NEFROLOGIA. Vol. XVIII. Suplemento 7. 1998 XENOTRANSPLANTATION Recommendations for the regulation of xenotransplantation activities in Spain Extracted from the Report of the Xenotransplantation Commission of the National Transplant Commission SUMMARY In the past years the development of tissue and organ transplants has been such both in number and in results obtained, that the demand of these types of therapies has grown enormously, creating an important disproportion between the offer of available organs and tissues and the created needs. The scientific community has been considering xenotransplantation as a possible solution to this problem for a long time. In fact, several research teams dedicate their efforts to this interesting field. Despite the undeniable therapy possibilities which have been brought about a priori, there exists an evident international concern related to the outcome of the research being carried out, more specifically related to an hypothetical clinical phase or even to an established clinical application: · The future behaviour of animal infectious agents in the human being and viceverse remains unknown. · The functional viability of organs from animal origin, both from a qualitative point of view as well as the average duration of this function, is unknown. · There are no specific regulations for xenotransplantation practices, neither at a national nor at an international level. Furthermore, there are no clear ethical statements on this issue, although several documents and recommendations are being published by different national and international bodies. · The psychosocial impact of an eventual clinical phase also remains unknown. Based on the above statements, the Heath Committee of the Council of Europe, as requested by the Transplant Committee, approved in June 1997 a proposal of recommendation to member states to establish mechanisms to control xenotransplantation activities. In Spain, in May 1997, the National Transplant Commission approved the creation of a Xenotransplantation Commission. Also in June 1997, the Plenary Session of the Spanish Congress urged the Government to closely monitor these activities. Thus, the Spanish Heath Department has set up a multi-disciplinary Commission (The Xenotransplantation Commission) in which experts on different fields related to the topic will be officially responsible for informing and reporting about xenotransplantation research in Spain. Its functions can be summarised as follows: · Knowledge and follow-up of all research projects being carried out in our country affecting primates and/or humans in any way. · Follow up of international advances in the field. · Elaboration and approval of recommendations to be followed by the different research teams, mostly in issues referring to the control of transmissible diseases. · Preparation of official reports and general information on xenotransplantation. · Analysis, evaluation and eventually approval of any clinical research projects on xenotransplantation. · Development and maintenance of a registry including data from both recipients and source of organs. This commission was officially set up on June 29th, 1997 remaining at the service of the scientific community and the different medical and sociomedical institutions. It commits itself to maintaining all health and social agents implicated or related to xenotransplantation informed about the research and progress being made in the area. The Commission will also provide support to all research projects. The Working Document of the Xenotransplantation Commission is attached, as an exposition of the problems brought up in the field. Also attached is the Recommendation for Regulation approved by all the members of The Xenotransplantation Commission. The National Transplant Commission of the National Health System supports both the Working Document and the Recommendation. 35 NEFROLOGIA. Vol. XVIII. Suplemento 7. 1998 RECOMMENDATIONS OF THE XENOTRANSPLANTATION COMMISSION FOR THE REGULATION OF THESE ACTIVITIES IN SPAIN Definitions and basic requirements For the purpose of the work of this commission, xenotransplantation is defined as any graft of cells, tissues or organs from non-human animal sources into a human. With the aim of creating an adequate framework for the development of xenotransplantation studies in accordance with the state of the scientific knowledge and the ethical and public health requirements: 1. This Commission will evaluate any «in vivo» study affecting primates or humans. 2. This Commission will be aware of any investigations affecting cell grafts in the field of xenotransplantation. 3. This Commission will establish the basis to create a Registry to monitor the evaluated research programmes. · Demonstrated absence of any non-accidental transmission of infectious agents to the caretakers and other personnel involved in the research programme. CONDITIONS TO BE TAKEN INTO CONSIDERATION WITH RESPECT TO ANIMAL PROCUREMENT SOURCES a) Facilities in animal research Animal facilities should meet safety guaranties, supervised by Public Health Authorities and Transplantation Teams. They should have adequate health surveillance systems with documented results. Animal facilities will have on staff veterinarians with expertise in the infectious diseases prevalent in the animal species and should maintain active collaboration with accredited microbiology laboratories. Research protocols must include the following aspects: 1. Criteria for animal admission. 2. Description of the disease monitoring programme. 3. Criteria for the isolation or elimination of diseased animals. 4. Studies of health screening and surveillance of humans in contact with the animals in the facility. 5. Facility cleaning measures. 6. Origin and delivery of feed, etc. 7. Measures to exclude arthropods and other animals. 8. Animal transportation. 9. Dead animal disposition. 10. Facilities legally regulated for genetically modified animals. Entry and exit of animals, animal care staff and other personnel involved in the programme should be controlled to minimise inadverted exposure to transmissible infectious agents. Movement of animals through the facilities should be described in the operating proceedings. All new animals introduced into the colony other than by birth should go through a period of quarantine and study. With regard to the reproduction and origin of suitable animals, the use of methods such as artificial insemination, embryo transfer, hysterotomy/hysterectomy and fostering, can minimise the possible colonisation with infectious agents. During final screening and qualification of individual source animals for xenotransplantation, the potential risk of transmission of an infectious agent will be minimised by utilising a step-wise «batch» or «all Pre-clinical Protocol Definition: Any investigation affecting non-human primates. Basic requirements: a) Strict follow-up of any known infectious agents (agents and recommended tests for their follow-up in accordance with the actual scientific knowledge). b) Strict compliance with animal research regulations, Public Health and Veterinary rules in force at the time. Clinical Trial Definition: Any investigation affecting human beings. Basic requirements: The existence of a pre-clinical study having achieved the following results: · Survival and adequate function of the cells, tissues or organs grafted during a period of at least 6 months. · Demonstrated absence of transmission of infectious agents in the recipient animal during a period of at least 6 months. · In the case of transmission of any infectious agents, a minimum follow-up of one year to evaluate the consequences both to the recipient and its surrounding animals will be required. 36 RECOMMENDATIONS FOR THE REGULATION OF XENOTRANSPLANTATION IN SPAIN in/all out» method of source animal movement through the facilities. With these methods, one or more source animals from the colony will be selected and will remain in quarantine while undergoing final screening qualification and organ procurement. After the entire batch of source animals is removed, the quarantine and graft procurement areas will be disinfected prior to the introduction of the next batch of animals. Nourishing components including medicines or additives should be documented for a minimum of one generation prior to the source animal. Food of animal origin should be specifically documented, Conditions of procurement and confinement for genetically modified animals. SPECIFICATIONS Experimental Xenotransplant among non-human species 1. Obtaining of donor candidates: Conventional MD (minimal disease) methods such as MEW (Premature weaning medicated) Yes Minimise entrance Minimise risk of contact CATHEGORY Experimental Xenotransplant on human species Hysterectomy and fostering 2. Viable animals shall be confined in physically separate facilities. 3. Access ways will be treated to. 4. Obtaining of samples, addition of materials and movement of animals or other viable organisms should. 5. Water used to drink and should be previously treated to guarantee total innocuousness 6. Precincts should be designed to. 7. Facilities for confinement should be located in a controlled zone: a) Only authorised personnel will have access. b) Criteria of quarantine should be established for personnel visiting and/or taking care of the animals, habing had previous contact with other animals. c) A specific health accreditation will be issued to the personnel managing the animals on a daily basis. d) Personnel should shower before entering the controlled zone. e) Work clothes will be washed and disinfected in the controlled zone. Entrance of materials foreign to the area will be forbidden. f) The controlled zone should be adequately ventilated and should maintain a positive air pressure in relation to the atmosphere. g) Air entering the controlled zone should be treated with HEPA filters. h) Feed, materials and other equipment entering the controlled zone shall be disinfected with the most efficient known means. Yes Forbid entrance Impede contact Facultative Minimise entrance Yes Yes Compulsory Forbid entrance Yes Yes Facultative Compulsory Facultative Compulsory Yes Yes Facultative Yes Facultative Yes Facultative Yes Facultative Yes 37 NEFROLOGIA. Vol. XVIII. Suplemento 7. 1998 and the animals feed with them could be discarded, since the absence of such food is important for the prevention of prion-associated diseases and slow viral infections. Facilities should maintain a registry documenting each animal, organ, tissue or type of cells supplied or used for transplantation and the transplant centres where these were sent. Such documentation should be maintained in the lifelong heath history of the source animal, the herd health surveillance registry and the operating proceedings of source animal procurement facilities. Animal numbering or other system of identification should be used to allow an easy, quick and accurate tracking of the information in the different registry systems. In the event of a closing-down of biomedical animal facilities all animal health records and specimens should be transferred to the respective clinical transplant centres or the centres should be notified of the new archive site. In the case of genetically modified animals, a communication should be addressed to the appropriate institution/body for the first use of facilities for operations with high or low risk organisms. (Art. 10.3 of the Royal Decree 951/1997). Special degree of origin and confinement of genetically modified animals used in a xenotransplantation programme. b) Pre-clinical screening for known infectious agents Known infectious agents in the colony, the source animal and in the xenograft must be studied. Protocols for screening and detection of known infectious agents in the colony, the individual source animal and the xenograft must be tailored to de source animal species and clinical application and updated periodically to reflect advances in the knowledge of infectious diseases. Xenotransplantation teams will be responsible for the adequacy of the screening protocols, as well as for the documented specificity and sensibility of the tests used. Samples from xenografts should be tested preclinically with cocultivation assays that include a panel of appropriate indicator cells, including human peripheral blood mononuclear cells, to facilitate amplification and detection of xenotropic endogenous retroviruses and other xenogeneic viruses capable of producing infection in humans. The selection of indicator cells on the cocultivation panel should be determined by the xenograft and its clinical applications. For instance, xenotransplantation involving human the central nervous system may warrant co38 cultivation of samples from the xenograft with a human neuronal cell line in the attempt to detect neurotropic viruses. Serial blind passages and observation for cytopathic effect, focus formation, reverse transcriptase assay and electron microscopy may be appropriate. Detection of latent viruses may be facilitated by chemical or irradiation methods. PCR probes can be used to detect possible bacteria in xenotransplantation. c) Colony health maintenance and surveillance The principal elements to qualify a herd or colony as a source of animals for use in xenotransplantation include: closed herd or colony and an adequate surveillance programme. Documentation on the herd or colony and individual qualified source animals should be maintained indefinitely. Aseptic techniques and sterile equipment should be used in all parenteral interventions, including vaccination, phlebotomy and biopsies. All incidents that may affect herd or colony health should be recorded (e.g. breaks in the environmental barriers of the secured facility, disease outbreaks or sudden animal deaths). Vaccinations and screening procedures must be described in detail. The use of living vaccines is discouraged although it would be justified when dead or acellular vaccines are not available. Routine screening of closed herds or colonies should concentrate on zoonoses known to exist in captive animals according to their geographic location. Veterinarians familiar with the prevalence of different infectious agents in the geographic area of origin of the source animal and the location where the source animals are to be maintained should be consulted. As part of the surveillance programme, routine serum samples should be obtained from randomly selected animals representative of the herd or colony population and tested for infectious agents relevant to the species. Additional directed serologic analysis or active culturing of individual animals should be performed in response to clinical indications. Infection in one animal of the herd or colony justifies a clinical and epidemiological evaluation of the rest of the herd or colony. In addition, serum samples should be stored indefinitely at the animal research facilities for investigation of unexpected diseases either in the herd or colony, individual source animals or in the xenograft recipient or contacts In the event of animal deaths where the cause is unknown or ambiguous, including abortions or foetal stillbirths, a full necropsy study and evaluation for possible infectious etiologies should be performed. RECOMMENDATIONS FOR THE REGULATION OF XENOTRANSPLANTATION IN SPAIN d) Individual source animal screening and qualification The qualification of individual source animals should include breed and lineage, and documentation of general heath, including vaccination history with attention to use of any live attenuated vaccines. The presence of pathogens resulting in active infections, should be controlled for by clinical examination and application of appropriate quarantine periods that extend beyond the incubation period of pathogens of concern, and by surveillance of the herd or colony from which the source animal is selected. During quarantine, individual source animals should be screened for infectious agents relevant to the particular clinical application. Individual source animals should be quarantined for at least three weeks prior to xenograft procurement. This time is sufficient to show any acute illness caused by infectious agents to which the animal may have been exposed. When the quarantine period is shortened, a justification should be documented in the protocol and the potential increased infectious risk incurred should be indicated in the informed consent document. During the quarantine period candidate source animals, should be screened for the presence of infectious agents (bacteria, parasites and viruses) by appropriate serologies and complete blood cultures, peripheral blood smear and faecal exam for parasites. Evaluation for viral agents which may not be recognised zoonotic agents but which have been documented to infect either human or non-human primate cells in vivo or in vitro should be considered. Particular attention should be given to viruses with a recognised capacity for recombination, complementation or pseudotyping. These tests should be performed as close as possible to the date of transplantation while ensuring availability of results prior to clinical use. Screening of a candidate source animal should be repeated prior to xenograft procurement if a period greater than 3 months has elapsed since the initial screening and qualification was performed, or if the animal has been in contact with other animals during the quarantine period and the time of cells, tissue or organ procurement. Transportation of source animals may compromise the protection ensured by the closed colony. Careful attention to the conditions of transport can minimise but not eliminate disease exposures during shipping. A more extensive quarantine period and screening comparable to that used for entry of new animals into a close herd or colony should be instructed upon arrival. Xenografts should be procured, when feasible, at the animal facility and transported as the cells, tissues or organ to be transplanted. All procured organs, tissues or cells intended for clinical use should be as free of infectious agents as possible. The use of source animals in which infectious agents, including latent viruses, have been identified should be avoided. The presence of an agent in certain anatomic sites, for example the alimentary tract, may not exclude use of the source animal if the agent is documented to be absent in the xenograft. When feasible and when it is unlikely to compromise the xenograft, a biopsy should be studied for infectious agents by appropriate screening assays and appropriate histopathology prior to transplantation. The results from all studies should be reviewed by the principal investigator prior to clinical use of xenograft. The health history of the colony and/or individual source animals should be available to the reviewing committees. All relevant health records for the life of the animal, including both the herd and the individual source animal records and a full history of vaccinations should be available and reviewed prior to candidate animal selection and procurement of cells, tissues and organs. These records will be maintained indefinitely for retrospective review. A copy of the individual source animal record should accompany the xenograft and be archived as part of the permanent medical record of the xenograft recipient. The responsible for the biomedical animal facility will notify the clinical centre in the event that an infectious agent is identified in the source animal or herd subsequent to xenograft procurement (e.g. identification of delayed onset prion-mediated disease in a sentinel animal). e) Procurement and screening of xenografts Procurement and processing of cells, tissues or organs should be performed using documented aseptic conditions designed to minimise contamination. These procedures will be conducted in facilities accredited and subject to inspection. Procedures that may inactivate or remove pathogens without compromising the integrity and function of the xenograft should be employed. Cells, tissues and organs intended for transplantation that are maintained in culture prior to transplant should be periodically screened for maintenance of sterility, including screening for viruses and mycoplasma. To ensure reproducible quality control of the procurement and screening process, all events involved in procurement of the xenograft up to the point of transplanting the tissue into the patient should be documented. 39 NEFROLOGIA. Vol. XVIII. Suplemento 7. 1998 When the animal is sacrificed during the procurement of cells, tissues or organs, a full necropsy should be conducted including gross, histopathological, and microbiological evaluation. When xenografts are procured without sacrificing the animal, the animal's health should be monitored for life. When these animals die or are euthanatised, a full necropsy should follow, regardless of the time elapsed between graft procurement and death. The animal's permanent health record, including the results of the necropsy will be archived indefinitely. In the event that the necropsy findings suggest infections pertinent to the health of the xenograft recipient(s) (e.g. evidence of prion-associated disease) the finding should be communicated to all transplant centres that have received cells, tissues or organs from this source animal. f) Archives of source animal medical records and specimens Systematically archived source animal biologic samples and record keeping allowing rapid and accurate linking of xenograft recipients to the individual source animal records and archived biologic specimens are essential for public health investigation and containment of emergent xenogeneic infections. All these records should be maintained indefinitely and samples should be banked. Responsibility for the care of, access to, archive and gathering of data should be clearly designated in the research and clinical protocol. Ideally, at least five 0,5cc aliquots of each source animal serum and plasma should be banked. At least 3 aliquots (1X107) of viable leukocytes should be cryopreserved. Optimally, DNA and RNA extracted from leukocytes should also be aliquoted and stored. Additionally, paraffin-embedded, formalin fixed, and cryopreserved tissue samples representative of major organ systems (e.g. spleen, liver, bone marrow, central nervous system), should be collected from source animals who die during the procurement of the xenograft. CLINICAL STUDIES The Xenotransplant recipient Post-transplantation clinical and laboratory surveillance of xenograft recipients is critical to monitor for the introduction and propagation of xenogeneic infectious agents in the general population. Performance and documentation of this surveillance should be the responsibility of the clinical centre and should conti40 nue throughout the life of the recipient. Appropriate surveillance methods should include the following: ­ Adverse clinical events potentially associated with xenogeneic infections should be surveyed and evaluated during periodic clinic visits following the transplant procedure. ­ Biological specimens should be collected and archived to allow retrospective investigation of possible xenogeneic infections. These specimens should be designated for public health investigative purposes. Specimens to be collected should be appropriate to the specific transplant situation. Serum, plasma, and peripheral blood mononuclear cells (PBMC's) should be collected. Preferably, at least three to five 0.5cc aliquots of citrated or EDTA-anticoagulated plasma should be banked at the predetermined time points outlined bellow. At least 2 aliquots of viable leukocytes (1X107) should be cryo-preserved. Additionally, aliquots of DNA and RNA extracted from leukocytes and/or serum should also be stored. Specimens of any xenograft that is removed (e.g. post rejection or at time of death) should also be banked. The following schedule for specimen collection is recommended: 1. Two sets of samples should be obtained one month before xenotransplantation. If this is not possible they will be obtained as temporally separated from the xenotransplant procedure as possible. 2. One set of samples should be obtained and archived in the immediate post transplant period and at approximately 1 month and 6 months post transplantation. 3. A series of samples will be obtained annually during the first 2 years after the xenotransplant procedure. 4. After that, samples should be obtained every 5 years during the remainder of the recipient's life. 5. More frequent archiving of samples may be indicated by the specific protocol or the recipient's medical course. ­ In the event of death of the recipient, snap-frozen stored at ­70º C, paraffin embedded tissue, and tissue suitable for electron microscopy should be collected at autopsy from the xenograft and all major organs related to either the transplant or the clinical syndrome resulting in death. These specimens should be archived indefinitely for potential public health use. ­ The clinical centre is responsible for maintenance, follow-up and security of the archive of biological samples. In the absence of a central facility, the designated public health biologic samples should be archived with appropriate safeguards to ensure long term storage (e.g., a monitored storage freezer alarm system and specimen archiving in separate freezers) and ensuring an efficient system for prompt RECOMMENDATIONS FOR THE REGULATION OF XENOTRANSPLANTATION IN SPAIN retrieval and linkage of data between medical records of recipients and source animals. ­ In addiction to archiving of biologic specimens, an active laboratory surveillance programme of the xenograft recipient should be instituted when xenogeneic agents are known or suspected to be present in the xenograft. This active screening is intended to detect sentinel human infections prior to dissemination in the general population. Serum, PBMC's, or tissue should be assayed at periodic intervals post transplantation for xenogeneic agents known to be present in the transplanted tissue. Active surveillance should include more frequent screening in the immediate post transplant period (e.g. 2, 4 and 6 weeks after transplantation) with subsequent decreasing frequency in the absence of clinical indication. Assays intended to detect general unknown agents may also be appropriate. Assays should also be used to detect classes of viruses known to establish persistent latent infections in the absence of clinical symptoms (e.g., herpesviruses and retroviruses). When the xenogeneic viruses have similar human counterparts (e.g., simian CMV), assays to distinguish between the two should be employed. Depending upon the degree of immunosuppression in the recipient, serological assays may or may not be useful. Methods for analysis include cocultivation of cells coupled with appropriate detection assays. The sensitibity, specificity, and validity of the testing methods should be predetermined and documented under conditions simulating those employed in the xenotransplant procedure. ­ In response to a potential xenogenic infection related to a clinical episode, post transplantation testing of archived biologic specimens should be conducted in association with an epidemiologic investigation to assess potential public health significance of the infection. This investigation should proceed under the direction of the appropriate health authorities following immediate notification to the appropriate institution. Contacs of the recipient The clinical protocol should include a procedure to inform the recipient of the responsibility to educate his/her close contacts regarding the possibility of the emergence of xenogeneic infections from the source animal species and to offer the recipient assistance with this education process, if needed. Education of close contacts should address the uncertainty regarding the risks of xenogeneic infections, information about behaviours known to transmit infectious agents from human to human (e.g., unprotected sex, intravenous drug use with shared need- les and other body fluids) and methods to minimise the risk of transmission. Recipients should educate their close contacts about the need to inform their physician and the research co-ordinator at the institution where the xenotransplantation was performed of any significant unexplained illnesses. Hospital control of infections 1. Standard precautions should be used for the care of all patients, including appropriate hand-washing, use of barrier precautions, and care in the use and disposal of needles and other sharp instruments. Strict adherence to these recommended procedures will reduce the risk of transmission of xenogeneic infections and other blood-borne and nosocomial pathogens. 2. Additional infection control or isolation precautions should be employed as indicated in the judgement of the hospital epidemiologist, infectious disease specialist and the xenotransplant team. The appropriateness of infection control measures should be considered at the time of transplant and re-evaluated during each readmission. Isolation precautions should be continued until a suspected xenogeneic infection has been proven and resolved or has been effectively ruled out in the recipient. 3. Xenotransplant teams should adhere to recommended procedures for handling and disinfection/sterilisation of medical instruments and disposal of infectious waste. 4. Acute infectious episodes. Most acute viral infectious episodes among the general population are never etiologically identified. Xenograft recipients remain at risk for these infections and other infections common among immunosuppressed allograft recipients. When the origin of a significant illness in a recipient remains unidentified despite standard diagnostic procedures, further testing of body fluid and tissue samples should be conducted. The infectious disease specialist, together with the hospital epidemiologist, the veterinarian, the clinical microbiologist and other members of the xenotransplant team should assess each clinical episode and make a considered judgement regarding the need and type of diagnostic testing and appropriate infection control precautions. Experts on infectious diseases and public health may also need to be consulted. 5. Immunosuppressed transplant patients may be unable to mount a sufficient immunological response for serological assays to detect infections reliably. In this setting, appropriate validated culture systems, genomic detection methodologies and other techniques may be necessary. Clinical centres where xe41 NEFROLOGIA. Vol. XVIII. Suplemento 7. 1998 notransplantation is performed should have the capability to culture and to identify viral agents using in vitro and in vivo methodologies. Specimens should be handled to ensure their viability and to maximise the probability of isolation and identification of these agents. Algorithms for evaluation of unknown xenogeneic pathogens should be developed in consultation with appropriate experts, including persons with expertise in both medical and veterinary infectious diseases, laboratory identification of unknown infectious agents and the management of biosafety issues associated with such investigations. 6. Archiving of acute and convalescent sera obtained during any acute unexplained illnesses should be performed when appropriate as judged by the infectious disease physician and/or the hospital epidemiologist. This would allow retrospective study and perhaps an etiologic diagnosis of the clinical episode. 7. Healthcare workers: A health program should be designed to educate workers regarding the risks associated to xenotransplantation and to monitor for possible infections in workers. Healthcare workers, including laboratory personnel, who handle the animal tissues/organs prior to transplantation will have a risk of infection not exceeding that of animal care, veterinary or abattoir workers routinely exposed to the source animal species, and consequently equivalent biosafety standards should be employed. However, the risk of healthcare workers in direct/indirect contact with xenograft recipients is undefined. Decisions regarding work restrictions or assignments for inmmunocompromised workers should be determined by each institution. The healthcare service programmes should include the following: ­ Education of healthcare workers ­ Surveillance of healthcare workers. ­ Post-exposure management and evaluation. Education of healthcare workers. All centres performing xenotransplantation procedures should develop appropriate educational materials for their staff tailored to each procedure. These programmes shall describe the xenotransplantation procedures and the known and potential risks associated to each procedure. Those activities that are considered to be associated with the greatest risk of infection should be emphasised in order to minimise exposure and transmission of both zoonotic and nosocomial agents between the recipient and the healthcare workers. The use of standard precautions should be reviewed. Education programmes should detail the circumstances for use of personal protective equipment (gloves, gowns, masks etc.) and the importance of hand-washing before and after all patient contacts, even if gloves are worn. The poten42 tial for transmission of these agents to the general public should be discussed. Surveillance of healthcare workers. Protocols should be developed for the collection and archiving of baseline sera (i.e., prior to exposure to xenografts or recipients) from healthcare workers either on the xenotransplant team or caring for xenograft recipients and any laboratory personnel who may handle the animal cells, tissues and organs or future biologic specimens from transplant recipients. Archived sera will serve as a baseline specimen for comparing sera collected following nosocomial exposures. In addition, these protocols should describe methods of recording, storing, and retrieving information related to healthcare workers and specific nosocomial exposures. The activities of the occupational health service should be coordinated with the infection control programme to ensure appropriate surveillance of infection in personnel. Post-exposure management and evaluation. Written protocols should be in place for the evaluation of healthcare workers who experience an exposure where there is a risk of transmission of an infectious agent (e.g., accidental needle stick). Healthcare workers, including laboratory personnel should be instructed to report exposures immediately to the occupational health service. The post exposure protocol should describe the information to be recorded including the date and nature of exposure, the xenotransplantation procedure, recipient information, actions taken as a result of such exposures (e.g., counselling, post exposure management and followup) and the outcome of the event. This information should be archived and maintained indefinitely at the xenotransplantation centre despite any change in employment of the healthcare worker or discontinuation of xenotransplantation procedures in the centre. Healthcare and laboratory workers should be counselled to report and seek medical evaluation for unexplained clinical illnesses occurring after the exposure. Healthcare workers Registry Each clinical xenotransplantation centre should maintain indefinitely a three cross-referenced record system: 1. An institutional xenotransplantation record with documents for all xenotransplanation procedures: the principal investigator, the individual source animal and its procurement facility, the date and type of procedure, the xenograft tissue recipient and a summary of the recipient's clinical course, close contacts, and the healthcare workers associated with each procedure. RECOMMENDATIONS FOR THE REGULATION OF XENOTRANSPLANTATION IN SPAIN 2. A xenotransplantation nosocomial health exposure log witch documents the dates, involved persons, and nature of all nosocomial exposures which are associated with a xenotransplantation protocol and which potentially pose risk of transmission of xenogeneic infections. 3. Individual xenotransplant recipient heath records which document comprehensively each patient's clinical course, the results of post-transplant surveillance studies and contain a summary of both the heath status report and the results of the scree- ning assays performed on source animal(s) from which the xenograft was obtained. These records should be current and accurately cross-referenced. This systematic data maintenance will facilitate epidemiologic investigation of adverse events. In the future, these data should be linked to any national registry to facilitate recognition of rates of occurrence and clustering of adverse heath events, including those that may represent the outcomes of xenogeneic infections and mortality patterns and linkage of those events to specific exposures on a national level.