Insulin Allergy

Insulin allergy is an immune reaction to insulin or to its additives. It is rare with recombinant human and analogue insulins, and most local skin reactions are caused by technique or additives.

Pathophysiology. Reactions are IgE-mediated (immediate), type III or type IV (delayed). Targets include insulin itself, protamine (in NPH insulin), zinc, metacresol, phenol, glycerol and latex stoppers. IgG and IgE anti-insulin antibodies can form on any insulin, but few cause clinical allergy.

Local reactions occur in up to 2 to 3% of patients, and generalised reactions are very rare. Protamine allergy is more frequent in people with prior NPH insulin, fish allergy or vasectomy, and carries a risk of reactions to protamine used in cardiac surgery.

Reactions mostly start in the first weeks of treatment or on restarting insulin after a break.

• Immediate local reaction: itching, redness and wheal at the injection site within minutes
• Biphasic reaction: immediate, then a late reaction at 4 to 8 hours
• Delayed nodules or induration at 4 to 24 hours (type III and IV)
• Generalised urticaria, angio oedema, wheeze
• Anaphylaxis (rare)
• Local lipohypertrophy or lipoatrophy (not allergic)
• Insulin resistance in rare high titre antibody states

• History: type of insulin, timing, pattern (immediate, biphasic, delayed), and number of sites affected.
• Skin prick and intradermal tests with the insulin preparations in use, alternative insulins, and additives (protamine, zinc, metacresol, phenol, glycerol), using non-irritating dilutions and controls.
• Specific IgE to insulin and total anti-insulin antibodies.
• Review of injection technique: needle length, site rotation, cold insulin, alcohol on skin, and latex in the vial or cartridge.
• Exclusion of other causes: infection, lipohypertrophy, skin disease, and allergy to needles or adhesive.

Differential diagnosis.

• Injection technique and irritant reaction
• Lipohypertrophy and lipoatrophy
• Reaction to latex or adhesive
• Allergy to additives (protamine, metacresol, zinc)
• Hypoglycaemia symptoms and other drug reaction
• Mastocytosis and urticaria

• Local reactions: correct technique, rotate sites, warm the insulin to room temperature, and give cetirizine 10 mg orally once daily in adults (children 1 to 5 years 2.5 mg twice daily; 6 to 11 years 5 mg twice daily). Most settle within 2 to 4 weeks.
• Change the preparation: switch brand or type (human, analogue, or a formulation with different additives), choosing the one with negative skin tests. Avoid protamine containing NPH insulin when protamine allergy is suspected.
• Continuous subcutaneous insulin infusion with a rapid acting analogue is helpful for patients with persistent local reactions.
• Systemic reactions: adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) into the anterolateral thigh, repeated after 5 minutes if no improvement, plus oxygen and intravenous fluids, and observation for at least 6 hours.
• Desensitisation when insulin is essential and allergy persists: in hospital, starting with a dose of about 0.001 units and doubling every 15 to 30 minutes until the usual dose is reached, followed by daily dosing to maintain tolerance.
• Adjuncts: short courses of corticosteroid (prednisolone 0.5 mg/kg daily for 1 to 2 weeks) in selected patients, and omalizumab in specialist care.
• Protamine allergy: tell the anaesthetist and cardiac surgeon before surgery.

Special groups.

• Pregnancy: insulin is needed, so use tested alternatives and avoid delay in treatment.
• Type 1 diabetes: ketoacidosis risk means insulin must not be stopped without a plan.

Monitoring. Review skin at each visit, with glucose monitoring and HbA1c every 3 months. Inspect injection sites. Review after any change of insulin preparation.

Referral and escalation. Refer to allergy and diabetes specialists for generalised reactions or persistent local reactions. Emergency for anaphylaxis, or for ketoacidosis if insulin is withheld.