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The International Registry on Hand and Composite Tissue Transplantation

Petruzzo, Palmina1,9; Lanzetta, Marco2; Dubernard, Jean-Michel1; Landin, Luis3; Cavadas, Pedro3; Margreiter, Raimund4; Schneeberger, Stephan4; Breidenbach, Warren5; Kaufman, Christina5; Jablecki, Jerzy6; Schuind, Frédéric7; Dumontier, Christian8

doi: 10.1097/TP.0b013e3181ff1472
Clinical and Translational Research

Background. The International Registry on Hand and Composite Tissue Transplantation was founded in May 2002, and the analysis of all cases with follow-up information up to July 2010 is presented here.

Methods. From September 1998 to July 2010, 49 hands (17 unilateral and 16 bilateral hand transplantations, including 1 case of bilateral arm transplantation) have been reported, for a total of 33 patients. They were 31 men and 2 women (median age 32 years). Time since hand loss ranged from 2 months to 34 years, and in 46% of cases, the level of amputation was at wrist. Immunosuppressive therapy included tacrolimus, mycophenolate mofetil, sirolimus, and steroids; polyclonal or monoclonal antibodies were used for induction. Topical immunosuppression was also used in several cases. Follow-up ranges from 1 month to 11 years.

Results. One patient died on day 65. Three patients transplanted in the Western countries have lost their graft, whereas until September 2009, seven hand grafts were removed for noncompliance to the immunosuppressive therapy in China. Eighty-five percent of recipients experienced at least one episode of acute rejection within the first year, and they were reversible when promptly treated. Side effects included opportunistic infections, metabolic complications, and malignancies. All patients developed protective sensibility, 90% of them developed tactile sensibility, and 82.3% also developed a discriminative sensibility. Motor recovery enabled patients to perform most daily activities.

Conclusions. Hand transplantation is a complex procedure, and its success is based on patient's compliance and his or her careful evaluation before and after transplantation.

1 Department of Transplantation, Hopital Edouard Herriot, Lyon, France.

2 Italian Institute of Hand Surgery, Monza, Italy.

3 Pedro Cavadas Foundation, “La Fe” University Hospital, Valencia, Spain.

4 Department of General and Transplantation Surgery, Universitatsklinik fur Chirurgie, Innsbruck, Austria.

5 Kleinert Kutz and Associates and Christine M. Kleinert Institute for Hand and Microsurgery, Louisville, KY.

6 Pododdzial Replantacji Konczyn, Szpital sw. Jadwigi Slaskiej w Trzebnicy, Wroclaw, Poland.

7 Department of Orthopaedics and Traumatology, Erasme University Hospital, Brussels, Belgium.

8 Unité de Chirurgie du membre superieur. Serv. de Chirurgie Orthopedique, Hopital St Antoine, Paris, France.

The authors declare no conflict of interest.

9 Address correspondence to: Palmina Petruzzo, M.D., Ph.D., Department of Transplantation, Hopital Edouard Herriot, 5, place d'Arsonval, 69437 Lyon, France.

E-mail: petruzzo@medicina.unica.it

All the authors have performed the study and reported the data of their patients; P.P. collected the data and wrote the article; and L.L. helped in the preparation of the article.

Received 29 July 2010. Revision requested 27 August 2010.

Accepted 22 September 2010.

The International Registry on Hand and Composite Tissue Transplantation (IRHCTT) was founded in May 2002, 4 years after the first hand allotransplantation performed in September 1998 (1), and at present, it includes 33 patients corresponding to 49 cases of upper extremity transplantations, 16 bilateral and 17 single transplantations that have been performed all over the world.

The purpose of the Registry is to collect detailed information on a voluntary basis from every case of hand transplantation providing a unique opportunity for centers performing composite tissue allotransplantation (CTA) to share their experience. Moreover, the Registry allows to inform the scientific community what is happening in this new field of transplantation.

One of the main issues in CTA is to establish the risk benefit ratio in reconstructive transplant procedures. Therefore, the IRHCTT collects data regarding functional recovery using different systems, such as Hand transplantation score system (HTSS) and the disabilities of the arm, shoulder, and hand (DASH) score (2, 3), and all complications. The analysis of all cases with follow-up information up to July 30, 2010 is presented here.

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RESULTS

Only one patient, who simultaneously underwent bilateral hand transplantation and face transplantation, died from cerebral anoxia as a result of obstruction of airways on day 65. Three patients transplanted in the Western countries have lost their graft: a case of bilateral hand transplantation lost the right hand for a bacterial infection on day 45, another patient lost his grafted hand for intimal hyperplasia on day 275, and a patient was amputated of his grafted hand 29 months after the transplantation as he was not compliant to the immunosoppressive regimen. Seven hand grafts have been removed until September 2009 in China, and in all cases, the cause was noncompliance to the immunosuppressive therapy because of abstention from therapy, long distance from the transplantation center, and unreported episodes of acute rejection (AR).

Rejection episodes were at first suspected by visual inspection of the transplanted hands and confirmed by histologic evaluation of a skin biopsy. The episodes of rejection were always characterized by cutaneous lesions, which usually started with faint, hardly visible pink macules that may progress to red infiltrated lichenoid papules with or without edema of the upper limb. Banff CTA score (4) was used to evaluate the severity of the rejection, and the median grade of rejection value was 2, ranging from 1 to 4.

Twenty-eight patients (85%) presented at least 1 episode of AR in the first year after transplantation: 15 of them presented only 1 episode, 7 presented 2 episodes, 3 presented 3 episodes, 2 presented 4 episodes, and 1 presented 5 episodes. The events often occurred when patients were not compliant to the immunosuppressive regimen or the latter was decreased for various reasons (i.e., side effects or team decision). It is important to remark that the AR episodes were reversible in all compliant patients when they were promptly reported and treated.

Treatment of rejection episodes included high-dose intravenous steroids (60% of cases); increase in oral steroid treatment (30%); and antithymocyte globulins, basiliximab, or alemtuzumab (7.5%) in the steroid-resistant episodes of AR. In addition, tacrolimus and corticosteroid ointment administered alone or in combination in 95% of cases displaying signs of rejection.

Although no case of chronic rejection was declared to the Registry, one case of single hand transplantation showed intimal hyperplasia of graft vessels with acute ischemia of the extremity and consequent amputation on day 275, after four untreated episodes of AR. No graft versus host disease was reported from any team.

The functional results achieved in the unilateral and bilateral hand transplantations are shown in Figures 1 and 2 where only the recipients (n=31) with a follow-up of at least 1 year were included. All patients developed protective sensibility, 30 of them (90%) developed tactile sensibility, and 28 (84%) also developed discriminative sensibility (8 patients: S3, 12 patients: S3+, and 8 patients: S4 according to Highet scale modified by Dellon et al. [5]).

FIGURE 1.

FIGURE 1.

FIGURE 2.

FIGURE 2.

Motor recovery began with extrinsic muscle function, allowing all patients to perform grip and pinch activities. Recovery of intrinsic muscles was observed only at a later stage, starting between 9 and 15 months posttransplantation in the majority of patients. This was also confirmed by electromyographic studies in several hands. Extrinsic and intrinsic muscle recovery enabled patients to perform most daily activities, including eating, driving, grasping objects, riding a bicycle or a motorbike, shaving, using the telephone, and writing. When performed, functional magnetic resonance imaging (MRI) demonstrated that after transplantation, the hand representation regained the cortical site that corresponds to the hand knob area in normal subjects.

Patient quality of life improved in more than 75% of the recipients, and going back to work has been a consistent feature for the majority of them. The velocity of sensorymotor recovery was correlated to the level of amputation although the case of bilateral arm transplantation showed a score of 79.5 points (HTSS) on both sides and a DASH score of 37.93 after only 1 year, experiencing a certain difficulty to perform a precision grip.

Complications requiring additional surgical interventions were arterial thrombosis (n=2) and venous thrombosis (n=1) in the first postoperative day, early postoperative necrosis of a small skin area (n=6), and the occurrence of multiple arterio-venous fistulae (n=1). All these events were treated successfully. All the complications correlated to the immunosuppressive treatment are reported in Table 1. One patient presented serum sickness because of antithymocyte globulins treatment. The majority of the recipients experienced opportunistic infections including cytomegalovirus reactivation, with three cases presenting clinical signs of infections, Clostridium difficile enteritis, herpes simplex blisters, herpes zoster, cutaneous mycosis, ulnar osteitis (by Staphylococcus aureus), and bacterial infection of connective tissues of the grafted hands. In addition, 69% of the recipients presented metabolic complications such as transient hyperglycemia (in three cases, it was not reversible and the patients needed hypoglycemic agents), increased serum creatinine values with a single case of end-stage renal disease and consequent hemodialysis 8 years after the hand transplantation, arterial hypertension, Cushing's syndrome, and aseptic necrosis of hip with bilateral replacements. In the follow-up, one patient developed a posttransplant lymphoproliferative disease, and another one developed a basal cell carcinoma of nose.

TABLE 1

TABLE 1

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DISCUSSION

Since 2002, several reports on the IRHCTT have been already published (6–8). At present, it includes 33 patients corresponding to 49 allografts, 16 bilateral, and 17 single transplantations. The Registry offers the unique opportunity to have a complete view of this new procedure and the possibility to study its evolution. The results showed that hand transplantation is technically feasible with encouraging functional results, and in 2008, the first bilateral arm transplantation was successfully performed. However, it is important an exhaustive pretransplantation study of the recipient to avoid some surgical and infectious complications being hand transplantation the result of a complex reconstructive operation and a long-life immunosuppressive treatment. Thus, the Registry recommends a careful study of stumps (MRI or computed tomography scan, angiography or angio-MRI, muscle, and nerve chart), psychologic evaluation and check up for infections (particularly in case where burn or crush was the cause of amputation), malignancies, renal, or metabolic diseases.

The most common maintenance immunosoppressive regimen used in hand transplantation was low dose of steroid, tacrolimus, and mycophenolate mofetil (MMF); in the follow-up, several teams changed or reduced the treatment to avoid side effects, such as hyperglycemia or increase in serum creatinine values as in solid organ transplantation. In some cases, the teams decided to decrease the immunosoppressive regimen as the recipients did not show any sign of rejection for several years. The switch from tacrolimus to sirolimus was performed to avoid metabolic complications and malignancies.

Although the immunosuppressive drugs currently used in solid organ transplantation were indispensable to ensure graft viability, the majority of patients experienced at least one episode of AR. On the other side, it is important to note that the diagnosis of AR in hand transplantation is easier than in organ transplantation because it is based on visual inspection and skin biopsy, thus explaining the high rate of AR episodes reported in this field of transplantation. Therefore, a constant watch over the grafts and periodic biopsies are recommended. The choice of AR treatment is based on the Banff score grade, the frequency of the episodes, and the sensibility to steroid treatment. In the majority of cases, the episodes were reversed increasing oral steroid dose or using intravenous steroids plus local immunosuppressants. The early diagnosis and the prompt treatment of the AR episodes are indispensable to avoid graft loss.

Currently, no case of chronic rejection has been reported to the Registry; however, one patient presented acute ischemia of the transplanted hand, which was removed and showed intimal hyperplasia of the vessels. Myointimal proliferation of vessels is one of the classic features of chronic rejection; consequently, it might be considered as the first case of chronic rejection.

The majority of the reported side effects were infections and metabolic complications. Most of them were transient and reversible, and perhaps, some of them might be avoided using lower doses of immunosuppressive drugs or changing them and performing a long-term prophylaxis for Candida, Pneumocystis carinii, and cytomegalovirus (9). One patient required hemodialysis as he developed end-stage renal disease also because of calcineurin inhibitors (indeed increases in creatinine values are often correlated to the high doses of tacrolimus). For this reason, four patients were switched to sirolimus, and other two patients received low dose of tacrolimus and everolimus. Hyperglycemia is a common side effect reported by several teams in the first period after the transplantation, and it is probably because of the high doses of steroid and tacrolimus. Other two recipients developed a malignancy, which was treated successfully. Hand allotransplantation as other CTAs is limited by the current need for long-life multidrug immunosuppression to prevent rejection. Several experimental studies tried to induce tolerance administrating bone marrow in the form of vascularized bone graft with demonstration of bidirectional trafficking of bone marrow cells between donor and recipient. The question how this strategy can be translated into a clinical trial remains to be addressed; indeed, the administration of donor bone marrow cells in some cases of CTAs did not induce tolerance (10). At present, further researches are needed to develop donor-specific tolerance.

The balance risk/benefit must always be considered because the goal of hand transplantation is to improve patient quality of life. For this reason, the evaluation of functional outcome was important, and the Registry decided to adopt its own functional score system. It is important to note that in addition to the HTSS (2), the DASH (3) score has been also used to compare the results obtained with the two different systems of evaluation and grading. The Registry score allows an evaluation of both cosmetic and functional results, and it takes into account “what really happened to the patient” after hand transplantation. It includes assessing his or her psychologic outcome, social behavior, work status, subjective satisfaction, body image, and well being. It measures the “ability and performances” of the grafted patients instead of measuring the disabilities of proximal or distal parts of upper extremities. One important aspect assessed by the HTSS is the appearance of the grafted hands as skin color and texture, hair, and nail growth are important markers of hand vascularization and skin trophism and of chronic rejection. The importance of body image must specifically be taken into consideration, as the patient has been carrying and, therefore, showing his or her own disability for some time, causing a severe adjustment of his or her personality and ability to engage in social and affective relations.

From a functional point of view, a remarkably good recovery of sensibility has been documented in all transplanted hands, while recovery of motor function has enabled the patients to perform most daily activities. It is interesting to note that bilateral hand transplanted patients were only slightly more satisfied than unilateral hand grafted patients and that motor and sensory functions improved at least the first 5 years after transplantation in unilateral and bilateral hand transplantations. Functional recovery has been well documented, and it is based on not only nerve regeneration and cortical reorganization (11) but also good compliance of the recipient to the long and hard rehabilitation program. In conclusion, patient compliance to the immunosoppressive regimen and to the rehabilitation program and his or her careful evaluation before and after transplantation are essential in hand transplantation.

This study presents some limitations that are principally because some teams did not report their cases to the Registry, such as those from China, Germany, and Pittsburgh, and other teams did not fill all the items of the Registry. Moreover, the rejection grading scales were adjusted on the basis of the Banff CTA classification, which was adopted in 2007.

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MATERIALS AND METHODS

The total number of transplants reported to IRHCTT was 49 upper extremity transplantations, 16 bilateral, and 17 single transplantations for a total of 33 patients and a follow-up period ranging from 1 to 142 months (median 48 months).

Because it has been impossible to obtain complete information on patients grafted in China, they are not included in this analysis. However, Chinese patient and graft survival are here reported as GX Pei and DY Xiang kindly informed the Registry about them.

In China, from September 1999 to March 2009, 15 hand/forearm/palm/digit allotransplantations (5 unilateral and 1 bilateral hand transplantations, 3 unilateral and 2 bilateral forearm transplantations, 1 palm transplantation, and 1 thumb transplantation) have been performed in 12 patients (11 males and 1 female). Follow-up period ranged from 12 to 116 months.

Recipient and donor characteristics are reported in Tables 2 and 3. Crossmatch was always negative, whereas there were two cases of unmatched gender. Upper extremities were harvested in heart-beating donors in 26 cases. In 19 donors, limbs were harvested before solid organs, whereas in the remaining cases, limbs were procured after solid organs. University of Wisconsin solution was used for cold flush and limb preservation in 27 cases, heparinized saline solution in 2 cases, IGL-1 solution in 3 cases, and histidine-tryptophan-ketoglurate solution in 1 case. Cold ischemia time ranged from 30 min to 12 hr (mean time 6 hr), largely depending on local circumstances including geographical distance between donor and recipient hospital.

TABLE 2

TABLE 2

TABLE 3

TABLE 3

The repair sequence of the different tissues varied considerably; however, in 100% of hands, bone fixation was first performed, followed by arterial and venous anastomoses in 51% of cases, then suture of nerves and tendons. Two arteries were always anastomosed and a variable number of veins (two veins in 44.6% of limbs). Median and ulnar nerves were always repaired, whereas the radial nerve was reconstructed in only 45% of hands. In 52.5% of cases, tendon repair was achieved by suturing individual tendons, whereas in the remaining cases, it was necessary to repair them suturing a single flexor or extensor recipient tendon to a few donor tendons to achieve a group suture as described by Pulvertaft.

All patients followed an intense rehabilitation program (five times a week for a period lasting 365 days in the majority of cases), which included physiotherapy, electrostimulation, and occupational therapy. The induction therapy included antithymocyte globulins (n=16) or alemtuzumab (n=8) or basiliximab (n=5), associated to tacrolimus, MMF, and steroids. Only two patients did not receive any induction, and they were treated with tacrolimus, MMF, and steroids plus a steroid ointment.

A triple drug combination was used for maintenance therapy based on tacrolimus, MMF, and steroids; in the first 3 months after transplantation, all recipients received tacrolimus, 27 of them received steroids, and 26 received MMF. During the follow-up period, eight recipients were switched from tacrolimus to sirolimus; in five cases, steroids were withdrawn; two recipients received steroids and low dose of tacrolimus and everolimus; and two received sirolimus and MMF.

Topical applications of steroid and tacrolimus ointments were performed in the recipients who did not receive induction therapy, in two of the patients who did not receive the triple immunosuppressive regimen, and in the majority of cases of AR. In the postoperative period, wide-spectrum antibiotics were given in 100% of the cases. A complete prophylaxis covering Candida, cytomegalovirus, and Pneumocistis jirovecii potential infections was given in 40% of the cases. A limited prophylaxis was used in 30% of the cases, and no prophylaxis was administered in 30% of the cases.

The functional results were evaluated on the basis of the HTSS (2), which evaluates six aspects with different weight for a total of 100 points: appearance (15 points), sensibility (20 points), motility (20 points), psychologic and social acceptance (15 points), daily activities and work status (15 points), and patient satisfaction and general well being (15 points). A total result of 81 to 100 points is graded as an excellent outcome, 61 to 80 as good, 31 to 60 as fair, and 0 to 30 as poor. The DASH score (3) of the population from the United States is 10.10, and higher values indicate disability. During the follow-up, the annual form, the HTSS, and the DASH score have to be filled for all hand-grafted patients.

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ACKNOWLEDGMENT

The authors thank Prof. Barbara Trudu for proofreading.

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REFERENCES

1. Dubernard JM, Owen E, Herzberg G, et al. Human hand allograft: Report on first 6 months. Lancet 1999; 353: 1315.
2. Lanzetta M, Petruzzo P. A comprehensive functional score system in hand transplantation. In: Lanzetta M, Dubernard JM, eds. Hand transplantation. Springer-Verlag, Italy 2007, pp 355.
3. Gummesson C, Atroshi I, Ekdahl C. The disabilities of the arm, shoulder and hand (DASH) outcome questionnaire: Longitudinal construct validity and measuring self-rated health change after surgery. BMC Musculoskelet Disord 2003; 4: 11.
4. Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff 2007 working classification of skin-containing composite tissue allograft pathology. Am J Transplant 2008; 8: 1396.
5. Dellon AL, Curtis RM, Edgerton MT. Reeducation of sensation in the hand after nerve injury and repair. Plast Reconstr Surg 1974; 53: 297.
6. Lanzetta M, Petruzzo P, Margreiter R, et al. The international registry on hand and composite tissue transplantation. Transplantation 2005; 79: 1210.
7. Lanzetta M, Petruzzo P, Dubernard JM, et al. Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation. Transpl Immunol 2007; 18: 1.
8. Petruzzo P, Lanzetta M, Dubernard JM, et al. The international registry on hand and composite tissue transplantation. Transplantation 2008; 86: 487.
9. Schneeberger S, Lucchina S, Lanzetta M, et al. Cytomegalovirus-related complications in human hand transplantation. Transplantation 2005; 80: 441.
10. Dubernard JM, Lengelé B, Morelon E, et al. Outcomes 18 months after the first human partial face transplantation. N Engl J Med 2007; 357: 2451.
11. Giraux P, Sirigu A, Schneider F, et al. Cortical reorganization in motor cortex after graft of both hands. Nat Neurosci 2001; 4: 691.
Keywords:

Composite tissue allotransplantation; Hand allotransplantation

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