Prolonged Allograft Survival in a Patient With Chronic Immunosuppression: A Case Report and Systematic Review

A 41-year-old man with past medical history of kidney-liver transplantation requiring chronic immunosuppression presented 2 years posttransplant with a necrotizing soft tissue infection of his right thigh. Serial debridement to remove necrotic tissue was performed, and a Matrix HD Allograft Fenestrated (RTI Surgical, Alachua, FL) was applied. At 5-months post grafting, the patient demonstrated fully vascularized and intact skin. Under normal circumstances, a cadaveric allograft sloughs over several weeks and is not usually considered a permanent solution for wound closure. A systematic review of transplant patients on chronic immunosuppression with skin allografts demonstrates the potential for the indefinite survival of an allograft. Necrotizing soft tissue infections can definitively be treated using serial debridement and allograft transplantation in the chronically immunosuppressed. 

Transplant patients on chronic immunosuppression may demonstrate indefinite survival of skin allograft. Necrotizing soft tissue infections can be treated using serial debridement and allograft transplantation in the chronically immunosuppressed. As most of the published research on this topic is from case reports or animal models, additional research is required to garner generalizable results.

A 41-year-old man with past medical history of hepatorenal transplantation requiring chronic immunosuppression presented to the Emergency Department at the University of Kentucky (Lexington, KY) 2 years posttransplant with a necrotizing soft tissue infection of his right thigh. He was placed on tacrolimus, prednisone, and mycophenolate mofetil after his transplant and had been compliant with his medications for the duration (about 17 months). The patient arrived at the University of Kentucky Hospital in septic shock after a 1-day to 2-day history of fevers, altered mental status, and vomiting. On physical exam, he was found to have crepitus of the right thigh with erythema extending to the right abdominal wall. Laboratory values revealed a white blood cell count of 6.5 k/µL, creatinine of 2.39 mg/dL, hemoglobin of 8.6 g/dL, glucose of 86 mg/dL, and sodium of 130 mmol/L. Serial debridement to remove necrotic skin and subcutaneous tissue was performed, and the Matrix HD Allograft Fenestrated (RTI Surgical, Alachua, FL) was applied after the final debridement. At 5-months post grafting, the patient demonstrated fully vascularized and intact skin. 

Necrotizing soft tissue infections are potentially fatal infections of the subcutaneous tissues and deep fascia. Often, traumatic defects in the skin provide an entry for bacteria to spread rapidly through the surrounding tissues. Risk factors for necrotizing soft tissue infections include diabetes, smoking, drug abuse, and immunosuppression. Immunosuppression inhibits the body’s ability to combat the rapid spread of infection by preventing a normal physiologic immune response.

Skin is the largest and most antigenic organ, making acute and chronic rejection of skin allografts a serious problem.¹ Epithelial healing, both with autografts and allografts, as well as the histologic appearance of allograft rejection were described by Brown and McDowell² in 1942. T cells mediate acute skin allograft rejection through activation of a cell-mediated response by antigen-presenting cells such as epidermal Langerhans cells.³ Typically, a skin allograft is vascularized for 5 to 14 days before it is rejected by the host immune system. However, it is possible for human skin allografts to survive indefinitely on patients receiving therapeutic doses of chronic immunosuppressive therapy. Chronic immunosuppression permits allograft survival by preventing the ability of T cells to be activated by persistent antigen-presenting cells in the allograft tissue. Immunosuppression permits a > 90% allograft organ survival rate in patients with the use of steroids, calcineurin inhibitors, and monoclonal antibodies that limit the immune response.⁴ The challenge is to allow the immune system to maintain normal function to fight infection while simultaneously preventing allograft rejection. (Figure 1)

The viability of skin allografts in transplant patients who have been chronically immunosuppressed was demonstrated in a study by Mindikoǧlu and Çetinkale.¹ Renal transplant patients treated with cyclosporine, a potent calcineurin inhibitor that affects T-cell proliferation, have prolonged survival rates of skin allografts with no effect on wound healing. In a case study by Mindikoǧlu and Çetinkale,¹ a woman with extensive and severe burns received cyclosporine to extend the survival of skin allografts obtained from unmatched donors. After 3 months, the wounds healed completely. Once immunosuppression was discontinued, rejected regions of allograft subsequently revealed the presence of healthy granulation tissue that was then covered with a partial-thickness autograft.¹ 

In a case series, Wendt et al⁵ described 100% take and long-term clinical survival of human skin allografts in renal transplant patients with therapeutic doses of immunosuppressive therapy. When immunosuppression was discontinued 5 years postoperatively in 1 patient, the skin allograft cells were replaced with autogenous cells. However, the skin graft did not acutely reject. The skin allograft was thought to act as a lattice framework for native cells to migrate into and replace the rejected skin cells.

Animal studies also support the concept of prolonged persistence of skin allografts. Topical tacrolimus, a calcineurin inhibitor, in conjunction with preoperative T-cell depletion has been shown to limit or reverse acute rejection in rats, thus permitting prolonged allograft survival.³ Solari et al³ divided rats into 4 groups: group 1 was treated with topical tacrolimus; group 2 with antilymphocyte serum and 21 days of cyclosporine; group 3 with antilymphocyte serum, topical tacrolimus, and 21 days of cyclosporine; and group 4 had tacrolimus concentrations measured in blood, skin, and muscle as a control. The authors were able to conclude that immunosuppression had the potential to prevent rejection of composite allografts with 67% of mice in the group receiving topical tacrolimus and cyclosporine reaching the endpoint of the study without any rejection. Calcineurin inhibitors are often used in organ transplant patients for long-term immunosuppression and provide an advantage in the ability of the host to accept the allograft. This study³ eloquently showed that an effective immunosuppression regimen could allow for indefinite allograft survival.

In a separate study by Jones et al⁶ using pigs, 1 group without immunosuppressive therapy compared with another group with therapy consisting of daily tacrolimus, mycophenolate mofetil, and prednisone, showed the pigs not receiving immunosuppression failed to accept a skin allograft and went into acute rejection on day 7 after the procedure. Conversely, those pigs that received the regimen of drugs all accepted the allograft indefinitely. This further demonstrates the efficacy of immunosuppression regarding the acceptance of the antigenic skin allograft. Of the 9 pigs in the study that received daily immunosuppression, 4 faced early acute rejection, but the rejection resolved spontaneously with limited effects on wound healing.⁶

Patients with burns and temporary immunosuppression, when combined with immediate excision of nonviable tissue, show success in accepting allografts due to T-cell depletion. Burke et al⁷ showed that patients who underwent debridement, grafting, and immunosuppressive therapy had their allograft replaced with an autograft over time. Immediate wound coverage and prolonged graft survival reduced the risk of reinfection compared with the control group and demonstrated strong support of early debridement and coverage of the wound with an allograft and adjuvant immunosuppressive therapy.⁷ 

Chronic comorbidities leading to an immunocompromised state can also enable prolonged allograft survival. A study by Pomahac et al⁸ showed that critically ill patients with conditions leading to chronic immunosuppression had long-term allograft survival. Combining debridement of nonviable tissue and coverage using skin allograft in the setting of chronic immunosuppression led to long-term acceptance of the allograft without complication. With debridement and immediate coverage, the patient has protection from potential further infection.⁸ In the chronically immunosuppressed transplant patient, the allograft should theoretically survive indefinitely and allow for complete wound coverage as well as protection against invasive infection if immunosuppression is maintained. 

Current research has been ongoing to attempt to prolong allograft survival while ending immunosuppressive therapy by inducing mixed chimerism with hematopoietic stem cell transplantation. A 2014 cohort study by Mathes et al⁹ reported that canines receiving a bone marrow transplant with simultaneous vascularized composite allograft maintained tolerance of their allograft at 62 weeks, whereas 3 of the 4 canines without the hematopoietic stem cell transplantation rejected their allograft once immunosuppression was halted. The group of canines receiving the hematopoietic transplant showed increases in regulatory T cells, which may lead to further acceptance of the allograft.⁹ Future treatment may lead to advances in transplantation, but no successful results have been shown in human subjects.  

In the present case of a chronically immunosuppressed transplant patient, the immunosuppressive treatment that allowed his organ survival also enabled the use of allograft skin as the definitive wound coverage. Allografts have been shown to have prolonged survival in animal and human subjects with immunosuppressive therapies, allowing for the treatment to be used effectively to treat the chronically immunosuppressed with large soft tissue wounds.

Necrotizing soft tissue infections can be treated using serial debridement and allograft transplantation in the chronically immunosuppressed. In an immunosuppressive state, it is possible that the skin allograft will not be rejected as long as the other transplanted organs are not being rejected as well. Without rejection, the skin allograft will be able to vascularize and provide long-term wound coverage, as well as protect from further infectious agents, making this a viable option to treat similar cases. As most of the published research on this topic is from case reports or animal models, additional research is required to garner generalizable results. 

From the Division of Plastic Surgery, University of Kentucky College of Medicine, Lexington, KY; and Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN

Address correspondence to:
Krishna S. Vyas, MD, PhD, MHS 
Division of Plastic and Reconstructive Surgery
Department of Surgery
Mayo Clinic
200 1st Street SW
Rochester, MN 55905
vyas.krishna@mayo.edu

Disclosure: The authors disclose no financial or other conflicts of interest.