Type I, type III, and type IV insulin hypersensitivity reactions are rare, but potentially serious complications of insulin treatment of type 1 diabetes (T1D). Type I, IgE-mediated reactions often present within seconds to minutes as localized urticaria. More rarely, they may be delayed by several hours or present with anaphylaxis. Type III, antigen–antibody complex-mediated reactions often present as localized Arthus reactions within 24 h with painful subcutaneous nodules. However, they can present 4–10 days later as generalized serum sickness reactions. Delayed, type IV hypersensitivity reactions are triggered by T-cell activation and may present within days as contact dermatitis with eczematous, erythematous areas (1, 2).

Insulin reactions can be refractory to treatment leading to poor glycemic control and quality of life (1, 2). Although there are several reported adult cases (3–6), data in children are limited. We present four pediatric cases of insulin hypersensitivity reactions, including one of the youngest pancreas transplant recipients at the age of 12 years. These cases were identified at four pediatric hospitals, which collectively treat approximately 7,100 patients with T1D, between 2016 and 2023.

Patient A is an 18-year-old female adolescent, diagnosed with T1D at age 4 years. She was initially managed exclusively with lispro given a low hemoglobin A1c (HbA1c) of 7.6%. Three days later, upon discharge, she developed a type I, IgE-mediated hypersensitivity reaction with respiratory distress when glargine was added ( Table 1 ), prompting intramuscular epinephrine administration and an emergency room visit. She was transitioned to detemir but developed type IV, localized skin reactions within days. After 3 weeks, similar localized eczematous plaques to glulisine developed. The localized reactions were partially abated by oral diphenhydramine. Allergy evaluation and reports of prior anaphylaxis to pickles and whipped cream identified the suspected trigger as polysorbate 20, which is common to glargine, glulisine, and the aforementioned foods. She was transitioned to lispro, which does not contain polysorbate 20. However, localized eczematous-like reactions persisted, and increasing insulin doses were required. This raised concern for a meta-cresol allergy since it is found in all insulins. However, patch testing was negative. She was switched to aspart, which was better tolerated despite containing meta-cresol, but the localized skin reactions persisted.

Patient A trialed a Tandem T:Slim insulin pump in an effort to decrease reactions by continuously administering small insulin doses. She developed large local reactions with Teflon pump cannulas ( Figures 1A, B ), which improved modestly with a stainless-steel cannula. She was simultaneously trialed on mycophenolate and prednisone but developed infusion site cellulitis and bacteremia. These immunosuppressants also led to cataracts and peripheral neuropathy. High-dose antihistamines led to intolerable fatigue, and reactions persisted. By age 11, she required a total daily insulin dose (TDD) of 1.26 units/kg/day and hemoglobin A1c’s ranged from 7.2% to 7.7%.

Intravenous (IV) insulin desensitization was trialed. Although she had significant discomfort and localized, eczematous reactions with peripheral insulin infusions, central infusions were better tolerated. Ultimately, these localized reactions persisted and desensitization was deemed unsuccessful.

After 8 years, she was referred for pancreas transplant. In February 2018, at age 12, she became one of the youngest pancreas transplant recipients to date. Despite two episodes of rejection at 1 and 14 months post-transplant, pancreatic autoantibodies remain negative. There was no evidence of endocrine pancreatic failure during the acute rejection episodes. Though it has not been required, a plan was formulated to pursue a preservative-free insulin through special manufacturing and a single patient compassionate investigational new drug (IND) use through the Food and Drug Administration (FDA). She remains euglycemic off insulin therapy nearly 5 years post-transplant. The immunosuppressant medications include tacrolimus, everolimus, and prednisone (15.8 mg/m²/day of hydrocortisone equivalent). She has transiently required insulin to correct for hyperglycemia while on high-dose glucocorticoids for acute rejection management, which was well tolerated after pre-treatment with diphenhydramine and anti-thymocyte globulin. Two years post-transplant, she developed pancreatitis with no known trigger. Pancreatic enzyme supplementation was initiated for possible pancreatic insufficiency.

At the most recent endocrinology follow-up 4.75 years post-transplant, body mass index (BMI) was in the 97th percentile with fasting glucose 100 mg/dL and HbA1c 5.3%. Metformin was incrementally increased from 500 mg to 2,000 mg daily, then decreased to 1,000 mg daily due to abdominal discomfort.

In case of mild hyperglycemia and despite a prior episode of pancreatitis, a glucagon-like peptide-1 receptor agonist will be considered, paired with a proton pump inhibitor to stimulate beta cell neogenesis and gastrin-mediated glycemic improvement (7). If severe hyperglycemia develops, a peripherally inserted central catheter (PICC) line would be placed for an aspart infusion at 0.03 units/kg/h, titrating glucoses to 150–200 mg/dL.

Patient B is a 16-year-old female adolescent, diagnosed with T1D at age 7 years. She tolerated insulin injections with lispro and glargine for 2 years, but within 6 weeks of initiating Tandem T:Slim insulin pump therapy with lispro, she developed suspected type III hypersensitivity reactions with localized erythema and swelling ( Figures 1C, D ). Pump use was discontinued in favor of multiple daily injection therapy. Aspart, lispro, glulisine, glargine, and detemir injections were trialed, but localized, large, painful, erythematous skin lesions occurred. Pump therapy was trialed again 1.5 years later, but the reactions remained unchanged.

She was admitted for evaluation by endocrinology, dermatology, allergy/immunology, and pharmacy. Skin biopsy demonstrated extravasated red cells suggestive of type III hypersensitivity. However, type I hypersensitivity features included eosinophils, mast cells, and spongiosis. Alternate complement (AH50), classical complement (CH50), immune complex assay, insulin antibody, and insulin IgE laboratory studies were normal. Injections with neutral protamine Hagedorn (NPH), regular insulin, lispro, and detemir yielded similar reactions. Adjuvant systemic prednisone, cetirizine 10 mg twice daily, ranitidine 150 mg twice daily, montelukast, topical steroids, and tacrolimus were trialed. High-dose prednisone (100 mg/m²/day of hydrocortisone equivalent) provided some improvement but caused significant hyperglycemia. Dexamethasone 0.02 mg twice daily mixed with insulin injections was trialed but caused discomfort without significant improvement in the reactions.

In an effort to bridge to pump therapy, inpatient insulin desensitization was performed with cetirizine, ranitidine, and montelukast pre-medication. Lispro was incrementally increased, starting with smaller doses through an IV pump, followed by larger doses through the Tandem T:Slim pump. Despite desensitization, localized reactions persisted. Colchicine 0.3 mg twice daily was trialed but was unsuccessful in decreasing reactions. Subcutaneous lispro and twice daily detemir injections were resumed upon discharge.

Additional immunotherapies including weekly methotrexate, monthly IVIG (1 g/kg), and triannual rituximab were initiated, but localized reactions continue. Despite a TDD of 2.26 units/kg/day, HbA1c was 9.5%. She was also followed for hypercholesterolemia and BMI above the 97th percentile. She was approved for a pancreas transplant 6 years after reactions first developed. At the time of writing, she had received her transplant 6 weeks prior. She was receiving 10 units of Levemir daily (TDD of 0.15 units/kg/day), which is being weaned off, and she has not required rapid-acting insulin.

Patient C is an 8-year-old boy, diagnosed with T1D at age 14 months. He developed an eczematous localized type IV reaction to lispro 1.8 years after diagnosis ( Figure 1E ). He trialed all available insulins, but localized reactions recurred 6–8 h after injections. Glucoses fluctuated from 50 to 450 mg/dL despite adherence to the recommended basal bolus insulin regimen. He also trialed insulin pump therapy with lispro and aspart but developed firm nodules and persistent hyperglycemia. Localized erythematous, nodular reactions persisted despite topical glucocorticoids and local phototherapy.

He underwent extensive testing with allergy/immunology, dermatology, and genetics. A skin biopsy 2 years after initial reactions demonstrated perivascular and interstitial dermatitis with inflammatory cell infiltrate containing lymphocytes and histiocytes. Percutaneous skin prick testing was negative for cresols, glulisine, glargine, lispro, and aspart. Patch testing was negative to these allergens, but positive to nickel and acrylates, which are found in pump infusion sets (8). Intradermal skin testing was performed, with a 1:100 dilution for insulins, zinc, and cresol and 1:20 dilution for glycerin. This was positive at 24 h for all insulins including aspart, lispro, degludec, glargine, and regular insulin, but negative for additives. Insulin IgG antibody was 2.33 nmol/mL (from 0.09 nmol/mL at diabetes diagnosis) and insulin IgE was negative. Whole exome sequencing was negative for FOXP3 mutation, involved in regulatory T-cell development (9). IgG, IgA, C3, C4, and lymphocyte counts were normal.

He was started on methotrexate and up titrated to 13.5 mg/m². He continued aspart and glargine injections. The localized eczematous-like reactions improved. However, rare cutaneous injection site erythema 12–24 h after injections persisted, partly relieved by topical triamcinolone. Upon resuming pump therapy, he had recurrence of erythema and small nodules on days 2–3 of pump site wear, though less extensive than previously reported. Three years after starting methotrexate, he started to develop more frequent local reactions and methotrexate was titrated up to 18 mg/m²/week. Dupilumab was trialed for 4 months without improvement. At the time of writing, HbA1c was 8.3% on a TDD 0.67 units/kg/day. The older brother was diagnosed with T1D at 18 months and has had no insulin reactions to date.

Patient D is a 15-year-old male adolescent, diagnosed with T1D at age 2 years. He tolerated glulisine for 6 years, but upon transitioning to insulin aspart, the patient developed erythematous, firm, tender nodules presenting several hours after injection and lasting several days ( Figure 1F ). Upon resuming glulisine, he developed similar reactions. He trialed all available insulins, pump therapy with a steel and Teflon cannula, and a trial of desensitization, but reactions persisted. Delivery of steroids mixed with insulin via pump was ineffective. Oral dexamethasone slightly improved symptoms, but exacerbated hyperglycemia. Treatments with cyclosporine, IVIG, dupilumab, and dapsone led to adverse events, including malaise, emesis, and aseptic meningitis, without improvement in the injection site reactions. Additionally, topical tacrolimus and cromolyn were ineffective. The family considered traveling to Europe to pursue the Accu-Chek® DiaPort, which delivers insulin via a percutaneous port with intraperitoneal catheter (6). However, they ultimately refrained since it was not FDA approved in the US.

Despite receiving 1.7 units/kg/day of aspart via an Omnipod pump, with site changes every 36–48 h, HbA1c remains elevated at 9.0% at the time of writing.

Although rare, given the life-sustaining nature of insulin in T1D, it is crucial to learn from these cases of insulin hypersensitivity. Successful treatment remains elusive despite trials with various insulins, antihistamines, and even pancreas transplantation. Further studies to elucidate the underlying pathophysiology and development of targeted treatments are needed.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Institutional review board approval for publication was obtained per institutional guidelines for case series that involve more than three patients. Ethics guidelines were met in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). Written informed consent was obtained from the patient’s parents/legal guardians for publication of the details of this medical case and any accompanying images, and patient assent was obtained for patients aged >12 years old.

EHA authored this manuscript in close collaboration with BEM. All authors reviewed the manuscript prior to submission. EHA, JBG, AMA, MDB, JPB, and BEM were involved in the clinical care of patient A; EMJ and MDB were involved in the clinical care of patient B; MK, KPM, and BIP were involved in the clinical care of patient C; and KSB and TLP were involved in the clinical care of patient D.