Biologic Agent Hypersensitivity

Biologic agent hypersensitivity is a reaction to monoclonal antibodies and fusion proteins, which can be infusion related, IgE-mediated, delayed or caused by anti-drug antibodies. Reactions may be severe, and the choice of response depends on the mechanism.

Pathophysiology. Infusion reactions are often cytokine release or complement activation during the first infusions (rituximab, infliximab). IgE-mediated reactions occur in some (cetuximab with pre-existing alpha gal IgE, omalizumab, natalizumab). Anti-drug antibodies cause infusion reactions and loss of effect, in particular for infliximab. Delayed reactions include serum sickness like illness and injection site reactions.

Rates vary by drug: infusion reactions with infliximab occur in about 5 to 20% of patients, and omalizumab anaphylaxis in about 0.1 to 0.2%.

Chimeric agents (infliximab, rituximab, cetuximab) are more immunogenic than humanised or fully human antibodies.

• During infusion: flushing, itching, rash, fever, chills, headache
• Dyspnoea, wheeze, chest tightness, hypotension
• Anaphylaxis with collapse
• Delayed (days): serum sickness like illness with fever, arthralgia, rash
• Injection site reactions with subcutaneous agents
• Loss of response with anti-drug antibodies
• Omalizumab anaphylaxis, which may occur up to 24 hours or more after injection

• History: drug, infusion number, rate, premedication, features, and timing.
• Classification: cytokine release (first infusions, fever and rigors, tryptase normal), IgE-mediated (urticaria, bronchospasm, hypotension, tryptase raised), delayed, or anti-drug antibody mediated.
• Serum tryptase within 1 to 2 hours of the reaction, with a baseline later.
• Drug levels and anti-drug antibodies for infliximab, adalimumab and others where a reaction coincides with loss of response.
• Skin testing with the drug (undiluted prick, then diluted intradermal) in specialist centres.
• Alpha gal specific IgE before cetuximab if the patient has had tick bites or unexplained delayed reactions to meat.

Differential diagnosis.

• Cytokine release syndrome
• Infusion reaction from excipients (polysorbate)
• Alpha gal syndrome (cetuximab)
• Serum sickness and vasculitis
• Cardiac event or pulmonary embolism
• Sepsis and underlying disease flare

• Stop the infusion at the first sign of reaction.
• Mild or moderate infusion reaction: chlorphenamine 10 mg intravenously, hydrocortisone 100 mg intravenously, and paracetamol 1 g orally. After symptoms resolve, restart at 50% of the previous rate and increase stepwise.
• Severe reaction or anaphylaxis: 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.
• Premedication for later infusions after a mild reaction: paracetamol 1 g, chlorphenamine 10 mg and hydrocortisone 100 mg given 30 to 60 minutes before, with a slower infusion rate.
• IgE-mediated reactions: avoid the drug, or use rapid desensitisation in a monitored unit when it is needed.
• Anti-drug antibodies: switch to another agent or add an immunomodulator (such as methotrexate or azathioprine) under specialist direction.
• Omalizumab: observe for 2 hours after each of the first 3 injections and 30 minutes afterwards, and give an adrenaline auto injector (150 microgram for 7.5 to 25 kg, 300 microgram for 25 to 50 kg, 500 microgram for over 50 kg).
• Cetuximab: avoid in patients with alpha gal IgE.
• Serum sickness like reaction: stop the drug, give prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) tapered over 1 to 2 weeks.

Special groups.

• Patients on a first infusion: slow rates and observation with resuscitation facilities.
• Patients with prior reaction: joint decision by the prescriber and allergy team about continuing or switching.

Monitoring. Vital signs every 15 minutes during the first infusions. Observation after the end of the infusion. Drug levels and anti-drug antibodies when response falls.

Referral and escalation. Refer to allergy for any reaction beyond mild, or when a biologic is essential after a reaction. Emergency for anaphylaxis.