Side Effects of Allergy Immunotherapy: A Clinical Overview of AIT Adverse Events

The most common adverse effects of allergy immunotherapy are local reactions at the allergen delivery site. For SCIT (injections), injection-site reactions — erythema, swelling, and induration at the injection arm — affect 26-86% of patients and are considered expected. For SLIT (drops or tablets), oral-local reactions — oral pruritus, throat irritation, ear pruritus, and mild sublingual edema — affect 40-75% of patients during the build-up phase. Both types of local reactions are self-limiting and rarely require treatment beyond ice or antihistamine for SCIT, or patience for SLIT. Systemic reactions affecting the whole body are substantially less common: approximately 0.1-0.2% of SCIT injection visits and 0.056% of SLIT doses. The discontinuation rate due to adverse events is approximately 3% for both modalities across controlled trial data (Dretzke 2013).

Uncontrolled asthma is a contraindication to both SCIT and SLIT — but well-controlled asthma is not. The critical distinction is pulmonary function: patients with FEV1 below 70% predicted should not receive AIT injections, as impaired respiratory reserve dramatically increases the risk of fatal anaphylaxis. In the Bernstein 2004 SCIT fatality survey, 88% of detailed fatalities occurred in patients with asthma, most of it suboptimally controlled. The 2011 Practice Parameter (Cox et al., JACI) and CSACI guidelines define FEV1 less than 70% as a defined risk factor. Conversely, well-controlled asthma patients can benefit substantially from AIT: the PAT 10-year follow-up (Jacobsen 2007, Allergy) found SCIT-treated children were significantly less likely to develop asthma (25% vs 45% of controls). SLIT also reduces asthma development risk in pediatric populations.

No evidence from population-level studies supports the claim that AIT causes autoimmune disease. A Danish nationwide registry study (Linneberg 2012, JACI) comparing SCIT-treated patients with pharmacotherapy controls found that SCIT was associated with lower autoimmune disease risk, lower acute MI risk, and lower all-cause mortality — an anti-inflammatory signal opposite to the theoretical concern. Case reports exist of various autoimmune phenomena (Sjogren's syndrome, scleroderma, vasculitis, thyroiditis) temporally associated with SCIT, but these have not been confirmed at the population level. Active autoimmune disease is a contraindication to AIT in EAACI guidelines — classified as a precautionary relative contraindication rather than evidence-based. Well-controlled or in-remission autoimmune disease is managed on an individualized basis.

Epinephrine administered intramuscularly is the first-line treatment for systemic reactions at WAO Grade 2 with respiratory involvement and all Grade 3-4 reactions — it cannot be replaced by antihistamines or corticosteroids for anaphylaxis treatment. Standard AAAAI dosing is 0.3-0.5 mg of 1:1000 solution (1 mg/mL) IM into the mid-outer anterolateral thigh for adults; 0.01 mg/kg (max 0.3 mg child) for pediatric patients. Adjunctive treatments include high-flow oxygen, IV isotonic saline, inhaled albuterol for residual bronchospasm, and H1/H2 antihistamines as adjuncts only. Patients with beta-blocker use require glucagon (1-5 mg IV) as epinephrine rescue bypassing beta-receptor blockade. The AAAAI Anaphylaxis Practice Parameter recommends at least 4-8 hours of observation for moderate reactions and up to 24 hours for severe reactions due to biphasic recurrence risk.

The World Allergy Organization subcutaneous immunotherapy systemic reaction grading system (Cox et al., JACI 2010) classifies reactions by the most severe organ system involved: Grade 1 involves one organ system with mild symptoms (generalized pruritus, urticaria, rhinitis, or conjunctivitis); Grade 2 involves multiple organ systems or mild lower-respiratory asthma responding to bronchodilator; Grade 3 is severe lower-respiratory asthma with FEV1 drop greater than 40% not responding to bronchodilator, or laryngeal/uvula/tongue edema; Grade 4 is anaphylaxis with respiratory failure or hypotension; Grade 5 is death. In SCIT surveillance data, Grade 1 accounts for 74%, Grade 2 for 23%, and Grade 3 for 3% of all systemic reactions. This classification system also applies to SLIT, where approximately 98% of systemic reactions fall in Grades 1-2.

The 2011 Practice Parameter Summary Statement 20 is clear: allergy immunotherapy can be continued during pregnancy, but is usually not initiated in a pregnant patient. The rationale is that systemic reactions carry fetal risk — hypoxia from anaphylaxis can cause fetal distress, and uterine contractions have been reported. Patients already at maintenance dose may safely continue at that dose; dose escalation during pregnancy is discouraged. Evidence supporting continuation is reassuring: Metzger 1978 found no excess prematurity, toxemia, or congenital malformations in 121 pregnancies of SCIT-treated mothers; Larsson 2022 in a Swedish nationwide registry of 743 AIT-exposed pregnancies found no association with congenital malformations, preterm birth, or stillbirth. For venom immunotherapy in a patient with life-threatening sting allergy, the risk-benefit calculation reverses and treatment is recommended during pregnancy.