Supplementary Material for: Predictors of Fatal Anaphylaxis: A Systematic Review

Background:
Fatal anaphylaxis is a rare but devastating outcome of severe allergic reactions. Identifying predictors of fatal anaphylaxis is essential to guide prevention, early intervention, education and management strategies.

Methods:
A systematic review was conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive health sciences librarian -assisted search of MEDLINE, Embase, Cochrane Library, Scopus, and Web of Science identified studies published from inception to December 2024. Inclusion criteria encompassed observational studies and randomized controlled trials investigating fatal anaphylaxis in adults and children. Risk of bias was evaluated using the Newcastle-Ottawa Scale.

Results:
A total of 3,006 studies were identified through five databases. After removing 1,038 duplicates, 1,968 unique records were screened. Of these, 136 full-text articles were assessed for eligibility, and 28 met the inclusion criteria. The included studies were conducted across 20 countries. Of the 28 included studies, 27 were retrospective cohort designs and one was a case-control study. This predominance of retrospective designs is expected given the rare and unpredictable nature of fatal anaphylaxis. Food allergens (particularly peanuts and cow's milk), medications (e.g., antibiotics, contrast media, and neuromuscular blockers), and insect stings were the most common triggers of fatal anaphylaxis. Asthma, cardiovascular comorbidities, and older age (≥65 years) were frequently reported predictors of mortality. Delayed epinephrine administration defined as more than 30 minutes after symptom onset or failure to administer in the pre-hospital setting was also associated with fatal outcomes. Subgroup analyses identified higher risk among patients with multiple comorbidities and those exposed to high-risk allergens, including peanuts and cow’s milk in children (<18 years) and perioperative medications in older adults (≥65 years). Risk of bias analysis indicated moderate study quality, with limitations largely due to retrospective designs and inconsistent reporting.

Conclusions:
Asthma, cardiovascular comorbidities, older age, and delayed epinephrine administration were key predictors of fatal anaphylaxis. These findings highlight the need for timely intervention and targeted strategies, while emphasizing the importance of improved global data and standardized methodologies.