Table 3 Clinical History

ANAMNESIS

Clinical history, e.g.:

 -patient demographics: age, gender^#, medical and atopic history, ongoing medications, jobs, hobbies, sports

 -family history (including unusual reactions/clinical manifestations not otherwise diagnosed)

 -description of episodes: suspect/known triggers, timing of onset, temperature exposure, time of the day/night, duration, location (e.g. school, home, indoor, outdoor), presence of cofactors*

 -if further hospital/urgent care access: tests prescribed, therapy needed, response to medications, recovery time or recurrences, need for admission in Pediatric Intensive Care Unit (PICU)

IF DIAGNOSIS SUGGESTS ALLERGY-DRIVEN ANAPHYLXIS

Foods

Medications

Sting/bites

 -ask for new ingredients (e.g., spices, herbs or foods coloring)

-ask for new restaurants/food delivery companies

 -if fish preparations are a possible trigger: check also for Anisakis (Ani s1) [30]

 -if wheat is a possible trigger: check for omega-5-gliadin (Tri a19), Tri a14, high-molecular-weight glutenin [31]

 -if fruit and vegetables are involved: check for oral allergy syndrome to Lipid Transfer Proteins (LTPs), gibberellin-regulated proteins (GRPs), and oleosins proteins [32]

 -check presence of bee pollens in honey products [33, 34]

-check presence of edible insect proteins [35]

-ask for consumption of herbal and tea drinks, soft drinks and cocktails [36,37,38]

 -if available, read ingredient labels carefully (e.g., synonyms for food allergens) [39]

 -do not forget of pancakes syndrome [40]

-also consider disinfectants, herbal and alternative products, vitamins, supplements, beauty products as medical products

-investigate for possible vaccine allergens: e.g., gelatin, neomycin

-although quite rare, Kounis syndrome to drugs or other allergens [41, 42] must be excluded in case of potential clinical manifestations

-although rare, pigeon tick could trigger anaphylactic reactions: the bite of Argas Reflexus, a parasite with nocturnal activity, could elicit allergic reactions including anaphylaxis. In case of skin insect bites, ask about presence of pigeons nearby. Diagnosis could be confirmed with specific IgE determination (Arg r1) [43]

-check for insect or animal bites: e.g., Hymenoptera, fire ants, spiders, uncommon insects [44]

Think about allergy to alpha-gal (e.g., mammalian meat or biologic drugs derived from mammalian cell lines), which typically presents as a nocturnal anaphylaxis especially in areas with a high prevalence of tick bites [45]^§

Investigate for possible exposure to latex: e.g., hospital/clinic visits, Band-Aid use, toys, balloons, swimming equipment; cross reactivity with fruits (banana, avocado, kiwi, chestnut)

Aeroallergens: e.g., marijuana

IF THE CLINICAL SCENARIO SUGGESTS A NON-ALLERGEN DRIVEN ANAPHYLAXIS

1) exclude mast-cellactivation diseases (MCAD): patients, including children, with systemic mastocytosis (SM) have a higher risk of severe anaphylaxis due to mast cell activation and release of mast cells mediators [46]; therefore, a MCAD must be carefully investigated [47, 48] to exclude SM or other MCAD. Although the most common pediatric presentation of mastocytosis is cutaneous mastocytosis [49, 50], both forms should be investigated, as patients could present systemic signs and symptoms suggesting an anaphylactic reaction

2) exclude HaT: the increase in tryptase should be an indicator to take into account. Be aware that normal tryptase levels vary upon age [51], but a genetic consultation is generally advised if basal tryptase > 8 ng/mL, since more severe reactions are associated with HaT [52, 53]

3) consider other medical diseases with signs and symptoms similar to anaphylaxis such as vancomycin therapy (vancomycin infusion reaction). The latter occurs on exposure to the drug through Mas-related G-protein-coupled receptor member X2 (MRGPRX) activation, pheochromocytoma, carcinoid syndrome, medullary thyroid carcinoma, pancreatic cell tumors [54]

4) consider chronic urticaria/angioedema aggravated by NSAIDs

5) Consider complement activation (CARPA) such as preceding exposure to nanomedicines or biological drugs