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Pediatric and congenital hand transplantation

Amaral, Sandraa,b; Levin, L. Scottc

Current Opinion in Organ Transplantation: October 2017 - Volume 22 - Issue 5 - p 477–483
doi: 10.1097/MOT.0000000000000453
VASCULARIZED COMPOSITE ALLOTRANSPLANTATION: Edited by Christina L. Kaufman
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Purpose of review We review the approach and challenges associated with pediatric hand transplantation, including new knowledge gleaned from our recent case of bilateral hand–forearm transplantation in an 8-year old child.

Recent findings Bilateral heterologous hand–forearm transplantation was performed in a child with a prior kidney transplant in July 2015. The initial surgery necessitated a large team of experts in microvascular surgery, transplant surgery, orthopedics and plastic surgery as well as pediatric anesthesia. Medical management has highlighted the need for extensive multidisciplinary support with pediatric expertise in transplant medicine, occupational therapy and rehabilitation, neurology, and neuroradiology. The clinical course has been complicated by the need for robust immunosuppression to control ongoing, even though low-grade, and intermittent rejection. Neurological findings have demonstrated cortical neuroplasticity with reorganization of the somatosensory cortex.

Summary Heterologous hand–forearm transplantation in a child is feasible and has the potential for functional benefit to improve quality of life; however, immunological and ethical concerns warrant proceeding with caution. More data are needed to inform patient and family selection to achieve optimal functional and quality of life outcomes.

aDepartment of Pediatrics, Division of Nephrology

bCenter for Clinical Epidemiology and Biostatistics

cDepartment of Orthopaedic Surgery, Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia and the University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA

Correspondence to Sandra Amaral, MD, MHS, Department of Pediatrics, Division of Nephrology, The Children's Hospital of Philadelphia and the University of Pennsylvania, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA. Tel: +1 267 425 3934; e-mail: amarals@email.chop.edu

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INTRODUCTION

Although allogenic hand transplantation is not life-saving, its potential benefits to improved quality of life are numerous, including direct effects of restoration of function, sensation, and appearance and indirect benefits to improve socialization and reduce stigma [1]. Complications can include vascular thrombosis, skin necrosis, and surgical wound infections as well as acute graft loss. Long-term complications are primarily the sequelae of immunosuppression, such as infection, diabetes, and renal injury or chronic rejection as well as graft loss from chronic rejection.

Given the risk of complications observed in adult hand–forearm recipients and the nonlifesaving nature of the procedure, the possible extension of hand–forearm transplantation procedures to children has not yet been widely embraced by society. It has been posited that there may be greater surgical risk in children due to the smaller size and structure of the limbs, composite tissue, and vasculature. One prior case of lower extremity transplantation in a conjoined twin at 3 months of age demonstrated surgical feasibility [2]. However, that case did not require immunosuppression. The long-term sequelae of immunosuppression and risks of eventual graft rejection may be greater in children given their longer life expectancy and these concerns contribute to hesitancy in moving pediatric vascular composite allograft (VCA) transplantation forward.

In July 2015, an 8-year old African American kidney transplant recipient underwent heterologous bilateral hand–forearm transplantation at The Children's Hospital of Philadelphia (CHOP) in the United States. We recently reported on the 18-month outcomes of this child [3▪▪]. The child's case report documents the carefully planned procedure and describes the patient's clinical course, from preoperative planning to postoperative medical and therapeutic management by a large, diverse multidisciplinary team. This recent pediatric case provides many insights to inform prudent future approaches in donor and candidate selection as well as short-term and long-term management [3▪▪,4▪,5▪].

Box 1

Box 1

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TRANSPLANT EVALUATION FOR A CHILD VASCULAR COMPOSITE ALLOGRAFT CANDIDATE

The prospective pediatric candidate at CHOP underwent a transplant evaluation that spanned for approximately 18 months [3▪▪]. At 2 years of age, he had contracted staphylococcal sepsis with systemic ischemic injury, leading to quadrimembral amputation and kidney failure. Right upper limb amputation was at the radiocarpal joint. Left upper limb amputation was at the level of the distal radius. The child had failed attempts at upper extremity prostheses. He had received peritoneal dialysis at home for 2 years until undergoing a living-related kidney transplant from his mother at age 4. He had normal renal function and was maintained on a steroid-free protocol comprised of mycophenolate mofetil and tacrolimus.

Pretransplantation assessment included repeated visits with orthopedic surgery, plastic surgery, transplantation medicine, and occupational and physical therapy [3▪▪]. Preoperative occupational therapy assessment focused on child-centered functional goals for independence. The caregiver identified child goals for toileting, using clothing fasteners, brushing teeth, and cutting food. The child sought to be able to climb monkey bars and grip a baseball bat. Preoperative assessment explored cognitive endurance, ability to perform multistep directions, problem solving, and frustration tolerance – essential components of postoperative rehabilitation.

A child psychologist, pediatric transplantation pharmacist, and social worker assessed psychosocial readiness to undertake surgery and rehabilitation. The child and his mother, his primary caregiver, had demonstrated resilience through his initial critical illness, peritoneal dialysis, and kidney transplantation. No psychosocial contraindications to transplantation were identified.

The case was presented to the ethics committee and the Institutional Review Board. The relative increase in immunosuppression following VCA for this child was deemed to be an acceptable risk, given the potential benefits. The procedure was deemed novel clinical care and Institutional Review Board (IRB) exempt. In keeping with clinical practice in solid organ transplantation, the transplant team obtained informed consent and assent for transplant evaluation, listing, and surgery. Consent and assent discussions with the patient and caregiver occurred on multiple occasions throughout the evaluation and were based on available risk and benefit data from outcomes in pediatric solid organ transplant and adult VCA recipients, with clear communication regarding the large number of unknowns, including the impact on kidney allograft survival [6–10].

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SURGICAL PLANNING FOR A PEDIATRIC VASCULAR COMPOSITE ALLOGRAFT CASE

Before embarking on the first pediatric case, diverse stakeholders at CHOP and the University of Pennsylvania conducted careful planning to achieve a successful outcome and minimize complications. They implemented the operating room set-up, operational flow chart, and forearm transplant checklist that had been previously used in an adult hand transplant recipient at the University of Pennsylvania [11]. Multiple cadaver rehearsals were performed, including the design and practice with custom cutting guides for osteotomies.

Based on prior reports from replantation of severed extremities in children, transplanted limbs are expected to continue to grow as long as the bony growth plates remain intact. There is a critical need to reconstruct joints, preserve epiphyses, and minimize bone shortening as much as possible to optimize complementary growth of the donor and recipient extremities [12]. Yet, the proper size matching of donor and recipient limbs is particularly challenging in children, given significant age-related variability. Gálvez et al.[4▪] leveraged the use of computed tomography imaging studies and a three-dimensional printer to inform donor selection for the first bilateral hand–forearm transplantation in this child. Gálvez et al. generated three-dimensional anatomical models of the recipient's forearms using Mimics (Materialise, Leuven, Belgium) and then created similar models of potential donor hands using de-identified CT subjects with same sex and approximate age. The donor model depicted the bones and soft tissues from the proximal ulna epiphysis to the fingers, which was then overlaid on the patient's CT image. Volumetric scaling was applied to achieve spatial alignment of bony landmarks between the two models. The resulting modified donor model, complete with soft tissue, was then scaled up and down by 20% to create an additional two potential donor models. The three models (80, 100, and 120% scale) were then printed using an Objet Connex 500 Poly-Jet printer (Stratasys, Edina, Minnesota, USA).

In addition to optimizing sizing compatibility between the potential donor and recipient, other listing parameters included blood type, human leukocyte antigen (HLA) compatibility, skin tone, and 2-h air travel distance to reduce ischemic time. Shared maternal HLAs were also excluded to reduce the risk of inducing collateral rejection to the kidney allograft. A suitable donor became available within 3 months of listing. The surgical transplant team traveled to the donor location, visually inspected the donor hands and compared them with the printed models, enabling more precise size matching of the donor and recipient. The models later served as molds for the donor hand prostheses.

Before the surgery, the aforementioned 3-D technology had been used to customize bone-cutting guides that facilitated intraoperative efficiency and improved precision in preparation of the bone ends for osteosynthesis; this likely foreshortened the cold ischemia time (Fig. 1). In addition, the cutting guides ensured adequate bone-to-bone contact that contributes to reduced risk of osseous nonunion, a recognized challenge after hand transplantation.

FIGURE 1

FIGURE 1

Gurnaney et al. recently detailed the anesthetic and intraoperative management of the child's case. In particular, they noted how they approached obtaining adequate vascular access. This child had a right subclavian port-a-cath in situ at the time of hand transplantation due to his preexisting need for frequent bloodwork for his kidney transplant care [5▪]. In future, for pediatric hand transplant recipients who may be at risk for renal damage due to calcineurin toxicity, the preservation of vascular access for possible future dialysis is critical. In addition, postoperatively, frequent peripheral blood draws to check immunosuppressive drug levels can be challenging in children as well as pain and anxiety-provoking. A priori placement of in-situ vascular access should be strongly considered before pediatric hand transplantation.

Gurnaney et al. also describe some challenges in maintaining adequate hemodynamics in the pediatric case. Vascular composite allograft procedures generally necessitate substantial volume of blood products for volume resuscitation and hemostasis [5▪,14]. Our pediatric recipient received approximately 60 ml/kg of washed, irradiated, CMV-seronegative and leukoreduced packed red blood cells and fresh frozen plasma in the operating room. In children, a protocol for intra-operative volume management should be developed a priori to optimize hemodynamics while minimizing the use and risks of heterologous blood products to reduce the risk of future allosensitization.

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POSTOPERATIVE SURVEILLANCE AND MANAGEMENT IN A PEDIATRIC HAND–FOREARM TRANSPLANT RECIPIENT

For the pediatric case, occupational therapy posttransplantation was initiated on postoperative day 6 and focused on integration of the hands into the child's body schema and on transitioning from pretransplantation adaptive movements to using the hands to engage in daily activities [3▪▪]. Daily therapies occurred throughout the first year posttransplant. Therapies were tailored to accommodate the attention span, motivation, occupations, and emotions of the child, including time for naps and leisure breaks. Biofeedback video games, age appropriate motor imagery, and exercises using finger lights and puppets were implemented.

Medical management of the pediatric case relied on frequent skin biopsies to monitor graft rejection and laboratory tests to monitor kidney function and immunosuppressive drug levels. The child also underwent periodic structural brain MRI and magnetoencephalography (MEG) to record neural correlates of sensory responses and hand movement, and motor cortex mapping with transcranial magnetic stimulation (TMS) motor evoked potentials (MEP). The patient and his mother regularly met with the psychologist and social worker to assess and support coping with transplantation and rehabilitation, and to plan for school and social reintegration.

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EIGHTEEN-MONTH OUTCOMES AFTER THE FIRST PEDIATRIC VASCULAR COMPOSITE ALLOGRAFT

The pediatric hand–forearm recipient received thymoglobulin induction, tacrolimus, mycophenolate mofetil, and solu-medrol at the time of transplant. He experienced numerous rejection episodes of the hands over the first 18 months [3▪▪]. Although rejections were completely resolved, the child was maintained on four immunosuppressive medications, mycophenolate mofetil, tacrolimus, sirolimus, and prednisone, to maintain the grafts. The sirolimus was added to reduce tacrolimus toxicity. Notably, there has been a rise in the serum creatinine, although no proteinuria or hypertension. The child has experienced several minor infections but has not had any serious adverse events and has not developed any antibodies against the kidney or hand allografts.

Functionally, digit movement was evident within days of transplantation because the patient's extrinsic hand muscles were connected to the tendons of the transplanted hands [3▪▪]. Short bursts of small amplitude, easily fatigable movements progressed to movements supportive of self-care and leisure skills over the first year. The child was able to self-feed with his right hand by 6 months posttransplant and had bimanual coordination for scissors and crayon skills by 8 months posttransplant (Fig. 2). He could swing a bat, use his hands for dressing and was able to toilet himself without assistance by 1-year posttransplant. The child achieved scores within the normative reference range for the Box and Block Test bilaterally by 1-year posttransplant. By 18 months, functional outcomes exceeded preoperative function.

FIGURE 2

FIGURE 2

The child demonstrated cortical recovery of hand motor and primary sensory representation, including intrinsic muscle re-innervation, despite the absence of hands during a rich fine motor developmental window between the ages of 2 and 8 years. Transcranial magnetic stimulation elicited MEP from intrinsic hand muscles could be evoked in the right hand at 7 months and in the left hand by 10 months. The child experienced gradual recovery of sensory function over the first year. He adapted to the presence of the new hands within weeks, adjusting his perception of limb length and peri-personal space around the hands. By 12 months, tactile sensation over the dorsal and palmar surfaces of both hands was sensitive to a 4.08 or smaller Semmes Weinstein monofilament, above the protective sensation threshold. Corresponding to this, MEG measures of somatosensory responses to tactile stimulation of the digits showed large amplitude somatosensory evoked fields (SEFs) with typical latencies and orthotopic source localization to the primary somatosensory area in the postcentral gyrus.

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IMPLICATIONS FOR FUTURE PEDIATRIC VASCULAR COMPOSITE ALLOGRAFT CASES

The recent findings of the first pediatric VCA case highlight several unique challenges in moving forward. First, the pediatric candidate was previously immunosuppressed and his family understood the risks of immunosuppression. He has required four immunosuppressive agents to manage his hand allografts, whereas he had a functioning kidney allograft on dual immunosuppressive therapy. In children, one must consider their longer potential life years at risk of complications from immunosuppression. Pediatric solid organ transplant recipients face higher risk of developing chronic kidney disease and end-stage renal disease [6]. One must infer that similarly pediatric VCA recipients will be at greater risk for needing kidney transplantation later so minimizing allosensitization is critical. In the first pediatric candidate, shared maternal HLA antigens were avoided to minimize risk of collateral damage from antibody formation against the previous maternal kidney allograft. Also, although there is well documented benefit of tacrolimus on nerve regeneration, that may confer better intrinsic recovery, the risk of nephrotoxicity must also be considered [15–17]. There have been some protocols in adult recipients with the goal of immunosuppression reduction, including steroid withdrawal, induction of donor specific tolerance and the use of Belatacept [1]. In our pediatric case, steroid withdrawal has not been feasible. Belatacept, although promising in adult kidney transplant recipients, has not been tested for safety and efficacy in children and is not currently approved for pediatric use by the Food and Drug Administration (FDA) [18]. Thus, immunosuppression reduction, although a long-term goal, may not be feasible in the short term in children.

Another challenge in the pediatric VCA case was objectively assessing meaningful functional and quality of life outcomes. In adult hand–forearm recipients, functional outcomes are commonly assessed via tools such as The Disabilities of the Arm, Shoulder and Hand Score (DASH), the Carroll test, and the Hand Transplant Score System [19]. Unfortunately, none of these tools are validated in children. Thus, there is a critical need to find pediatric-specific validated metrics to measure and understand functional gains as these are the desired outcomes.

There are also unique psychosocial implications of VCA in children. Adult psychosocial assessment tools are not standardized; specific tools assess adaptation, body image issues, social stigma, and media attention [20]. Pediatric-specific metrics that address these constructs are limited. To inform longitudinal outcomes, pediatric measures must be responsive to developmental changes in intellectual and social maturity. Particularly for younger children, psychosocial evaluation must also include parental quality of life measures and family dynamics. In the first pediatric case, semi-structured interviews with the child and parent were conducted through the evaluation process and postoperative period and are ongoing during the long-term rehabilitation period [3▪▪]. Future cases should consider use of standardized tools so that data can be compared across small numbers of patients.

Another challenge lay in optimizing a child's engagement in rehabilitation. The first pediatric VCA recipient fatigued with therapy and required creative approaches from therapists to foster participation and attention [21]. Recent research in the use of virtual and augmented reality systems and rehabilitation robotics to create interactive rehabilitation environments may provide a unique opportunity to support neuroplasticity and cortical somatosensory reorganization in pediatric VCA candidates [22]. In the recent pediatric case, the child is being assessed longitudinally with fMRI, an imaging modality that demonstrates cortical processing during specific tasks and activities, to track progress and this approach is strongly encouraged before and after transplantation to inform targeted rehabilitation strategies.

Recently, Arthur Caplan and Duncan Purves, bioethicists, noted that ‘doctors, patients, regulators, donors, and payers need to rethink the risk and benefit ratio represented by trade-offs between saving life, extending life, and risking the loss of life due to the quality of life-enhancing transplant surgery’ [23]. As the authors point out, the greatest risk transplant recipients now face is related to the secondary adverse effects of immunosuppressives, including risks of life-threatening infections, cancer, and even organ failure. For children, there is more lifetime-at-risk for these negative effects and most likely VCA transplantation will foreshorten the child's overall length of life. However, a child also has more potential benefit from VCA transplantation, both with regard to potential functional benefit from the immature brain with greater plasticity as well as longer lifetime to benefit from enhanced social relationships and sensory experiences.

In adults, 22% of the worldwide transplanted hands have suffered graft loss [24]. Thus, the possibility of a child having to undergo amputation of the grafts is significant. However, when transplanted hands have been re-amputated, subsequent prosthetic fitting has been successful [25]. The concept of losing functioning hands may be challenging for the young child to imagine and understand as a risk. It is thus essential that clinicians and researchers disseminate positive and negative outcomes over time as this field expands [1].

The question then remains: for whom is pediatric VCA appropriate? Based on our experiences with case 1, we would suggest that a child be a minimum of age 8 at time of transplant to be able to successfully engage in the exhaustive rehabilitation demands. We would also be reluctant to incur the adverse effects of immunosuppression and potential nephrotoxicity with chronic kidney disease (CKD)/end-stage renal disease (ESRD) development for unilateral hand transplantation in a child at this time [26]. We agree with prior authors that candidates should only be considered for hand transplantation after failure of previous prosthesis trials [20].

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CONGENITAL HAND ANOMALIES

With surgical interventions to congenital anomalies of the hand, the goals are primarily to improve function and appearance of the hand. A recent review of 19 children who underwent autologous toe-to-hand transfers in a single center in the United Kingdom reported very positive outcomes for motor and sensory functional improvements [27]. Sixteen of the 19 children underwent 31 toe-to-hand transfers for a variety of congenital anomalies of the hand, including symbrachydactyly, constriction ring syndrome, intrauterine amputation, and transverse growth arrest and three children had experienced prior traumatic amputations. The majority of physes in the transferred toes remained open with near normal longitudinal growth. Despite the limited range of motion, functional outcomes were quite positive.

Multiple studies demonstrate the feasibility of improved quality of life and hand function with autologous tissue for several common congenital deficits of the hands and arms. Knowing the robust immunosuppression required for heterologous hand–forearm transplant and its attendant risks, the available evidence would not support heterologous VCA for these defects at this time. However, as surgical approaches, such as toe-to-hand transfers, advance, these procedures may confer even greater aesthetic and functional benefits with potentially lower rates of complications. Of course, these reconstructive options assume that there are autogenous donor sites, such as lower extremities, that can provide autologous tissues. In quadrimembral amputees, this is not possible. Over time, better understanding of allogenic immunologic responses to VCA tissue may enable minimization of immunosuppression. Thus, clinicians considering hand autologous microsurgical reconstruction versus transplantation must continue to re-assess risk–benefit ratios as scientific progress in both these arenas advances.

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CONCLUSION

Recently, a child received a heterologous bilateral hand–forearm transplantation and his 18-month functional outcomes exceeded his preoperative function. This case illustrates how careful planning by a multidisciplinary team of pediatric experts in microvascular surgery, orthopedics, transplant medicine, nephrology, rehabilitation and occupational therapy, psychology, and social work can make pediatric VCA feasible. Future efforts are needed to refine donor and patient selection criteria, develop pediatric validated tools for functional and quality of life outcomes and explore approaches toward tolerance and immunosuppression minimization.

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Acknowledgements

The authors acknowledge the first pediatric hand–forearm transplant recipient and his mother for embarking on this novel surgical and medical pathway, permitting us to study his clinical course and disseminate our findings.

The authors also acknowledge the CHOP VCA Working Group members who have contributed to the thoughtful surgical, medical and psychosocial care of the first pediatric hand transplant recipient.

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Financial support and sponsorship

The surgical and clinical care of the pediatric hand–forearm transplantation recipient was supported by The Children's Hospital of Philadelphia.

S.A. is supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (K23DK083529, R03DK099486 and R01DK110749).

L.S.L. is supported by The Hansjorg Wyss Fund and the Department of Defense.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. Shores JT, Malek V, Lee WA, Brandacher G. Outcomes after hand and upper extremity transplantation. J Mater Sci 2017; 28:72.
2. Fattah A, Cypel T, Donner E, et al. The first successful lower extremity transplantation: 6-year follow-up and implications for cortical plasticity. Am J Transplant 2011; 11:2762–2767.
3▪▪. Amaral S, Kessler S, Levy T, et al. 18 Month outcomes of heterologous bilateral hand transplantation in a child: a case report. Lancet 2017.

This manuscript describes the surgical and medical management and 18-month outcomes of the first successful heterologous bilateral hand–forearm transplant in a child.

4▪. Gálvez JA, Gralewski K, McAndrew C, et al. Assessment and planning for a pediatric bilateral hand transplant using 3-dimensional modeling: case report. J Hand Surg 2016; 41:341–343.

This manuscript describes how 3D printing technology was leveraged to optimize the surgical case of the first pediatric bilateral hand–forearm transplant recipient.

5▪. Gurnaney HG, Fiadjoe JE, Levin LS, et al. Anesthetic management of the first pediatric bilateral hand transplant. Can J Anesth 2016; 63:731–736.

This article describes the anesthetic management on the first pediatric bilateral hand-forearm transplant recipient.

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25. Ungar L. Louisville doctors remove transplanted hand. Courier Journal: part of the USA Today Network. 2014. http://www.courier-journal.com/story/news/local/2014/12/01/louisville-doctors-remove-transplanted-hand/19753277/. [Accessed June 10, 2017].
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Keywords:

hand transplantation; pediatric; vascular composite allografts

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