Vascularized Composite Allotransplantation in the United

Received: 22 October 2019 | Revised: 30 April 2020 | Accepted: 3 May 2020 DOI: 10.1111/ajt.16086

ORIGINAL ARTICLE

Vascularized composite allotransplantation in the United States: A retrospective analysis of the Organ Procurement and Transplantation Network data after 5 years of the Final Rule

Holly C. Lewis | Linda C. Cendales

Department of Surgery, Duke University Medical Center, Durham, North Carolina On July 3, 2014, the Organ Procurement and Transplantation Network (OPTN) began overseeing vascularized composite allotransplantation/allografts (VCA) in the United Correspondence Linda C. Cendales States. For the past 6 years, centers performing VCAs have been requested to submit Email: [email protected] data into a biometric repository, in parallel with systems used by solid organ transplant centers. Currently, 62 VCAs are reported in the entire OPTN database, with 36 of these transplants reported as performed after VCA was added to the OPTN Final Rule. Of these 36 recipients, 16 received uterus transplants, most of which (11) occurred from living donors. Ten patients received hand transplants and 6 received face transplants. Two patients received abdominal wall transplants, 1 patient received a scalp transplant, and 1 patient received a penile transplant. The present manuscript represents the query of a nationalized database for VCA type, immunosuppression treatment, and clinical outcomes for VCAs. This manuscript provides a report of the current VCA data reported to the OPTN after the Final Rule.

KEYWORDS clinical research, health services and outcomes research, immunosuppressive regimens, Organ Procurement and Transplantation Network (OPTN), United Network for Organ Sharing (UNOS), vascularized composite allotransplantation

1 | INTRODUCTION remembered for his discovery of ABO blood groups, spent parts of 1.1 | Background his early career transplanting lymph nodes between guinea pigs,2 and Medawar began his immunology research by transplanting soft Vascularized composite allotransplantation (VCA) refers to the tissues in wounded British soldiers.3 Coupled with improved immu- transplantation of components such as nerve, tendon, skin, and/ nomodulatory drugs and refinement of vascular and microsurgical or bone as a functional unit to reconstruct tissues that cannot be techniques,4,5 VCAs have become technically feasible, with the first reconstructed with autologous tissue. VCA is an evolving field of successful hand transplantation in 1998.6 Today, an increasing num- transplantation that is built upon foundational science in vascu- ber of organs have been transplanted, including upper extremities, lar biology, microsurgery, and immunology. The first successful face, abdominal wall, and uterus. solid organ transplantation (SOT) by Joseph Murray in 1954 de- pended upon precepts developed decades earlier by immunolo- gists like Karl Landsteiner and Peter Medawar.1 Landsteiner, best 1.2 | VCA in the United States of America

Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; DASH, Disabilities of Arm, Shoulder, and Hand; OPTN, Organ Procurement Transplant Network; UNOS, The United Network for Organ Sharing (UNOS) has managed United Network for Organ Sharing; SOT, solid organ transplantation; UNOS, United the Organ Procurement and Transplantation Network (OPTN) Network for Organ Sharing; VCA, vascularized composite allotransplantation.

Am J Transplant. 2020;00:1–6. amjtransplant.com | 1 2 | LEWIS and CEndaLES contract from the US Department of Health and Human Services performed with Excel 16.29 (Microsoft, Redmond, WA) and Prism (HHS) since 1986. Under this contract, UNOS operates the na- 8.2 (GraphPad, San Diego, CA). Figures were produced with Adobe tion's solid organ donation and transplantation system. Effective InDesign 14.0.3 (Adobe, Mountain View, CA), with some image ren- July 3, 2014, these guidelines were amended such that VCA would dering by PowerPoint 16.29 (Microsoft). be included within the OPTN Final Rule's definition of “covered The OPTN database reports clinical data for patients who have human organs.”7–9 Under the OPTN Final Rule, all centers that per- undergone VCA beginning in 1999; the present analysis is focused on form SOT (and now VCAs) are required to submit a variety of data transplant surgeries and their follow-up encounters reported after the including patient demographics, wait times, blood types, donor Final Rule. Baseline or preoperative (preop) characteristics are defined authorization requirements, and clinical outcomes.10 The primary by 219 variables, and the follow-up (postop) clinical data are defined goal of such requirements is to promote safety and improvement by 463 variables. One challenge in VCA is the aggregation of differ- pf patient outcomes. ent organ types (ie, hand, face, abdominal wall) within a single analytic A previous publication from our group explored the state of framework; for example, variables for “decannulation of tracheos- VCAs in a 3-year period and another reviewed OPTN data on hand tomy” are not applicable for patients undergoing hand transplant. In transplantations.10,11 The present manuscript is an effort to analyze the present database, many clinical variables (eg, the perioperative all available OPTN data on VCAs, with a focus on all VCA types re- use of inotropes in VCA donors or the Banff score of recipients’ reported 5 years after the Final Rule. An advantage of OPTN data is jection episodes) have null values reported, imparting no clinical utility access to a large aggregated database that enables investigators to to the analysis. Given the small number of VCAs per organ type, no approach questions that any one center could not do alone. Just as attempt was made to mathematically impute missing values. Toward these tools are important for large-volume organs like kidneys, so generating a clinically legible manuscript, these underreported vari- too do smaller volume VCA centers have an obligation to openly ables have been excluded from analysis. Examples of these variables communicate and share their data. Given the small number of VCAs include donor crossmatch results, VCA recipients’ preop and postop occurring nationwide, it is essential that data-sharing be encouraged calculated panel-reactive antibodies (CPRA), social functioning scores, to move the field forward. and body mass index. Table S10 presents an excerpted list of such vari- What follows is an analysis of the OPTN data for all VCAs re- ables. Also excluded from this analysis is the location the transplant ported after the Final Rule from July 3, 2014 through March 31, procedures occurred. The OPTN database uses encrypted numbers 2019. We have used bioinformatic methods to define the drug ther- for regional transplant centers, but the data include state-of-origin in- apies, donor and recipient immunophenotypes, perioperative vari- formation for VCA recipients. Because of the small number of VCAs ables, and clinical outcomes for living- vs deceased-donor organs performed nationwide, and in keeping with OPTN principles of patient and outcome data per VCA type. confidentiality, no effort was made to analyze the data by geography. Variables of clinical significance that are electively included in the analysis despite underreporting include the Epstein-Barr virus 2 | MATERIALS AND METHODS (EBV) and cytomegalovirus (CMV)-seropositivity of donor–recipient pairs12 and all functional outcome data available (especially for hand The OPTN database was received directly from the OPTN with all and face transplants). All VCAs reported donor/recipient ABO status VCA types and follow-up data reported to the OPTN from 1999 to and matched congruently; it is not detailed herein for simplicity. As 2019; there are 62 total recipients reported. Our current analysis the degree of acute rejection episodes is not consistently reported, focused only on those recipients with transplant surgery dates re- any reported rejection episode is presumed to be at least Banff clas- ported from July 3, 2014 through March 31, 2019. Only patients sification I.13 with a documented date of transplant are included; patients who are The data reported here have been supplied by UNOS as the entered in the data set but without a transplant date (ie, waitlist pa- contractor for the OPTN. The interpretation and reporting of these tients) are excluded from analysis. data are the responsibility of the author(s) and not an official policy The database includes a discrete variable for “graft failure date,” of or interpretation by the OPTN or the US Government. Prior to which our analysis defines as a failed or graft loss. When a recipient initiation of this work, all authors signed an OPTN/UNOS Data Use is reported to have an “acute rejection episode,” this is noted as an Agreement, affirming their commitment to these principles of data event but is not a graft failure. For those recipients with reported integrity and patient confidentiality. visits, but with subsequent lack of reported entries, the last-reported clinical status of the graft is carried forward. Grafts that have not been reported as lost are thereby considered free from graft 3 | RESULTS failure for a set time period. This is computed as the number of days between the transplantation surgery and the latest clinical encoun- 3.1 | VCAs documented in OPTN database ter wherein the graft is reported as not failed. SAS 9.2 (SAS Institute, Cary, NC) was used to parse and an- In the period from July 3, 2014 to March 31, 2019, a total of 36 alyze organ-specific OPTN data. Additional data analysis was patients are reported to have undergone VCA transplantation LEWIS and CEndaLES | 3

(Figure 1, Figure 2, Table S1). A commonly transplanted organ is the transplant recipients underwent induction immunosuppression, uterus, with a total of 16 procedures, 11 of which occurred with liv- consisting of thymoglobulin and oral steroids; therapy duration and ing donors and 5 through a deceased donor. There are 10 total re- dosing are inconsistently reported in the data and therefore omitted. cipients of hand transplants in the OPTN data from 2014 to 2019 Intraoperative data include the length of ischemia time. The average (when combining those patients who received a bilateral or unilat- warm ischemia time is less than 1 hour for all reported uterus trans- eral procedure). Of the 10 hand transplant recipients, one patient plants (Tables S2 and S3). (10%) is reported to have had a graft loss. A total of 6 recipients of Postoperative maintenance immunosuppression included tac- face transplant are reported in the data; none (0%) have reported rolimus for 100% of uterus recipients. Tacrolimus and intravenous graft failure or a date of graft loss. Two abdominal wall transplants immunoglobulin (IVIG) are reported as drug therapy for acute rejec- are reported; neither of these have a reported date of graft loss or tion episodes in living-donor uterus recipients. Overall graft loss/ failure. There is 1 recipient of a penile transplant and 1 recipient of failure is the only outcome event reported; the Kaplan-Meier curve a scalp transplant; although the penile transplant recipient had an in Figure S1 presents the data as freedom from graft loss, plotted for episode of acute rejection, neither of these patients have reported all uterus recipients. graft loss or failure.

3.3 | Unilateral upper extremity transplantation 3.2 | Uterus transplantation A total of 4 recipients are reported to have undergone unilateral Overall, among the 16 uterus transplants, 44% (7 recipients) are upper extremity transplantation, with 1 of these recipients experi- reported as failures with reported dates of graft loss. Among the encing graft failure (Table S4). Of the 4 unilateral hand transplant 9 recipients whose grafts are not lost, the mean number of days patients, 3 have reported the degree of HLA mismatch, at an average free from graft failure is 159 days. One living-donor uterine recipi- of 4 loci. Common induction therapies include thymoglobulin, oral ent is reported to have had her graft in place for 436 days. Of the steroids, and alemtuzumab. The mean cold ischemia time reported 7 patients who are reported to have undergone graft failure, 3 of among unilateral hand transplants is 454 minutes; warm ischemia these report a specific etiology: 2 are described as due to “thrombo- time is reported for 1 patient, at 13 minutes. sis, outflow congestion,” and one reports “arterial thrombosis.” The The reporting of maintenance immunosuppression is not uniform other 3 failed grafts do not report a specific etiology. across the data; the most consistent drug is oral tacrolimus, report- Uterus transplants are the only VCA in the data reported to occur edly taken by 75% of recipients. The number of acute rejection ep- with a living donor. The degree of HLA mismatch is not reported isodes is reported for each of the unilateral hand recipients, with for the living-donor transplant procedures. Among deceased-donor all (100%) experiencing rejection episodes. The patient whose graft uterus recipients who lost their grafts, an average HLA mismatch of was lost was reported to experience one episode of acute rejection. 6 loci is reported. Among deceased-donor uterus recipients without Reported rejection treatments include oral steroids, topical steroids, reported graft failure, the average HLA mismatch is 5 loci (Tables S2 and topical tacrolimus. For the patient whose unilateral hand trans- and S3). The majority of uterus transplants occurred among donor/ plant is reported as a graft failure, the specific etiology is described recipient pairs who were seropositive for EBV and CMV. All uterus as “congestion/compartment syndrome.” Three functional metrics included in the OPTN database are the Carroll test, the Disability of Arm Shoulder and Hand (DASH) score, and the Semmes-Weinstein test. The Carroll score assesses hand function on a 0-99 scale where higher numbers denote better

FIGURE 1 Number of transplants reported after the Final Rule by VCA type. Number of vascularized composite allotransplantations (VCAs) in the Organ Procurement and FIGURE 2 Number of transplants reported after the Final Rule Transplantation Network (OPTN) database reported to have been by year. VCAs reported to occur between July 3, 2014 and March transplanted between July 3, 2014 and March 31, 2019 31, 2019 by year of transplantation 4 | LEWIS and CEndaLES function.14 The DASH score is a well-validated tool in hand surgery, thymoglobulin. A variety of functional outcomes are reported for where higher numbers denote worse disability.1,15,16 The Semmes- face transplants, with postop functional improvements reported for Weinstein test is a clinical assessment of light touch, measuring the 66% of recipients. Among the 6 face transplant recipients, 50% had patient's sensation with monofilaments; it is widely used in diabe- their tracheostomy decannulated, 50% regained the sense of smell, tes research and vascular and hand surgery.1,17–19 Of the 4 unilat- 33% had their feeding tube removed, and 33% regained the ability to eral hand recipients, 1 has reported preoperative and postoperative protect their corneas via eye closure. Carroll test scores, with a postoperative improvement of 48 points. No unilateral hand recipient has paired preoperative and postoperative DASH scores. No unilateral hand transplant recipient has 3.6 | Abdominal wall, penile, scalp transplantation postoperative Semmes-Weinstein tests. The Kaplan-Meier curve in Figure S2 presents freedom from graft failure for all hand recipients A total of 2 abdominal wall transplants, 1 penile transplant, and 1 (unilateral and bilateral). scalp transplant are reported (Tables S7,S8 and S9). Neither of the abdominal wall recipients are reported to have had an acute rejection episode or a graft loss; the average number of days free from graft 3.4 | Bilateral upper extremity transplantation failure is 374. The penile transplant recipient experienced an acute rejection episode after 365 days, and the scalp transplant is reported A total of 6 recipients are reported to have undergone bilateral as in place 1379 days without an acute rejection episode. Abdominal upper extremity transplantation, none of whom (0%) are reported wall, penile, and scalp recipients all underwent induction immuno- to have lost their grafts (Table S5). The degree of HLA mismatch suppression with thymoglobulin with some patients also receiving between donor and recipient is reported for all 6 of the trans- oral steroids, rituximab, or basiliximab. The mean cold ischemia time plantations, with the average being 5 loci. As with unilateral hand among abdominal wall transplants is 301 minutes, cold ischemia time transplants, the most common induction therapies include thymo- for the penile transplant 300 minutes, and for the scalp 127 minutes. globulin, oral steroids, and alemtuzumab. The mean cold ischemia The abdominal wall transplants reported an average of 21 minutes time among bilateral hand transplants is 198 minutes and the warm ischemia time and the penile transplant reported 180 minutes mean warm ischemia time is 267 minutes. Tacrolimus was report- of warm ischemia time; the scalp transplant did not report a warm edly taken by 100% of the recipients. Of the 6 recipients, 50% are ischemia time. Maintenance immunosuppression for abdominal wall, reported to have experienced zero or 1 acute rejection episodes. penile, and scalp transplants is similar to other VCAs, consisting of One patient is reported to have had 7 acute rejection episodes. oral tacrolimus and oral steroids. Common rejection treatments include oral or topical steroids and topical tacrolimus. Among the 6 bilateral hand transplant recipients, 4 (66%) have reported preoperative and postoperative Carroll test 4 | DISCUSSION scores; the average score improvement was 28 points per patient. Three of the 6 (50%) bilateral hand transplant recipients have docu- Unlike SOT, where improvements in serum creatinine or MELD score mented preoperative and postoperative DASH scores in the data- can be imputed as clinical improvement, the VCA field relies upon base; these show an average of 18 points per patient improvement. assessment of clinical function. The present analysis of VCAs re- Semmes-Weinstein tests are reported for 5 of the recipients (83%), ported after the OPTN Final Rule adds to an expanding body litera- with an average postop score of 3. ture that seeks to characterize the clinical indications and outcomes of VCA.20,21 In our study, the most well-reported variables in the analysis dataset are binary values for medications prescribed. Other 3.5 | Face transplantation well-reported variables include perioperative metrics (antibiotics, anticoagulation, ischemia times). A total of 6 face transplantations are reported, none of which are One of the most frequently transplanted organs in the database reported to have graft failure (Table S6). Among the 6 face trans- is the uterus, which has the fewest described functional outcomes. plant recipients, 5 (83%) report the degree of HLA mismatch, at an Whereas some VCAs are assessed on clinical scores, the functional average of 5 loci. The most commonly reported induction therapies indication for uterine transplant is to confer the ability to implant a for face transplant recipients are thymoglobulin and oral steroids. fertilized embryo, carry a fetus to term, and deliver a healthy human The mean cold ischemia time among face transplants is 174 minutes. child. Currently, the data from the OPTN on uterus transplants only Mean warm ischemia time is reported for 3 patients, for a mean report the organ's rejection/failure/loss. Of note, at least one of the time of 3 minutes. Oral tacrolimus, mycophenolate, and oral steroids uterus allografts is reported to be in place for well over 9 months, were reportedly taken by 100% of the recipients. Acute rejection but the data set does not contain information regarding embryo im- episodes are reported to occur for 66% of the face transplant replantation attempts. To better ensure patient safety and outcomes cipients, for a total of 1-2 per patient. Rejection therapy is reported and to advance clinical understanding, it will be helpful to collect for face transplants, with 33% using oral steroids and 17% using data on fertilizations, implantations, and parturition for uterus LEWIS and CEndaLES | 5 recipients. Similarly, little is known about the prognostic health of ACKNOWLEDGMENTS a child born from a uterus transplant: documentation of the child's This work was partially supported by the Duke Health Scholars birth and Apgar score should be collected in the neonatal period.22 Award (LC). The authors would like to thank Sarah Peskoe, PhD, As a reassuring Apgar score does not always accord with normal and Alec McConnell from the Duke University School of Medicine development milestones, data collection for children born from a Department of Biostatistics and Bioinformatics for their invaluable uterus transplant long term will be crucial to understanding long- assistance. term outcomes. Despite the inclusion of 3 validated clinical scoring systems DISCLOSURE for hand transplant patients, when examining the data, 40% of The authors of this manuscript have no conflicts of interest to dis- the hand recipients have reported preoperative and postoperative close as described by the American Journal of Transplantation. functional scores. Some of the more complete data on functional outcomes are among the facial transplant population, wherein 66% DATA AVAILABILITY STATEMENT of the patients have reported postop outcomes, including descrip- The data that support the findings of this study are freely availa- tions of tracheostomy decannulation and regained olfactory or al- ble through the Organ Procurement and Transplantation Network imentary function. Specific descriptions of surgical complications (OPTN). These data were derived from Standard Transplant Analysis are not uniformly reported in the OPTN VCA data. For a broad and Research (STAR) files, with permissions and access granted overview of such complications, the reader is referred to various through the OPTN: https://optn.trans plant.hrsa.gov/data/reque recent publications. 23,24 Within the database, we noticed there st-data were instances where confirmation of data submission might be beneficial. For example, in the perioperative data for face trans- ORCID plant recipients, although there was an option of a null value, there Holly C. Lewis https://orcid.org/0000-0002-5238-3774 was a data entry of 0 minutes, shifting the mean warm ischemia Linda C. Cendales https://orcid.org/0000-0002-3461-8824 time to 3 minutes. The reporting of donor and recipient immunophenotyping REFERENCES could also be more robust. Although ABO, EBV, and CMV serosta- 1. Tuffaha S, Broyles J, Shores JT. Experimental Models and Clinical tus are recorded for nearly each VCA, less than half of the pa- Tools to Assess Nerve Regeneration and Functional Outcomes. 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