenotransplantation?

Answer 5

Xenozoonoses

Question 6

6. What is a major risk factor for severe infections in the field of allotransplantation? Will this be a lesser or greater risk factor for xenotransplantation?

Answer 6

6. The use of nonspecific immunosuppression to prevent rejection of the new organ or tissue. This risk factor will still be present, perhaps to an even greater degree when attempting xenotransplantation.

Question 7

7. What are some sources of infectious microbes in allotransplantation? Which of these sources will be the same whether a person undergoes an allo- or xenotransplant? Which of these sources may lead to novel infections in human patients?

Answer 7

7. Recipient’s endogenous flora, the environment, or organisms harbored within the donated organ, tissues, or cells. The environment and the recipient’s endogenous flora will be the same for either type of transplantation. The graft itself may lead to novel infections in human recipients.

Question 8

8. What are some examples of donor-associated infections after allotransplantation that may be quiescent in the donor but may cause disease in the naïve recipient host?

Answer 8

8. Hepatitis B virus, hepatitis C virus, human immunodeficiency virus, retroviruses, some herpesviruses (i.e. human cytomegalovirus, Epstein-Barr virus), some parasites (i.e. Toxoplasma gondii)

Question 9

9. Give some examples of herpesviruses latent in the donor that are not transmissible by transplantation. Why is this true?

Answer 9

9. Herpes simplex and varicella zoster viruses are latent in sensory ganglia and as such are not usually present in blood or in the transplanted graft. They represent a very low risk of donor transmission based upon microbial tropism and individual properties of the microbe.

Question 10

10. What is one limitation of screening tests for potential donor-associated infections prior to transplantation? What is a limitation of donor screening in general?

Answer 10

10. If donor is infected and has not had time to mount a detectable antibody response prior to donation or death. Except in the case of living related donation, donor screening is limited by substantial time constraints.

Question 11

11. What is one way to reduce the risk of disease from donor-transmitted infections?

Answer 11

11. Prophylaxis and surveillance of recipients who are at risk can help with decreasing disease from donor-transmitted infections

Question 12

12. How could a previously nonzoonotic animal virus possibly become zoonotic via xenotransplantation?

Answer 12

12. During xenotransplantation, animal viruses similar to analogous human viruses come into communication with human cells to which they normally would not have access. Under these circumstances, such animal viruses might be capable of infecting humans. Also, some animal microbes that would not be pathogenic in a healthy person could cause disease after xenotransplantation due to immunosuppression of the recipient patient. Another concern is the potential for a crossover of genetic material between an animal and a human virus leading to a more virulent recombinant organism. It is also possible that some human viruses may cause disease in the animal graft.

Question 13

13. Give an example of a “species-specific” virus that can have severe consequences when transmitted to another species. What would be the risk of transmitting this virus via xenotransplantation and is this risk acceptable (risk versus benefit)?

Answer 13

13. Cercopithecine herpesvirus 1 (B virus) is generally innocuous in the host species (macaques) but can cause fatal disease after inadvertent infection of a human. Because this virus is latent in nerve endings and not in blood or organs, it is likely to have a low risk of transmission via xenotransplantation. However, disease severity makes any risk unacceptable.

Question 14

14. What are the two most common species being used as donor sources for xenotransplantation? Do they have species-specific viruses that may be of concern to the human recipient?

Answer 14

14. Baboon and pigs. These species have alphaherpesviruses but it is unclear if simian agent 8 in baboons and pseudorabies in pigs can be transmitted to human recipients. There has been some anecdotal data suggesting transmission of pseudorabies between pigs and humans but the transmission mechanism is unclear. Cytomegalovirus (CMV) transmission between disparate species has also been suggested.

Question 15

15. What is a major problem in assessing the true risk of xenozoonoses?

Answer 15

15. The lack of available and easy-to-perform techniques to differentiate human from animal viruses (i.e. cross reactivity of antigens from human Epstein-Barr virus and Herpesvirus papio).

Question 16

16. Besides herpesviruses, what is another type of virus that is often species-restricted but can sometimes have severe consequences when cross-species transmission occurs? Give an example.

Answer 16

16. Retroviruses. Simian immunodeficiency virus (SIV) is benign in its natural host, the African Green monkey, but progresses to an AIDS-like disease in macaques. Probable transmission of SIV to two humans who were occupationally exposed has been documented as well with no clinical consequences.

Question 17

17. What types of retroviruses may be transmissible with xenotransplantation? Give an example for each type of retrovirus.

Answer 17

17. Lentivirus – SIV; oncogenic retrovirus – simian T-lymphotropic virus (STLV); foamy virus – nonhuman primate spumavirus

Question 18

18. What is the difference between exogenous versus endogenous retroviruses and why would this distinction be important for xenotransplantation?

Answer 18

18. Exogenous retroviruses behave like conventional, transmissible viruses. Endogenous retroviruses are integrated into the host genome (provirus) and depend upon their chromosomally integrated state for transmission. Endogenous retroviruses, unlike exogenous retroviruses, cannot be removed from source-animal populations by current rearing methods.

Question 19

19. Give some examples of endogenous animal retroviruses that may be of concern in xenotransplantation.

Answer 19

19. All strains of pigs studied carry porcine endogenous retroviruses (PoERVs) within their genome. Likewise, baboon endogenous retrovirus (BaEV) is found in the baboon genome. Both PoERV and BaEV have been shown to be capable of infecting human cell lines in vitro.

Question 20

20. What are some other virus classes that have been transmitted after allotransplantation and may likewise cause disease after xenotransplantation?

Answer 20

20. Adenoviruses, hepatitis causing viruses (i.e. Hepatitis B, C, and E viruses), reoviruses, circoviruses, paramyxoviruses

Question 21

21. What is the etiologic agent for a recently discovered zoonotic disease infecting pigs and humans in Australia?

Answer 21

Menangle virus

Question 22

22. Give some examples of nonviral agents that may cause xenogeneic infections if present in tissues being transplanted.

Answer 22

22. Toxoplasma gondii cysts, Entamoeba histolytica, some schistosoma species, Hepatocystis kochi, Babesia species. Bacterial (i.e. Mycobacterium species) and fungal diseases require consideration as well.

Question 23

23. What is one way that xenozoonoses could be substantially diminished in source animals?

Answer 23

23. Raise source animals under strict germfree conditions

Question 24

24. Define a gnotobiotic animal. What are some issues in raising pigs under gnotobiotic conditions?

Answer 24

24. A gnotobiotic animal, or gnotobiote, has been born germ free and then infected with know microorganisms. The microflora and microfauna of these specially reared animals are therefore known in great detail. Gnoto is a Greek word for known, and biota is lifeforms (i.e. microorganisms). Pigs can be raised under gnotobiotic conditions but have problems after several months of age due to size and waste production. Gnotobiotic environments preclude normal colonizations of the GI tract with normal microbial agents that aid food digestion. This is why gnotobiotic pigs are less robust and may not be ideal organ sources.

Question 25

25. What are some alternatives to gnotobiotic animals?

Answer 25

25. Specific pathogen-free (SPF) animals. SPF animals are raised under controlled environments with which specific pathogens have been eliminated and the introduction of outside pathogens is prevented.

Question 26

26. What are some logistic difficulties in creating and maintaining specific pathogen-free (SPF) nonhuman primate colonies?

Answer 26

26. Long time until sexual maturity; variable gestational period; single offspring per pregnancy; and dependent state during infancy. Vigilance must be strictly maintained against accidental introduction of microbes to established colonies from human caretakers or outside animals. Concern would still remain for possible xenozoonoses that were not initially screened out of a SPF population.

Question 27

27. When developing protocols for screening source animals for xenotransplantation, into what four recommended categories should prospective microbial agents be placed?

Answer 27

27. Categories are defined with the most up-to-date information available but with the recognition that in the future, some infectious agents may be moved into different classes.
    (1) Absolute contraindications – microbial agents that are known to be zoonotic and dangerous to humans, even if they are not anticipated to be found in source animals
    (2) Relative contraindications – microbes hypothesized to be xenozoonotic but are unproven or with uncertain consequences
    (3) Treatable microbes – microbes that can be identified and eradicated prior to xenotransplantation
    (4) Unavoidable microbes – microbes that exist but are as yet unrecognized and thus of indeterminate risk.

Question 28

28. What is one problem in using serologic surveys to monitor etiological agents in source animals? How can one minimize this problem?

Answer 28

28. Serologic surveys have the potential to miss an immunologic response to a recently encountered agent. To minimize problems, select animals that tested negative initially should be quarantined and retested over time.

Question 29

29. What are some potential benefits of xenotransplantation?

Answer 29

29. (1) It is possible that xenotransplantation may decrease the risk of some infections after transplantation due to natural resistance of donor/source animal to specific infections (i.e. hepatitis B virus, HIV-1).
    (2) Xenotransplantation may avoid many donor-transmitted infections by permitting source animals to be reared in controlled, SPF environments and surveyed against acute infections.

Question 30

30. What are some of the guidelines recommended by the U.S. Public Health Service with respect to xenotransplantation?

Answer 30

30. Public Health Service guideline on infectious disease issues in xenotransplantation
    (1) Any recipient of xenogeneic tissue should undergo counseling about the potential risks and surveillance for infections after xenotransplantation
    (2) Serial samples from the recipient and transplanted tissues should be collected for cultures and/or assays to look for agents that were known or suspected to be in the source animal
    (3) Source animals should be reared in controlled, SPF environments and surveyed against acute infections.

Question 31

31. What U.S. Department of Health and Human Services committee has been formed to consider the complexities of xenotransplantation and to help with ongoing review of these procedures?

Answer 31

Secretary’s Advisory Committee on Xenotransplantation