1 INTRODUCTION

Pancreas transplantation in children is uncommon. Limited case series describe simultaneous kidney and pancreas transplants (SPK) in teenagers with type 1 diabetes and diabetic nephropathy. In the absence of indications for kidney transplantation, pancreas transplant alone (PTA) can be considered for patients in whom benefits from improved glycemia control would justify undergoing major surgery and the burden of lifelong immunosuppression.¹

Pancreas transplant alone was reported as a successful treatment of diabetes complicated with insulin allergy in adults in 1998.² In the modern era, there are desensitization strategies for antibody-mediated insulin allergy, but none of these were applicable for our patient.³

The youngest documented recipient of PTA was 11 years old but lost the graft within 6 months. Here we present a case of a 13-year-old girl with an allergy to manufactured insulin preparations who received a pancreatic transplant.

2 PATIENT AND METHODS

A 12-year-old girl with type 1 diabetes diagnosed at 4 was referred to the University of Minnesota for pancreas transplantation. She had hypersensitivity reactions to preservatives present in insulin preparations that ranged in severity from simple urticaria to life-threatening anaphylaxis. She developed a skin rash and respiratory distress with her first dose of glargine insulin and had a similar reaction after glulisine. Polysorbate 20 found in these two insulin formulations was thought to be the trigger. Drug hypersensitivity and anaphylaxis were reported for several biotherapeutics containing polysorbates. Polysorbate 80 is present in inhaled insulin.^4-7

She also developed immediate and delayed hypersensitivities to subcutaneous insulins not containing polysorbates. The skin rash in response to the insulin pump content was initially noted at the injection site but, with time, appeared all over her body. The skin test for purified insulin lispro was negative. Metacresol is a preservative present in the lispro solution. Hypersensitivity reactions to insulin preparations with metacresol as an excipient were described before in adults and children.⁸ A skin test with purified metacresol showed a delayed response.

She continued to experience glycemic lability with prolonged hyper and hypoglycemia events depside intensive medical management. Glycemic control was erratic, blood glucose ranged from 40 to 500, and hemoglobin A1c (HbA1c) was 7.6% (60 mmol/mol). Her basal insulin requirements via pump were high (1.23 u/kg/day) for her age, even with a low carbohydrate diet. She had hypoglycemic unawareness although not requiring hospital admission.

Even with topical steroids and multiple antihistamines, she struggled with localized hives, generalized painful maculopapular rashes, and dermatographism. She developed chronic abdominal pain and hyperalgesia all over her body, thought to be secondary to histamine release.

The increasing need for antihistamines significantly affected her quality of life. The formal neuropsychological assessment showed that she met her motor and language milestones, but her social development was of concern. Her ability to recall verbal information after the passage of time ranged from below average to average.

At the time of referral, her everyday functioning was grossly affected by somnolence, and therefore we expedited her transplant evaluation. She was listed for PTA within 2 months and a suitable donor became available 5 months later. It was a 23-year-old brain-dead male with a Body Mass Index (BMI) of 29 kg/m² who died of a self-inflicted gunshot wound to the head. HLA mismatch was 2-2-2.

The pancreas was placed intraperitoneally. The portal vein was anastomosed to the vena cava and the duodenum to the jejunum for enteric exocrine drainage. Cold ischemia time was 6 h and 17 min, and warm ischemia time was 30 min.

We followed our standard immunosuppression protocol. Induction was with 1.25 mg/kg Thymoglobulin (ATG) preceded by 500 mg of methylprednisolone. She received seven doses of ATG. Intravenous mycophenolate mofetil (MMF) and octreotide were given intraoperatively. Piperacillin-tazobactam and fluconazole were used for perioperative antimicrobial prophylaxis. Initial maintenance immunosuppression was 750 mg MMF and 2 mg tacrolimus twice daily, with a target tacrolimus level of 8–10 ng/ml. MMF was then switched to mycophenolic acid (540 mg twice daily). Valganciclovir and trimethoprim-sulfamethoxazole were used for cytomegalovirus (CMV) and pneumocystis pneumonia prophylaxis.

She was on intravenous insulin immediately following surgery, with an infusion rate of 0.02 u/kg/h, adjusted to maintain blood sugar levels of 80–130 mg/dl. It was discontinued on postoperative day one.

We initiated postoperative anticoagulation as per center protocol with fixed rate heparin infusion for 5 days and lifelong administration of 325 mg aspirin.

We routinely administer intravenous octreotide to ameliorate post-reperfusion graft pancreatitis, but it was discontinued due flushing and severe nausea.

3 RESULTS

With the pancreatic transplant, adequate glycemic control was achieved (Figure 1). Discontinuation of insulin allowed for complete resolution of hypersensitivity reactions. During an early postoperative period, our patient experience a series of minor complications, but these did not significantly affect her outcome.

4 DISCUSSION

Experience of pancreas transplantation in children is minimal due to concerns for subjecting them to surgical complications and side effects of immunosuppression. It should only be considered when there are no less risky alternatives available. Our patient suffered both from diabetic complications and side effects of medical treatment of her hypersensitivity to manufactured insulin preparations. PTA was a last resort for her and was undertaken after medical treatment continued to adversely affect her physical and cognitive development and quality of life. The surgical technique and the immunosuppression protocol were based on our institution's extensive experience in adult pancreas transplantation. We were also aware of cases of pancreas transplantation in teenagers reported in the literature.

Six patients younger than 18 underwent pancreas transplants at our institution between 1966 and 2000: two SPK (12 and 14 years old) and four PTA (older than 15). The two SPK recipients had functioning allografts at 5 years post-transplant. One PTA patient had a functioning allograft at 4 years follow-up, while the other three failed within less than 6 months.^{11, 12} Six more SPK teenage recipients (13–16 years old) are reported in the literature, three from the US, two from the UK, and one from Belgium.¹³

During the transplant evaluation of our patient, pancreatic islets were also considered. The multidisciplinary team agreed it would not be a good option for a patient requiring prompt and complete discontinuation of insulin.

Pancreas transplantation outcomes significantly improved over the last decade with a low incidence of early graft losses and good long-term survival. The previous year's program-reported early graft failure for PTA was 7.3%, 5-year mortality was 11.7%, and 10-year mortality was 20.7%.¹⁴ The long-term mortality data reflect cardiovascular comorbidity. Transplanting younger patients with no comorbidities and less disease burden should positively affect their long-term survival.

Treatment of complications experienced by our patient was as per adult protocol but modified and tailored to her young age. Specifically, we avoided too much ATG because loading with high doses of ATG has been associated with increased malignancy rates. It was the rationale behind administrating alemtuzumab. The reason for surveillance biopsies was to optimize immunosuppression long-term and detect early signs of failing graft. She might be a candidate for a pancreatic islets transplant in the future with the partial function of her pancreatic allograft.

Pancreatic transplant recipients are routinely anticoagulated.⁹ Splenic vein thrombosis is not an unusual CT finding, but the impaired graft function is rarely attributed to it. Treatment is not protocolized. Follow-up images help decide the length of the therapy.

Recipients of pancreas transplantation due to the use of T-cell-depleting antibodies are at higher risk of virus re-activation and fungal infection. In adults, we use a short-in-duration, systemic antifungal prophylaxis strategy, which we did in this case. Infectious risks remain a concern, given her immunosuppressed status and prolonged neutropenia. Fortunately, her subsequent bone marrow biopsy showed improvement, and she remains infection-free with ANC > 1500.

Based on PTA graft survival expectancy derived from data collected at our institution, we anticipate this pancreas to function for more than 10 years (PTA half-live in the current immunosuppression era is 10 years).¹⁵

The freedom from diabetes has been life-changing for our patient. The neuropsychological evaluation revealed that she no longer complained of ongoing pain affecting her everyday activities. Her sleep patterns were within normal limits, and her anxiety resolved. Her cognitive and social development accelerated. She creates artwork and has returned to in-person schooling. She does volunteer work with animals and has traveled abroad with her family.

A successful outcome of our recipient can be attributed to a combination of favorable patient factors, planning, and good family cooperation at every stage of the process. She received care from a multidisciplinary team comprised of transplant surgeons, pediatric endocrinologists, gastroenterologists, anesthesiologists, intensivists, pharmacists, and pre- and post-transplant coordinators. She was offered a high-quality organ recovered locally, which helped minimize cold ischemia time. Following her return home, local pediatricians communicated concerns directly to our team. The family was willing and able to promptly travel back to our transplant center when rejection was suspected.

In summary, we report a case of PTA in a teenager with graft survival exceeding 1 year. We do not advocate for pancreas transplantation in children as front-line therapy but rather to be merit consideration for a highly selected group of patients who can be appropriately evaluated and treated in experienced high-volume transplant centers.

AUTHOR CONTRIBUTIONS

The authors confirm their contribution to the paper as follows: AA wrote the manuscript; AA, KR, and TM collected the data; MB and RK edited the draft and supervised the writing of the manuscript; RK conceptualized the project and designed the study. All authors reviewed the results and approved the final version of the manuscript.

AKNOWLEDGEMENTS

We want to acknowledge input from the patient's parents. They contributed to the manuscript by providing updated information on their child's health issues and encouraging raising awareness of her case within the medical community.