Tissue and organ donation: research

How large is the corneal transmission risk?

Martheswaran and colleagues produced the most recent published estimate for the United States. A literature review identified ten reported cases of iatrogenic CJD transmission through corneal transplantation worldwide. Using mortality and cornea donation data, they estimated that in 2018 about 3.8 corneas from donors with undiagnosed latent CJD entered a pool of 111,703 transplant-intended corneas harvested from people aged 31 to 80, and that between 1979 and 2018 roughly 47 corneas may have entered the transplant-intended pool from donors aged 35 to 84 with latent disease. The risk factors they identify are advanced donor age and a history of multiple transplants in the recipient.

Every element of that estimate is modelled. It depends on an assumed prevalence of latent disease, on an assumed incubation distribution, and on mortality data that cannot distinguish undiagnosed prion disease from other causes. The ten transmissions, by contrast, are observed cases accumulated over decades of grafting. The gap between the two figures is the measure of how little direct observation this policy area has.

The tissue distribution evidence sits underneath that estimate. As described on decontamination, RT-QuIC detected prion seeding activity in every eye examined in a sporadic CJD series, including every cornea, with the highest levels in retina.

Which other donated tissues carry PrPSc?

Peden and colleagues screened autopsy skeletal muscle from 49 CJD patients in the United Kingdom using high-sensitivity western blotting with paraffin-embedded tissue blotting. PrPSc was identified in muscle from 8 of 17 variant, 7 of 26 sporadic and 2 of 5 iatrogenic CJD patients. Paraffin-embedded tissue blotting localised the signal to structures with the morphological and immunohistochemical characteristics of nerve fibres. The authors state that detection in muscle from all forms of CJD indicates the possible presence of infectivity in these tissues, with implications for assessing iatrogenic spread through contaminated surgical instruments.

Two points constrain the reading. The finding is PrPSc by immunoblot, not infectivity by bioassay. The localisation to nerve fibre structures suggests that what was detected is peripheral nerve within muscle rather than muscle fibre itself, which is relevant for which tissues a graft actually contains.

What do the donor rules require?

The UK guidelines show how the evidence is converted into exclusions. For bone marrow and peripheral blood stem cells and, in near-identical wording, for cord blood, donation must not proceed if the donor has been diagnosed with any form of CJD or other human prion disease, or has been identified at increased risk of a prion-associated disorder. The listed categories include people at familial risk, defined as having two or more blood relatives who developed a prion-associated disease or having been informed following genetic counselling that they are at risk; people told they have been put at increased risk by surgery, transfusion or transplantation; people told they may be at increased risk because a recipient of their blood or tissue developed a prion-related disorder; recipients of dura mater grafts; recipients of corneal, scleral or other ocular tissue grafts; recipients of human pituitary-derived extracts; and, since 1 January 1980, recipients of any allogeneic human tissue.

A discretionary provision allows acceptance where a donor has two or more affected blood relatives and has been informed after genetic counselling that they are not at risk, subject to confirmation by a Designated Clinical Support Officer. The pages record the reason for the 2016 change as reflecting guidance from the Committee on the Microbiological Safety of Blood Tissues and Organs, and state the concern as a possible second wave of variant CJD cases from donors who received tissue or organ transplants, in parallel with the concern about previously transfused donors. Both entries are version-dated 18 January 2016.

Note what the familial criterion does and does not use. It turns on family history and on what a person has been told after counselling, not on a genetic test result. Anyone trying to understand their own position should discuss it with a genetic counsellor and the relevant donation service; see counselling comes first and the plain-language tissue and organ donation page.

What is unresolved?

• Whether any screening assay could qualify a donor, given that no validated blood or tissue screening test exists. See blood and plasma.
• How much infectivity, as opposed to seeding activity, the peripheral tissues used in grafting carry.
• Whether the modelled latent prevalence used for cornea risk estimates holds, since it derives from appendix survey data for variant CJD and from sporadic incidence rather than from direct measurement in donors.

Related: biosafety, laboratory safety and the regulations atlas.