A major contribution of the Notify project was the participation of a diverse group of transplant professionals who come from different disciplines and who ordinarily do not communicate with one another. Transplant surgeons, orthopaedists, ophthalmologists, infectious disease specialists, pathologists, nurses, eye bankers, tissue bankers, regulators and scientists had the opportunity to interact and provide their own perspectives. From these discussions some common definitions that can be applied across all fields were agreed upon whilst others are under discussion.
The following definitions adopted in the European Directives for Tissues and Cells and for Organs were considered appropriate and useful for international application, although they were mapped to less technical language to improve accessibility by the general public:
1. Severe Adverse Event (SAE): any untoward occurrence, associated with the chain, from donation to transplantation that might lead to the transmission of a communicable disease, to death or life-threatening, disabling or incapacitating conditions for patients or which results in, or prolongs, hospitalization or morbidity. In the Notify project these are referred to as cases of ‘Risk of Harm’.
2. Severe Adverse Reaction (SAR): any unintended response, including a communicable disease, in the living donor or in the recipient that might be associated with any stage of the chain from donation to transplantation that is fatal, life-threatening, disabling, incapacitating, or which results in, or prolongs, hospitalization or morbidity. In the Notify project these are referred to as cases of ‘Harm to Donor’, ‘Harm to Recipient’ or ‘Harm to Fetus/Offspring’.
The EU definition for imputability of a potential adverse reaction should be assessed, based on available information, as either: proven, probable, possible, unlikely or excluded. A further category of ‘intervened upon without documentation’ has been used for organ transplantation situations where recipient treatment has been applied prophylactically in the context of a known risk. The stringent definition of proven or definite transmission should be used only if there is clear evidence of the same disease in the donor and at least one of the recipients. Absence of pre-transplant disease in the recipients should be documented. Variable involvement of different organs or tissues, different processing of organs and tissues, and recipient differences (i.e. pre-existing seroprotection or use of lymphocyte depleting induction in some but not all recipients) may contribute to variable disease transmission.
The stringent definition of excluded can be applied if there is clear evidence of an alternative, non-donor origin of disease. Often, this may occur if there was pre-existing infection in multiple recipients but infection could not be identified in the donor or if testing of the same infection failed to document a clonal or donor-phenotype in the identified infection.
The term probable should be applied if there is evidence strongly suggesting but not proving a reaction/event. Examples include if the same infection is documented in multiple recipients but not in the donor; or if there is epidemiologic evidence suggesting transmission (i.e. TB isolated from a recipient that types to a region where the donor lived, even if the donor studies are negative).
Possible transmission should be used for all situations where a) data suggest a possible transmission but are insufficient to fulfill criteria for confirmed transmission (proven and/or probable) or b) a transmission cannot be formally excluded. If only one recipient is available or other recipient(s) of the same donor cannot be appropriately tested, the maximum degree of indeterminate but probable transmission can be reached.
If all or some of the recipients received an intervention (i.e. antimicrobial therapy or organ removal) and no disease was recognized in any of the recipients, the term intervened upon without documented transmission (IWDT) was utilized.
If some but not all recipients had an intervention but disease transmission was recognized in even one recipient, this category should not be used. The following table describes the possible outcomes of an imputability investigation:
Table 1. Scale describing the possible outcomes of an imputability investigation
|ADAPTED FROM EUSTITE-SOHO V&S1||CRITERIA FOR INFECTIOUS AND MALIGNANT TRANSMISSIONS ADAPTED FROM DTAC2|
|Insufficient data for imputability assessment||Insufficient data for imputability assessment|
|Conclusive evidence beyond reasonable doubt
for attributing an adverse reaction to alternative causes
|Suspected transmission and fulfillment of at least one of the following conditions:
Laboratory evidence that the recipient was infected with the same pathogen
|The evidence is indeterminate for attributing adverse reaction
either to the quality/safety of tissues/cells, to
the donation process, or to alternative causes
|Suspected transmission and
Suspected transmission and
|The evidence is clearly in favor of attributing the adverse
reaction to the quality/safety of tissues/cells (for recipients)
or to the donation process (for donors)
|The following two conditions are met:
And it meets at least oneof the following conditions:
If there is pre-transplant laboratory evidence, such evidence must indicate that
|The evidence is conclusive beyond reasonable doubt for attributing
the adverse reaction to the quality/safety of tissues/cells (for recipients)
or to the donation process (for donors)
|All the following conditions are met:
|1SOHO V&S Guidance for Competent Authorities: Communication and Investigation of Serious Adverse Events and Reactions associated with Human Tissues and Cells
2Uniform Definitions for Donor-Derived Infectious Disease Transmissions in Solid Organ Transplantation Christian Garzoni and Michael G. Ison Transplantation • Volume 92, Number 12, December 27, 2011