Overview of Guidelines for Establishing a Face Transplant Program: A Work in Progress

Since 2005, nine face transplants have been performed in four countries: France, the United States (US), China and Spain. These encouraging short‐term outcomes, with the longest survivor approaching 5 years, have led to an increased interest in establishing face transplant programs worldwide. Therefore, the purpose of this article is to facilitate the dissemination of relevant details as per our experience in an effort to assist those medical centers interested in establishing a face transplant program. In this article, we address the logistical challenges involved with face transplantation; including essential program requirements, protocol details, face transplant team assembly, project funding, the organ procurement organization and the coroner. It must be emphasized that face transplantation is still experimental and its therapeutic value remains to be validated. All surgical teams pursuing this endeavor must dedicate an attention to detail and should accept a responsibility to publish their outcomes in a transparent manner in order to contribute to the international field. However, due to its inherent complexity, facial transplantation should only be performed by university‐affiliated medical institutions capable of orchestrating a specialized multidisciplinary team with a long‐term commitment to its success.     

Informed consent for facial transplantation

Now that partial face transplantation has been performed, attention is focused on likely functional, aesthetic and immunological outcomes, and full facial transplantation is the likely next step. Facial transplantation has been the source of ethical debate, a key part of which focuses on valid informed consent. We review the process of informed consent in health settings, assessing how applicable the current standards are for facial transplantation. The factors which need to be assessed during the screening programme are outlined. We conclude that both individual and process factors are important in obtaining consent for radical new procedures, and outline our own gold standard for ensuring informed consent in facial transplantation.     

Trauma-Management beim organtransplantierten Patienten

Due to improvements in allograft and patient survival after organ transplantation, the probability to be confronted with these patients and their complex pathophysiological processes as an emergency physician in the emergency room after traumatic injuries has also risen. Due to immunosuppression and alterations to anatomical relationships there are special risks after organ transplantation, which must be taken into consideration in the initial emergency treatment as well as in the further inpatient and outpatient treatment. For initial evaluation of the graft function and during the course of treatment, close monitoring by clinical examinations, laboratory parameters and radiographic examinations is critical; however, retrospective data analyses have demonstrated that overall outcomes following injury in organ transplant recipients are basically no worse than outcomes in non-transplanted individuals.     

Pancreatic Transplantation: 2. Surgical technique and post-operative complications

Since the first pancreatic allograft in 1966, pancreatic transplantations have been performed by numerous surgical teams throughout the world. Initial results were disappointing with a high percentage of technical failures and rejection. Over-optimistic enthusiasm for islet-cell allografts also retarded the development of pancreatic transplantation. Despite this slow start, results of pancreatic transplantation from 1995 onward have been very satisfactory and equivalent to or even better than the results of other solid organ transplants. This success has been due to better graft selection, improved surgical techniques and preservation solutions, and especially to improvements in immunosuppressive protocols. More than 19,000 pancreatic transplantations have now been performed throughout the world including both combined kidney-pancreas transplantations and pancreas-only transplantations. The most satisfactory results occur in the setting of dialysis-dependent renal failure due to diabetes; simultaneous combined kidney and pancreas transplantation is performed with the total pancreas implanted into the bowel and with venous drainage into the portal system. The long-term risks and constraints of chronic diabetes with renal failure must be weighed against the risks of a complex surgical procedure, significant post-operative complications, and the need for long-term immunosuppressive therapy.     

Immunosuppression in an emerging field of plastic reconstructive surgery: composite tissue allotransplantation.

Composite tissue transplantation (CTA) refers to the transplantation of an allograft consisting of heterogeneous cadaveric tissues. It provides a means of restoring structural, functional and aesthetic form in severely injured patients. Recent progress in facial transplantation has highlighted the immense strides made in this field of reconstructive surgery. However the potential for improvements in quality of life must be offset by the need for life-long immunosuppression in adults with non life-threatening injuries. The benefits and difficulties of immunosuppressive drugs have been established in solid organ transplantation. Regimens derived from renal transplantation have been successfully applied to CTA. However the published incidence of complications seen in organ transplant recipients may not be easily extrapolated to potential CTA candidates and may be overstated. Accepted views that high dose immunosuppression would be needed to overcome highly antigenic tissues such as skin have not been borne out by clinical experience. It is therefore important to assess the current state of affairs, attempt to quantify the perceived risks and explore novel research methods being investigated. In doing so one can make a well-informed judgment of the potential benefit of this surgical modality as an integral part of the reconstructive ladder.     

What is the true significance of donor-related cytomegalovirus transmission in the setting of facial composite tissue allotransplantation?

Face transplantation (FT) is fraught with complications parallel to solid organ transplantation (SOT). As such, donor-related cytomegalovirus (CMV) transmission remains one of the most commonly feared viruses associated with FT. With this in mind, a review of the literature seemed justified, knowing that two of the first four face transplant recipients acquired CMV donor-related viral infection. Although the risk of CMV transmission is acceptable in the setting of SOT, the scenario for those composite tissue allotransplantation (CTA) patients, who are often young and healthy, may be different. Experiences from France and Cleveland have both confirmed suboptimal events related to CMV transmission following transplantation. Therefore, using the information provided here, it is imperative that all FT teams remain aware of these potential risks. Furthermore, all patients pursuing facial CTA should be fully informed as to the risks of donor-related CMV transmission, understand the importance of prophylaxis, and be aware of alternative therapies required to prevent symptomatic disease.     

Restoration of Facial Form and Function After Severe Disfigurement from Burn Injury by a Composite Facial Allograft

Composite facial allotransplantation is emerging as a treatment option for severe facial disfigurements. The technical feasibility of facial transplantation has been demonstrated, and the initial clinical outcomes have been encouraging. We report an excellent functional and anatomical restoration 1 year after face transplantation. A 59‐year‐old male with severe disfigurement from electrical burn injury was treated with a facial allograft composed of bone and soft tissues to restore midfacial form and function. An initial potent antirejection treatment was tapered to minimal dose of immunosuppression. There were no surgical complications. The patient demonstrated facial redness during the initial postoperative months. One acute rejection episode was reversed with a brief methylprednisolone bolus treatment. Pathological analysis and the donor's medical history suggested that rosacea transferred from the donor caused the erythema, successfully treated with topical metronidazol. Significant restoration of nasal breathing, speech, feeding, sensation and animation was achieved. The patient was highly satisfied with the esthetic result, and regained much of his capacity for normal social life. Composite facial allotransplantation, along with minimal and well‐tolerated immunosuppression, was successfully utilized to restore facial form and function in a patient with severe disfigurement of the midface.     

Feasibility,Reproducibility, Risks and Benefits of Face Transplantation: A Prospective Study of Outcomes

Composite tissue allotransplantations can be indicated when autologous transfers fail to restore human appearance. We report the reproducibility, difficulties, serious adverse events and outcomes of our patients. Five patients were included in a registered clinical research protocol after thorough screenings assessed by an independent expert committee systematically discussing the alternative options. One patient suffered from plexiform neurofibromas, two from third degree burns and two from gunshot injuries. They were included on a national waiting list with a dedicated face procurement procedure. Transplants were harvested from heart beating brain‐dead donors before other tissues and organs. Induction immunosuppressive therapy included antithymocyte globulins, steroids, mycophenolate mophetil and tacrolimus. Maintenance therapy included the last three ones associated with extracorporeal‐photopheresis. Four patients were transplanted with 7‐ to 38‐month follow‐up. One could not due to multiple panel reactive antibodies after 18 months on waiting list. Acute cellular rejections were controlled by conventional treatment. Opportunistic infections affected all patients and lead one patient to die two month after the transplantation. Voluntary facial activity appeared from 3 to 5 month. Face transplantation has been reproducible under conventional immunosuppression. Major improvements in facial aesthetic and function allowed patients to recover social relations and improved their quality of life.     

Lipografting: autologous fat grafting for total facial rejuvenation

Surgeons who perform facial rejuvenation procedures have long recognized the importance of volume enhancement. The primary manifestation of aging is loss of subcutaneous tissue, especially the atrophy of fat, which directly contributes to laxity of skin. Autologous fat transplantation has been attempted for over a century with varying degrees of success but more recent techniques have provided more predictable, reproducible, and even permanent results. Fat is an ideal tissue filler substance because it is living tissue and because it is from the patient's own body it is nonallergenic. My technique has evolved over an 11-year period in more than 1800 patients. The procedure can be performed alone as a total facial rejuvenation or in combination with facelift or other facial surgery. The technique requires minimally traumatic fat harvesting, fat preparation, and multilevel facial infiltration. Excess fat not used in the initial procedure is frozen and stored at -16 degrees C and can be used successfully for minor touch-up procedures. Preoperative evaluation of the patient and their understanding of the benefits and limitations of volume restoration surgery is imperative. Structural improvement to the main support areas of the face in the appropriate aesthetic proportions is of prime importance.     

Considerations in retransplantation of the failed renal allograft recipient

Routine success in kidney transplantation has significantly improved the quality and length of life for the majority of recipients and made this option the treatment of choice for suitable candidates. Improved patient survival combined with a relative static improvement in long-term graft outcomes has led to an increasing number of transplant recipients with failed allografts who face the eventual option of either returning to dialysis or seeking retransplantation. Although retransplantation is presumed to be a favorable option for many, data to support this belief is limited. Given the wide variance in predicted outcomes for retransplantation, on the basis of the underlying kidney disease and other individual patient comorbidities as well as the expected wait time for a second transplant, each case should be evaluated independently. This review discusses available data and individual considerations that should be taken into account when retransplantation is proposed after failure of a primary allograft.     

Facial restoration by transplantation

Hundred years ago, Sir Harold Gillies laid a foundation to the modern plastic surgery trying to reconstruct facial defects of severely disfigured soldiers of World War I. Some years later, Joseph Murray experimented with rejection of skin grafts aimed for treatment of burned patients who sustained their injuries on battlefields of World War II. In 1954, the acquired expertise and intensive research allowed him to perform the first successful kidney transplantation in the world at Peter Bent Brigham Hospital in Boston. For his achievements in organ transplantation he was awarded Nobel Prize in 1990. The face transplantation appears to be a natural evolution of the work of these two extraordinary plastic surgeons. The first case of partial face transplant from 2005 in France revealed the world that facial restoration by transplantation is superior to conventional reconstruction methods. Since 2009, our team has performed 7 cases of face transplantation at Brigham and Women's Hospital, which is to our best knowledge the largest living single center face transplant cohort in the world. In this article, we want to reflect on the experience with face transplantation at our institution from the past years. We aim to briefly review the key points of the know-how which was given to us from the care of these unique patients.     

From experimental rat hindlimb to clinical face composite tissue allotransplantation: historical background and current status

The purpose of this article is to review the historical background and clinical status of composite tissue allotransplantation and to discuss the scientific evolution of clinical face transplantation. Composite tissue allotransplantation (CTA) rapidly progressed in the 1980s with the discovery of cyclosporine. Although the most success has been achieved with hand transplantation, others have made progress with allografts of trachea, peripheral nerve, flexor tendon apparatus, vascularized knee, larynx, abdominal wall, and most recently, partial face. The world's first partial face allotransplantation occurred in November 2005 in France. In April of 2006, there was a second performed in China. As of today, there are now multiple institutions with plans to attempt the world's first full facial/scalp transplant. Complete facial/scalp allotransplantation offers a viable alternative for unfortunate individuals suffering severe facial disfigurement and is a product of many decades of experimental research, beginning with rat hindlimb allografts.     

Cost Analysis of Conventional Facial Reconstruction Procedures Followed by Face Transplantation

For the first time, this study analyzes the cost of multiple conventional reconstructions and face transplantation in a single patient. This patient is a 46‐year‐old female victim of a shotgun blast resulting in loss of multiple functional and aesthetic subunits. For over 5 years, she underwent multiple conventional reconstructions with suboptimal results. In December 2008, she became the recipient of the first U.S. face transplant. This has provided the unique opportunity to present the cost of 23 separate conventional reconstructive procedures and the first face transplant in the United States. The combined cost of conventional reconstructive procedures and the first U.S. face transplant was calculated to be $353 480 and $349 959, respectively. The combined cost posttransplant totaled $115 463. The direct cost pretransplant was $206 646, $232 893 peritransplant and $74 236 posttransplant. The two largest areas of cost utilization were surgical ($79 625; 38.5%) and nursing ($55 860; 27%), followed by anesthesia ($24 808; 12%) and pharmacy ($16 581; 8%). This study demonstrates that the cost of the first U.S. face transplant is similar to multiple conventional reconstructions. Although the cost of facial transplantation is considerable, the alleviation of psychological and physiological suffering, exceptional functional recovery and fulfillment of long‐lasting hope for social reintegration may be priceless.     

The Helsinki approach to face transplantation

Aim

We herein describe the establishment of the Helsinki Vascularized Composite Allotransplantation (VCA) program and its execution in the first two face transplant cases.

Facial transplantation and immunosuppressed patients: a new frontier in reconstructive surgery

Composite tissue transplantation in reconstructing complex facial defects has developed tremendous interest over the recent years, since the first report of partial face transplantation performed in France in 2005. However, the controversy over the ethical, immunological, and psychological issues remains. Recently, we obtained IRB approval to perform partial face transplantation at Brigham & Women's Hospital, Boston. Here we present the rationale and IRB application process of our unique approach to this highly controversial procedure, which focuses on partial face transplantation on patients currently on immunosuppressants due to previous transplanted organ. 'Patient selection criteria', selection process, technical and immunological protocols are discussed. We currently share the concern that life-long immunosuppression associated with facial transplantation may not outweigh its benefits as compared to the alternative reconstructive methods. We asked ourselves the question of which patient population would risk less and overall benefit more from undergoing face transplantation, and identified those currently on immunosuppressive therapy the most suitable candidates. Organ transplant recipients are at increased risk of malignancy, particularly skin cancer commonly located in the facial region, necessitating surgical resection and facial reconstruction. They also have to take immunosuppressants to prevent rejection of their primary transplanted organ, which will minimize the need for additional immunosuppression associated with facial allograft. Being a previous organ recipient also diminishes the difficulty of complying with the strict postoperative immunosuppressive regimen, commonly encountered by organ transplant recipients. This approach could be very beneficial for previously immunosuppressed patients and perhaps take its place in our reconstructive ladder options.     

Psychosocial considerations in facial transplantation

The human face and facial transplantation have long captured the interest and imagination of scientists, the media and the lay public. The face is central to our identity, and our communication with the outside world. It is this great importance we attach to our face that makes facial disfigurement such a devastating condition. Facial transplantation could provide an excellent alternative to current treatments for facial disfigurement caused by burns, trauma, cancer extirpation or congenital birth defects. Herein we discuss some of the principal psychosocial considerations which have preceded the clinical introduction of facial transplantation, and which continue today after cases have been performed world-wide.     

The role of therapeutic apheresis in high immunologic risk renal transplantation: a review of current trends

Immunologic sensitization, defined by the presence of antibodies directed against donor human leukocyte antigen (or so called donor-specific antibodies [DSA]), is common among those awaiting kidney transplantation, and is associated with worse outcomes following transplant. Existing DSA have historically been screened for pretransplant using complement-dependent cytotoxic crossmatching and their risk circumnavigated through policies that prohibit transplants between incompatible donor-recipient pairs. This risk avoidance strategy maximizes outcomes following transplant, but at the expense of limiting access to transplant for sensitized individuals. Over the last decade, the field of kidney transplantation has moved to actively modify the risks posed by DSA, rather than to simply avoid them. More sensitive detection methods have provided detailed immunologic risk stratification of potential donor-recipient pairs. Desensitization protocols, in which therapeutic aphaeresis plays a central role, have been used to reduce the potential harms posed by DSA. More recently, desensitization and paired donor exchange programs have been used in combination to expand transplantation to highly sensitized patients with incompatible living donors. It is likely that this combination of risk mitigation and avoidance strategies will be used together more often to both maximize individuals' access to transplant, and optimize patient and graft outcomes.     

Hand transplantation: comparisons and observations of the first four clinical cases

Twenty, 15, and 8 months after the first four successful human hand transplant procedures were performed in Lyon (France), Louisville (U. S.), and Guangzhou (China), the transplant teams convened in Louisville, Kentucky, to share their experiences at the Second International Symposium on Composite Tissue Allotransplantation. This article presents reconstructive and immunological data from these landmark procedures in tabular format, in an attempt to answer some key questions about early outcomes of clinical hand transplantation. On the basis of these data, the initial outcomes of the first four hand transplants are encouraging and warrant proceeding with additional hand transplantations.     

Osteocutaneous face transplantation.

BACKGROUND: Facial transplantation has the potential to become a viable option in the treatment of acquired and congenital facial deformities. Transplantation of the bony maxillofacial skeleton with the soft tissues (osteocutaneous face transplantation) has not been performed clinically nor has it been described experimentally in a human cadaver model. METHODS: A mock osteocutaneous face transplant procedure was carried out on a cadaver model. The face was harvested in the subperiosteal plane and included the Le Fort III osseous segment. The allograft was inset by rigid internal fixation and soft tissue approximation. RESULTS: The face transplant procedure was technically feasible. On the basis of this experiment, review of prior investigations, and our experience in craniofacial surgery, the authors have identified 10 topics that present technical challenges specific to osteocutaneous transplantation of the face: customisation of the bony segment, sensory and motor innervation, extra-ocular movements, dentition, mastication, speech and swallowing, airway, vascular considerations, immunologic considerations, and identity issues. CONCLUSIONS: Once further advances in immunomodulatory therapy are made, face transplantation will likely still be reserved for only the most severe facial defects. Defects of such severity will likely include a substantial bony component in need of reconstruction. In addition to the challenges associated with facial allo-transplantation in general, there are many technical challenges associated specifically with osteocutaneous face transplantation. It is necessary to consider and discuss these challenges in anticipation of future advances that may allow composite face transplantation to become safe and clinically efficacious. This modality of transplantation has the potential to provide substantial benefit compared with autologous reconstruction.     

Establishing the Feasibility of Face Transplantation in Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis) is a rare vasculitis that commonly starts in the craniofacial region. We report a case that was masked by prior facial trauma and associated with pyoderma gangrenosum (PG). Disease progression and aggressive debridements led to severe facial tissue loss. The decision to perform a face transplant was controversial because of the risk of disease relapse on the facial allograft. We reviewed renal transplant outcomes in GPA for possible relevance. A PubMed search retrieved 29 studies. Patient and graft survival, relapse, morbidity, mortality, rejection and immunosuppression were assessed. Ten‐year patient survival and graft survival were 84.4% and 72.6%, respectively. GPA relapse occurred in 31.5%, and upper airway/ocular relapse occurred in 17.8% (resolved in 76.9%). Mortality was 12.3%. Acute and chronic rejection rates were 14.9% and 6.8%, respectively. Traditional posttransplant immunosuppression was effective. Our review suggests that GPA renal transplant outcomes are comparable to general renal transplant cohorts. Furthermore, transplanted GPA patients exhibit lower disease relapse secondary to lifelong immunosuppression. This supported our decision to perform a face transplant in this patient, which has been successful up to the present time (1‐year posttransplantation). Untreated GPA and PG are potential causes of worse surgical outcomes in the craniofacial region.