Adherence to adrenalin autoinjector prescriptions and immunotherapy in anaphylaxis patients with special focus on venom allergy

Anaphylaxis is a life-threatening reaction where several organs can be involved, and immediate treatment is needed. Elicitors for anaphylaxis are food, drugs, and venom. The primary treatment for anaphylaxis is adrenaline autoinjector (AAI). Venom allergy (from vespid or honeybee sting) can cause systemic allergic reactions, from mild skin symptoms to moderateto-severe symptoms with anaphylaxis. Allergic symptoms followed by a sting have been reported in 3.4% of children and 7.5% of adults. Venom immunotherapy (VIT) is a treatment that can prevent further systemic allergic reactions after a sting. Adherence to AAI and VIT depends on several factors, e.g., prescription and retrieval rate. AAI and VIT are important, potentially life-saving treatments heavily reliant on adherence, and more data are needed to identify factors associated with low levels of adherence. This thesis aimed to investigate adherence to AAI prescriptions and completion of immunotherapy in patients with anaphylaxis, focusing on venom allergy. The thesis is based on prescription registers (Study I, II, and III) and a questionnaire (Study III).

In Study I, we analyzed adherence to AAI prescriptions in a group of well-characterized patients with anaphylaxis and evaluated factors associated with low levels of adherence. We included patients from a prospective study with suspected anaphylaxis at the Emergency Department (ED), Odense University Hospital (OUH), Denmark, between 2013 and 2014, whoafterward had a diagnostic work-up at the Allergy Centre, OUH, to verify the diagnosis. InStudy II, we evaluated adherence to AAI and VIT in patients with venom allergy, factors associated with low levels of adherence, and compared adherence to VIT with adherence tosubcutaneous immunotherapy (SCIT) with inhalant allergens (grass, birch, and house dustmites). This study was also retrospective and register-based. All patients were registered forallergen immunotherapy (AIT) at the Allergy Centre, OUH, between 2010 and 2014 and purchased at least one maintenance immunotherapy vial at the pharmacy. In Study III, we investigated the self-reported course of VIT and evaluated factors associated with severe initialsting reaction, side effects during VIT, re-sting reactions after VIT, and adherence. The selfreported adherence was compared with the retrieval rate from the prescription database. Allincluded patients were registered for VIT at the Allergy Centre, OUH, between 2010 and2019 and purchased at least one maintenance immunotherapy vial at the pharmacy. 

In Study I, we report that 76% (53/70) collected their prescribed AAI and observed that severe anaphylaxis was associated with higher adherence to AAI (p=0.02). Furthermore, therewas a tendency to lower adherence in the groups with unknown elicitors and young adults. In Study II, we found that five-year adherence to VIT was 84% (222/264) in contrast to 75%(184/246) in SCIT with inhalant allergens (p=0.045). Females were associated with higheradherence to VIT (p=0.008). Adherence to AAI before treatment with VIT was 77%(204/264). Moreover, adherence to AAI after premature termination of VIT was 29%(12/42). In Study III, we report that 20% (88/452) of the cases had side effects during VIT.Risk factors for side effects were honeybee venom (p=0.009) and female sex (p=0.001).However, moderate-to-severe side effects were associated with female sex (p=0.004) andmoderate-to-severe initial sting reaction (p=0.049). Among those who completed VIT, 33%(75/224) were re-stung, and 17% (13/75) had allergic reactions after re-sting. Re-sting reactions (treatment failure) were associated with side effects during VIT (p=0.016). One factorrelated to high adherence to AAI before treatment with VIT was moderate-to-severe initialsting reactions (p=0.018). Based on the questionnaire, adherence to VIT was 84% (254/304)versus 79% (239/304) based on the prescription database.

In conclusion, this thesis demonstrates that i) severe anaphylaxis was associated with higheradherence to AAI, ii) patients treated with life-saving VIT were more adherent than patientstreated with conventional SCIT with inhalant allergens, and if premature termination of VIT,few purchased an AAI, and iii) moderate-to-severe side effect were associated with femalesex and moderate-to-severe initial sting reaction and re-sting reaction were associated withside effect during VIT. Since the studies, the settings have changed for patients in Denmark.Receiving VIT or SCIT with inhalant allergens in the hospital is now without cost to the patient. Therefore, a new study on adherence to VIT and to SCIT with inhalant allergens wouldbe interesting to evaluate the effect of free treatment. Additionally, future studies should focus on the subpopulation that does not retrieve their AAI after premature termination of VIT.