Surveillance for possible transmission of xeno-zoonoses

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U.S. Requirements for Surveillance of Fetal Cell Xenotransplant Recipient

Every patient/recipient of fetal precursor cell xeno-transplants should undergo a surveillance for 5 years in order to monitor the possible introduction and propagation of xenogeneic infections into a general population. All documentation of this surveillance must be kept by treating physician, entered also into the computerized data base, if possible, which documentation allows a prompt retrieval, and linkage of the medical records of the recipient to the records of manufacture of fetal precursor cell xeno-transplants, and of source animals.

During the scheduled office visits every recipient of fetal precursor cell xeno-transplants must be evaluated also for adverse clinical events potentially associated with xenogeneic infections. Careful attention must be paid to acute infectious episodes, that under usual circumstances in the general population are never etiologically identified. When the source of a significant illness in a fetal precursor cell xeno-transplants recipient remains unidentified after standard diagnostic procedures, more testing of samples of body fluids and tissues is carried out under the supervision of the hospital infectious disease specialist. Appropriate isolation precautions may be recommended until a suspected xenogeneic infection has been proven and resolved or ruled out in the recipient. Archiving of acute and convalescent sera obtained in association with acute unexplained illness may be recommended by the infectious disease specialist, which would permit retrospective study and etiologic diagnosis of the clinical episode.

All adverse events after cell xeno-transplantation must be recorded, even if most likely related to the patient’s chronic illness , or representing a concomitant illness. The date of discovery, or of the office visit when found out, of the adverse event and the time relationship to cell xeno-transplantation must be noted, classified as mild, moderate and severe, and as serious and non-serious, and their duration noted. Action taken and outcome must be recorded.

Deaths and other serious adverse events must be especially watched for. A narrative report must be obtained of each case describing the following: nature and intensity of event; the clinical course leading to an event, timing relevant to fetal precursor cell xeno-transplantation; relevant laboratory measurements; countermeasures; post-mortem findings; investigator’s opinion on casuality, as well as relevant concomitant/previous illnesses and relevant concomitant/previous medications.

As the adverse events have been non-existent in our experience, they all must be individually analyzed in detail.

In the U.S., biological specimens will have to be collected and archived from each fetal precursor cell xeno-transplants recipient to allow retrospective investigation of possible xenogeneic infections, marked for ‘public health investigative purposes’. Each set of biological specimens consists of five 0.5cc aliquots of citrated anticoagulated plasma, two aliquots of viable leukocytes (1x107) and blood mononuclear cells. Two sets should be obtained before cell xeno-transplantation, and after cell xeno-transplantation another set should be obtained one month after, and another 6 months after the transplantation. Subsequently a set should be obtained yearly twice, and then every 5 years thereafter until the death of the recipient. At the autopsy of the recipient snap-frozen samples stored at –70o C, paraffin embedded tissue and tissue suitable for electron microscopy must be collected from fetal precursor cell xeno-transplant implantation site and all major organs involved in the pathophysiology of the disease, as determined to be the cause of death. All these specimens must be archived for 50 years for ‘potential public health use’ as per U.S. FDA requirements.

In case that it would become known or suspected that xenogeneic agents were present in fetal cell xeno-transplants, an active surveillance of the recipient is instituted by collecting specimens of blood serum, peripheral blood mononuclear cells and tissue at frequent intervals. Assays for the detection of classes of viruses known to establish persistent latent infection (herpesviruses, retroviruses, etc.) would be used, along with co-cultivation of cells coupled with appropriate detection assays. The purpose is to detect sentinel human infections prior to their dissemination in general population. Testing of archived biological specimens would be conducted alongside epidemiologic investigation to assess potential public health significance of the infection.

In the process of obtaining an informed consent the treating physician must inform fetal precursor cell xeno-transplants recipient of the responsibility to educate his/her close contacts of the possibility, however distant, of the emergence of xenogeneic infections from the source animal species, without causing at the same time an undue alarm and panic. Most importantly the physician must educate fetal cell xeno-transplant recipient that whenever they or their close contacts would develop any significant unexplained illness they all must inform promptly their physician that treated them by fetal cell xeno-transplantation.

The U.S. rules do not apply in Europe where there is an ample experience with cell xeno-transplantation over the past 90+ years, and naturally if the cell xeno-trans-plants were prepared in Europe or the countries of the former USSR.

Health Care Records

Three cross-referenced record systems should be maintained by the fetal cell transplantologist in the U.S.:

a/ Institutional Xenotransplantation Record, which documents for all fetal cellxeno-transplantation procedures: the treating physician, the source animals for fetal cell xeno-transplants and their procurement facility, the date of procedure and what kinds of fetal cell xeno-transplants were used, the xeno-transplant recipient, and a summary of the recipient’s clinical course, close contacts, and the health care workers associated with each procedure.

b/ Xenotransplantation Nosocomial Health Exposure Log, which documents the dates, involved persons, and nature of all nosocomial exposures associated with a protocol for fetal cell xeno-transplantation and which potentially pose a risk of transmission of xenogeneic infections.

c/ Individual Xeno-transplant Recipient Health Records, which document each patient’s clinical course, the results of post-fetal cell xeno-transplantation surveillance studies and contain a summary of the results of the screening assays performed on rabbit females of the colony and of the health status of newborn rabbits (see above) from which fetal precursor cell xeno-transplant was obtained.

These records must be always current and accurately cross-referenced for an easy investigation of adverse events.