Table 1 Selected key interventions as product of recommendations

Emergency department/allergy specialist (ES)

 ES1

[19]

Document the acute clinical features of the suspected anaphylactic reaction (rapidly developing, life-threatening problems involving the airway [pharyngeal or laryngeal edema] and/or breathing [bronchospasm with tachypnea] and/or circulation [hypotension and/or tachycardia] and, in most cases, associated skin and mucosal changes)

Provide clinical symptoms of the acute phase in case of a suspected anaphylactic reaction

I1

 ES2

[16]

Base the diagnosis of anaphylaxis on the history and physical examination, using scenarios described by the National Institutes of Allergy and Infectious Disease (NIAID) Panel but recognizing that there is a broad spectrum of anaphylaxis presentations that require clinical judgment. Do not rely on signs of shock for the diagnosis of anaphylaxis

Diagnose anaphylaxis using scenarios described by the NIAID panel, and do not rely only on shock signs

I12, I13

 ES3

[7]

For diagnosis of doubtful reactions, collect blood (ideally within 1–2 h but no later than 4 h from the onset of symptoms) for serum tryptase testing (3 ml clotted sample, serum separated and froze)

Dose serum tryptase, within 4 h, in case of a doubtful reaction

I3

 ES4

[7]

Record the daily medication and any additional self-medication taken on the day of the sting, in particular ACE inhibitor or beta-blocker

Record drug therapy assumed on the day of the sting, paying close attention to cardiological and/or hypotensive therapies

I2

 ES5

[28]

Glucagon sometimes needed in patients taking a beta-adrenergic blocker who have hypotension and bradycardia and who do not optimally respond to adrenaline. Glucagon can be administered in adult patients intravenously at a dose of 1 mg as an initial IV bolus, repeatable every 5 min, increasing the dosage to 3–5 mg if necessary. The administration for continuous infusion in syringe pump should be carried out at the dose of 1–5 mg/h

Administer glucagone in patients under beta-blocking therapy with hypotension and low heart rate when they do not react optimally to adrenaline administration, taking into consideration it is an “off-label” therapy

I2

 ES6

[28]

The patient, after receiving the appropriate therapies and obtained the resolution of clinical picture, should be kept under observation and monitored for at least 6–8 h up to 24 h depending on severity and characteristics of the reaction at onset, comorbidity and risk factors

Observe and monitor the patient after clinical resolution for at least 6–8 h and up to 24 h depending on the patient’s clinical conditions

I4, I5, I6, I7

 ES7

[7]

After emergency treatment for suspected ISA, prescribe the patient (or, as appropriate, their parent and/or caregivers) an AAI that is appropriate for age and body mass. Patients must receive a referral to a specialist allergy service

Prescribe an adrenaline auto-injector after emergency treatment of the insect sting anaphylaxis

I10, I19

 ES8

[19]

Before discharge a healthcare professional with the appropriate skills and competencies should offer people (or, as appropriate, their parent and/or carer) the following:

  Information about anaphylaxis, including the signs and symptoms of an anaphylactic reaction

  Information about the risk of a biphasic reaction

  Information on what to do if an anaphylactic reaction occurs (use the adrenaline injector and call emergency services)

  A demonstration of the correct use of the adrenaline injector and when to use it

  Advice about how to avoid the suspected trigger (if known)

  Information about the need for referral to a specialist allergy service and the referral process

  Information about patient support groups

Before discharge, offer the patient suitable information regarding the recognition of anaphylaxis signs and symptoms and the correct use of the adrenaline autoinjector

I10, I18, I19

 ES9

[19]

After emergency treatment for suspected anaphylaxis, offer people a referral to a specialist allergy service (age-appropriate where possible) consisting of healthcare professionals with the skills and competencies necessary to accurately investigate, diagnose, monitor and provide ongoing management of, and patient education about, suspected anaphylaxis

After emergency treatment of suspected anaphylaxis, refer the patient to a specialist allergy service for future management

I10, I20

 ES10

[17]

Referral to an allergist-immunologist is recommended for patients who might be candidates for VIT

As for ES9

Diagnosis (D)

 D1

[28]

History includes the description of the symptoms and of the course of the reaction (possibly documented by a medical report), the number of stings, the characteristics of the culprit insect (where possible) and the identification of specific risk factors for the severity of reaction

Collect careful clinical history of the reaction, including the possible trigger factors

I1, I12

 D2

[28]

Since it is possible to document a sensitization to the venoms in 10–30% of subjects with negative history, only patients with a history of previous systemic reaction should be investigated

Perform diagnostic investigations only in patients with a clinical history of previous systemic reaction

I12, I13

 D3

[28]

In patients with a history of LLR, skin tests (as well as specific IgE determination) may be considered as optional, at the discretion of the clinician in specific cases, like in patients at a greater risk of re-sting with recurrent and bothersome LLRs (e.g. beekeepers, farmers) who could benefit from immunotherapy

Perform skin tests in patients with a clinical history of LLR at higher risk of re-sting with the aim of prescribing a possible VIT

I13, I20

 D4

[28]

Sting challenge with a live insect should not be used for diagnostic purposes, due to the risk of systemic, potentially severe reactions and low negative predictive value

Do not perform sting challenge for diagnostic purposes

I13

 D5

[28]

Allergy to bumble bees, due to its low aggressiveness, concerns a limited number of subjects, in particular professionally exposed individuals [8], and it should therefore be investigated on the basis of a specific anamnestic suspicion, provided that a suitable extract is commercially available for diagnosis

In case of a suspected clinical history, perform diagnostic investigations for Bumble bee also with the aim of prescribing a possible VIT

I12, I13

 D6

[28]

In Europe, standardized venoms of Apis mellifera, Vespula spp., Polistes spp., Vespa crabro are currently, available. The venoms of Vespula and Polistes consist of a mix of clinically relevant species. Because of low cross-reactivity between European and American Polistes venoms, extracts of Polistes dominula are now available for both diagnosis and VIT

Use Polistes dominula venom both for diagnostic tests and VIT

I13, I21

 D7

[28]

The prick test is carried out at the 100 μg/mL concentration

Perform skin prick tests to the biggest concentration of 100 μg/mL

I13

 D8

[28]

Intradermal tests should be performed even in case of positive prick test to identify correctly the cutaneous end-point which will be useful in VIT follow-up

Perform intradermal test even in case of positive skin prick test for diagnosis and VIT follow-up

I13

 D9

[28]

Intradermal tests should be carried out by the administration of 0.02 mL of the allergenic extract into the dermis, causing the development of a wheal approximately of 3 mm in diameter. The reading should be performed after 15–20 min; the positivity is documented by an increase of at least 3 mm of the average diameter of the initial wheal, with associated erythema. To allow comparison of results, a morphological score should be used, which consists in drawing, on transparent cellophane, the area injected and the area of the reaction after 15–20 min of time

Perform intradermal test administering 0.02 mL of the allergenic extract, collecting the result after 15–20 min. To allow the comparison of the results, use a morphological score consisting in drawing on a transparent tape the injected area and the reaction area after 15–20 min

I13

 D10

[28]

The panel of Italian experts, considering that available data are insufficient, recommends a preliminary step where the same concentration of more venoms is simultaneously used for skin testing. Only after reading the reactions to this first set, a higher concentration should be used. This caution is to be maintained specially in patients with severe anaphylactic reaction or suffering from mast cells disorders

Perform simultaneously the same concentration of different venoms and hereafter the following concentration

I13

 D11

[20]

Do not rely on the degree of sensitivity on skin or in vitro testing because it does not reliably predict the severity of a sting reaction

Do not use skin or serological reactivity to predict the reaction severity following the sting

I13, I14

 D12

[17]

If initial test results are negative in a patient with a clear history of systemic sting reaction, further testing (in vitro testing, repeat skin testing, or both) should be performed, as well as basal serum tryptase measurement

Perform additional tests (in vitro tests, skin tests repetition, or both, and basal serum Tryptase level) in patients with a clear history of a systemic reaction after a sting and negative skin tests

I13

 D13

[22]

If the allergic reaction in mastocytosis patients occurred many years before, the negativity of test could depend from this physiologic decrease and it could be useful to repeat further tests in order to detect a possible sensitization

If the allergic reaction in mastocytosis patients occurred many years before, repeat allergy tests when negative and perform second and third level diagnostic tests

I13, I15, I17

 D14

[28]

IgE to CCD can explain multiple in vitro positive results; serum determination for CCD (bromelain or MUXF3) allows greater diagnostic accuracy

Detect serum IgE to CCD (bromelin or MUXF3) in case of multiple in vitro positive results

I13

 D15

[28]

Api m 1, the most relevant allergen of bee venom, is not sensitizing in up to 43% of cases. The combination of 2 allergens (Api m 1 and 10) allows diagnosis in 86.8% of cases; the combination of 6 allergens (Api m 1–5, Api m 10) has a sensitivity of 94.4%

Simultaneously detect several bee recombinant allergens (all the disposable allergens on the market) to improve the diagnostic sensitivity

I13

 D16

[28]

Patients with Vespula spp. venom allergy are sensitized mainly to Ves v 1 and Ves v 5. The combined search of specific IgE toward these two recombinant allergens allows the identification of 92–94% of patients allergic to Vespula

Simultaneously detect specific IgE to Ves v 1 and Ves v 5 in patients with Vespula spp. (Yellow jacket) venom allergy

I13

 D17

[3]

More recently, some authors used Ves v 1 and Ves v 5 (Immulite system) to diagnose 27 patients with yellow jacket venom allergy and 53 patients with yellow jacket venom allergy and mastocytosis and/or elevated baseline serum tryptase. This study confirmed that the analyses of sIgE reactivity on a component-resolved level revealed no obvious differences in the reactivity profiles of Hymenoptera venom-allergic patients of two groups; in contrast, it showed that a diagnostic sensitivity of 100% was reached in the mastocytosis group using the recombinant allergens an the cutoff of 0.10 kUA/L, instead of the cutoff of 0.35 kUA/L

In patients with Vespula spp. (Yellow jacket) allergy suffering or not from mastocytosis and/or elevated basal serum tryptase, use a cut-off of 0.10 kUA/L to dose IgE specific levels to Ves v 1 and Ves v 5

I13, I15, I17

 D18

[28]

Another method to distinguish the double sensitization from cross-reactivity is CAP inhibition, although it may be relatively expensive and difficult to interpret. Its use, where available, appears to be very useful in case of double Vespula-Polistes cosensitization, when CRD does not suffice to discriminate the different possibilities

Perform CAP-inhibition in case of double Vespula-Polistes co-sensitization, when CRD is not discriminating

I13

 D19

[28]

The Basophil Activation Test (BAT) is the most widely used in Europe for diagnostic purposes, in selected situations. If performed in highly specialized laboratories, it can identify approximately two-thirds of patients with positive history and negative skin and serological tests

Perform basophil activation test (BAT) in patients with positive clinical history of a systemic reaction and negative skin and serological tests

I13

 D20

[28]

BAT is also recommended in patients with double positive results and inconclusive results of in vivo or in vitro tests with recombinant allergens

Perform BAT in patients with double positive results and inconclusive results of in vivo or in vitro tests with recombinant allergens

I13

 D21

[3]

In patients with HVA, the BAT was proposed as a third-level test for selected cases, and it can be useful in polysensitization patients

As for D20

 D22

[28]

The role of BAT as a diagnostic tool in patients with mastcell disorders and negative venom-specific IgE and skin test results is still controversial

Use with caution BAT for the diagnosis in patients suffering from mastocytosis with negative allergy tests

I13

 D23

[28]

It should be pointed out that patients should be investigated for mastocytosis even in the absence of cutaneous manifestations compatible with mast cell pathology and increased tryptase levels, in case a severe anaphylactic reaction with syncopal episode without urticaria and/or angioedema and a REMA score ≥ 2

Perform mastocytosis diagnostic tests in case of a severe anaphylactic reaction with syncopal episode without cutaneous/mucosal symptoms, with normal basal serum tryptase provided that REMA score is ≥ 2

I15, I17

 D24

[17]

Counsel patients with elevated basal serum tryptase about the clinical significance of potential underlying mast cell disorders

Counsel patients with elevated basal serum tryptase level and/or a severe systemic sting reaction about the potential underlying mast cell disorders

I15, I17

 D25

[17]

Consider measuring basal serum tryptase in all patients who are candidates for VIT

Measure basal serum tryptase level in all patients who are candidates to VIT

I13, I20

 D26

[6]

An anaphylaxis management plan should be used from the time of diagnosis to prevent future reactions, and aid recognition and treatment of any further reactions

Use an anaphylaxis prevention and management plan from the time of diagnosis

I18, I19

 D27

[20]

Individualize avoidance measures taking into consideration factors such as the patient’s age, activity, occupation, hobbies, residential conditions, access to medical care, and level of personal anxiety

Personalize the avoidance measures

I18

Pharmacological treatment (TF)

 PT1

[7]

Adrenaline is potentially lifesaving and must therefore promptly be administered as the first-line treatment for the emergency management of anaphylaxis

Administer adrenaline as the first-line anaphylaxis treatment because of its α- and β-adrenergic effect

I19

 PT2

[28]

Adrenaline slows the progression of symptoms and can prevent the development of fatal or biphasic reactions

Administer adrenaline as a first-choice anaphylaxis treatment, even for preventing biphasic reactions

I2, I19

 PT3

[18]

Epinephrine should be injected by the intramuscular route in the mid-anterolateral thigh as soon as anaphylaxis is diagnosed or strongly suspected, in a dose of 0.01 mg/kg of a 1:1000 (1 mg/mL) solution, to a maximum of 0.5 mg in adults (0.3 mg in children). Depending on the severity of the episode and the response to the initial injection, the dose can be repeated every 5–15 min, as needed

Administer adrenaline by an intramuscular route in the mid-anterolateral thigh in a dose of 0.01 mg/kg of a 1:1.000 (1 mg/mL) solution, to a maximum of 0.5 mg in adults (0.3 mg in children 30 kg of weight). The dose con be repeated every 5–15 min, as needed

I2, I19

 PT4

[7]

Aspiration of adrenaline from a vial is time-consuming and the delay may prevent the beneficial effects of the drug; therefore, AAIs are recommended

Prescribe adrenaline in autoinjector device

I19

 PT5

[28]

In obese or overweight patients, the reduced length of the needle does not always ensure the intramuscular administration, therefore the patient should be advised to press well the autoinjector on fatty thigh, to compress it and allow the penetration of the needle into the muscle

Instruct obese patients to press well the autoinjector on fatty thigh to compress it and allow the penetration of the needle into the muscle

I19

 PT6

[28]

If a correct dosage is administered, it can be used, without absolute contraindications, in pediatric and geriatric populations and in cardiopathic patients, except for some cardiac pathologies such as for example long QT syndrome (in this case, the administration should be performed with extreme caution, in case of real need and in the presence of the cardiologist)

Administer adrenaline in pediatric and geriatric population and in cardiopathic patients in case of anaphylaxis. In patients suffering from some cardiac pathologies, such as long QT syndrome, administer adrenaline in the presence of the cardiologist

I19

 PT7

[28]

Adrenaline remains the drug of choice for the treatment of anaphylaxis also for pregnant women

Administer adrenaline to pregnant women in case of secure anaphylaxis

I2, I19

 PT8

[20]

Supply any patient who has experienced an episode of anaphylaxis for which the allergen cannot be easily and completely avoided with an AIE and instructions as to when and how to administer this injector and emphasize that they should carry 2 AIEs with them at all times

Any patient with a clinical history of anaphylaxis should carry with him two adrenaline autoinjectors

I19

 PT9

[28]

Adrenaline autoinjector should be prescribed to the following categories of patients: children and adults undergoing VIT, but with risk factors for incomplete clinical protection (very severe onset reaction, adverse reactions during immunotherapy, lack of sting protection during VIT, bee venom allergy

Prescribe adrenaline autoinjector to children ad adults undergoing VIT with risk factors for incomplete clinical protection

I19, I21

 PT10

[7]

AAI prescription It is also indicated in healthy subjects with a documented anaphylactic sting reaction and negative testing for Venom Specific IgE until second allergy work-up within 6 weeks to 3 months later is not performed

Prescribe adrenalin autoinjector in patients with documented anaphylactic sting reaction and negative specific IgE until second allergy work-up

I10, I19

 PT11

[6]

Underlying mast cell disorders or elevated baseline serum tryptase concentrations together with any previous systemic allergic reactions to insect stings, even in VIT-treated patients are an absolute indications for prescription at least one adrenaline auto-injector

Prescribe at least one adrenaline autoinjector in patients with mast cell disorders or elevated baseline serum tryptase concentrations and with history of previous sting systemic reaction, even if in VIT treatment

I16, I19

 PT12

[7]

The prescription of a second AAI is indicated in patients with mast cell diseases and/or raised BST, previous requirement for more than one dose of adrenaline prior to reaching hospital, previous near-fatal anaphylaxis, lack of rapid access to medical assistance to manage an episode of anaphylaxis due to geographical or language barriers

Prescribe a second adrenaline autoinjector in patients with risk factors for a severe reaction

I16, I19

 PT13

[7]

The prescription of an AAI is indicated in patients with underlying mast cell disorders and anaphylactic sting reactions and negative testing for venom-specific IgE

Prescribe adrenaline autoinjector in patients with mast cell disorders and clinical history of anaphylactic reaction even if with negative IgE specific tests

I16, I19

 PT14

[28]

Patients affected by SM with a history of anaphylaxis should always carry two adrenaline autoinjectors, a recommendation also valid for patients receiving VIT

Prescribe two adrenalin autoinjectors in patients affected by systemic mastocytosis and with history of anaphylaxis, even if receiving VIT

I16, I19

 PT15

[3]

These patients should carry a self-administration emergency kit that includes oral antihistamines and corticosteroids as well as self-injectable epinephrine

Prescribe to patients with systemic mastocytosis: adrenaline autoinjectors, oral corticosteroids and antihistamines

I16, I19

 PT16

[28]

Adrenaline autoinjector should be prescribed to the following categories of patients: children and adults with systemic reactions more severe than systemic skin reaction or with a high risk of re-exposure to sting (e.g. beekeepers), before VIT

Prescribe adrenaline autoinjector to children and adults with systemic reactions or with high risk of re-exposure to sting

I19

 PT17

[7]

AAI prescription should be considered in patients with previous mild (cutaneous) sting reaction and remote from medical help

Take into consideration the prescription of an adrenaline autoinjector in patients with previous cutaneous reaction and remote from an Emergency Department

I19

 PT18

[8]

During and after VIT, AAI cannot be recommended in patients with mild-to-moderate initial sting reactions without risk factors for relapse

Do not prescribe adrenaline autoinjector to patients with mild to moderate initial sting reaction without risk factors for relapse if they are under VIT or have completed VIT

I19, I20

 PT19

[28]

The Italian experts do not rule out the possibility of prescribing adrenaline to patients at risk of multiple stings (e.g. beekeepers) and to those who have developed a single LLR, since in these subjects the risk of a subsequent systemic reaction to a re-sting cannot be completely excluded compared to patients who have already shown repeated LLR

Prescribe adrenaline autoinjector to patients with large local reactions when at risk of multiple sting (e.g. beekeepers) and to those who have developed a single LLR

I19

 PT20

[7]

Patients experiencing anaphylaxis should be advised on other interventions needed to manage the reaction. They should be advised to call for help, if possible, and adjust their position according to their leading symptoms: When respiratory distress is leading, they should sit or remain seated, and when symptoms of circulatory instability are leading, they should lie down on their back with the lower extremities elevated

Advise patients with history of anaphylaxis on the interventions needed to manage the reaction, in particular how to adjust their position

I18

 PT21

[17]

Advise the patient to treat acute systemic reactions to insect stings like any anaphylactic reaction, with timely transport to an Emergency Department

Treat acute systemic reactions to sting like potential anaphylactic reactions, with timely transport to an Emergency Department

I1, I2, I18

 PT22

[16]

Do not routinely administer antihistamines or corticosteroids instead of epinephrine. There is no substitute for epinephrine in the treatment of anaphylaxis

Administration of H1 and/or H2 antihistamines and corticosteroids should be considered adjunctive therapy

Do not administer antihistamines or corticosteroids instead of adrenaline during an anaphylactic reaction, but only as a second line adjunctive therapy

I2, I19

 PT23

[7]

Glucocorticoids in the treatment of anaphylaxis potentially relieve protracted anaphylaxis symptoms and are thought to prevent biphasic anaphylaxis, although these effects have never been proven

Administer corticosteroids to relieve protracted anaphylactic symptoms (however not in adrenaline replacement) and probably to prevent biphasic anaphylaxis, although this effect has never been proven with controlled randomized trials

I2

 PT24

[7]

Patients may receive a set of tablets containing an adequate dose of a rapidly effective non-sedating oral antihistamine (e.g. levocetirizine 10 mg, cetirizine 20 mg, or double dose for children according to the age) and corticosteroids (e.g. prednisone: for adults 50–100 mg and 1–2 mg/kg body weight in children). For mild SARs, oral antihistamines and corticosteroids are a sufficient treatment. However, their use should not delay self-treatment with an AAI if one is carried and extracutaneous symptoms occur

Prescribe oral antihistamines and corticosteroids only for mild systemic reactions

I2

 PT25

[17]

Treat large local reactions symptomatically, with antihistamines, cold compresses, and analgesics as needed. In severe cases a short course of oral corticosteroids may be useful. Antibiotics are usually not necessary and should be prescribed only if specifically indicated

Treat large local reactions with cold compresses, eventually with pharmacological therapy based on oral antihistamines and analgesics. In severe cases administer oral corticosteroids. Antibiotics are usually not necessary

I18

 PT26

[7]

Patients with asthma should be advised to carry their inhaled short-acting beta-2-agonist and to use as many inhalations as needed if respiratory difficulty follows a sting

Advise patients with asthma to use inhaled short-acting β2-agonist if respiratory difficulty follows a sting

I18

Venom immunotherapy (VIT)

 VIT1

[17]

Begin VIT with initial dose of up to 1 µg and increase to maintenance dose of at least 100 µg of each venom

Begin VIT with initial dose of up to 1 µg and increase to maintenance dose of at least 100 µg of each venom

I21

 VIT2

[8]

It is recommended to administer a standard maintenance dose of 100 µg venom

Administer a standard maintenance dose of 100 µg venom

I21

 VIT3

[8]

Purified venom preparations can be recommended as they have a lower frequency of local and systemic adverse events than non-purified aqueous preparations

Recommend aqueous purified venom preparations rather than non-purified aqueous venom preparations as they are better tolerated and have lower risk of systemic reactions during VIT

I21

 VIT4

[8]

It may be recommended that patients treated with bee venom and those on rapid up dosing protocols should be closely observed for side-effects as they are at a higher risk of experiencing adverse events

Closely observe patients under VIT with bee venom and those on rash or ultra-rash up-dosing protocols

I21

 VIT5

[8]

In case of VIT-related systemic adverse events during build-up phase, a temporary reduction of the venom dose (e.g. going one to two steps back in the protocol) may be recommended to avoid further adverse events

In case of VIT-related systemic reactions during build-up phase, temporarily reduce the venom dose of one to two steps in the VIT protocol

I21

 VIT6

[8]

It may be recommended to avoid insect stings during build-up phase by abiding by preventive measures (e.g. stop beekeeping) until maintenance dose is reached

Recommend avoiding hymenoptera stings during build-up phase by abiding preventive measures (e.g. stop beekeeping) until maintenance dose is reached

I18, I21, I22

 VIT7

[8]

In case of repeated systemic adverse events during up dosing, pretreatment with Omalizumab may be recommended

Pretreat with Omalizumab in case of repeated systemic adverse events during VIT up-dosing, taking into account it is an “off-label” therapy

I21

 VIT8

[3]

Several case reports showed that pretreatment with anti-IgE monoclonal antibodies may permit more rapid and higher doses of allergen immunotherapy: patients with ISM who experienced SRs to VIT were able to tolerate immunotherapy after pretreatment with Omalizumab

Perform “off label” treatment with Omalizumab in patients with mastocytosis who experienced systemic reactions during VIT

I21, I16

 VIT9

[8]

If patients still react to field stings or sting challenges, a dose increase to 200 µg of venom can be recommended

Increase venom maintenance dose to 200 µg if patient is not protected with the dose of 100 µg by a field sting

I21

 VIT10

[3]

In patients with HVA and SM not fully protected at field re-stings, an increase of the maintenance dose to 200 μg of venom could be recommended

Increase venom maintenance dose to 200 µg in patients with systemic mastocytosis not fully protect by standard dose of 100 µg

I21

 VIT11

[17]

Treatment with some venoms may not be needed if cross-reactivity can be demonstrated by a radioallergosorbent inhibition test

Treatment with different venoms is not needed if cross-reactivity can be demonstrated

I13, I21

 VIT12

[28]

VIT is indicated in the following circumstances: (a) Children and adults with a systemic reaction involving other apparatus besides the skin. (b) Systemic skin reactions at high risk of exposition and/or impairment of quality of life in adults. (c) Patients with clonal mast cell disorder and a history of a systemic reaction, even though sensitization can be weak or sometimes transitory

VIT is indicated in: (i) adults and children with a systemic reaction involving other apparatus besides the skin; (ii) systemic skin reaction at high risk of exposure and/or impairment of quality of life; (iii) patients with clonal mast cell disorders and a history of a systemic reaction, even though sensitization can be sometimes transitory

I20

 VIT13

[28]

In children with only cutaneous systemic reactions, VIT is not routinely performed. However, there may be particular situations of increased risk of re-sting (e.g. children of beekeepers), possibly associated with parents’ and children’s concern or with distance from the emergency room, or unavailability of school staff administering antiallergic drugs. These conditions warrant VIT also in cases of urticarial alone

Consider to perform VIT in children with only cutaneous systemic reactions if there are particular situations (e.g. increase risk of re-sting, concern, or distance from the Emergency Department, etc.)

I20

 VIT14

[17]

In a change from previous recommendations, advise both children and adults who have experienced only cutaneous systemic reactions without other systemic manifestations after an insect sting that VIT is generally not required but may be considered when there are special circumstances. This should be a shared decision with consideration of high-risk factors (frequent exposure, cardiovascular or respiratory conditions, or selected medications) and the effects on quality of life

Advise both children (and caregivers) and adults who have experienced only cutaneous systemic reactions after an insect sting that VIT is generally not required. VIT can be considered when there are special circumstances (cardiovascular or respiratory conditions, effects on quality of life)

I20

 VIT15

[28]

In patients allergic to Hymenoptera venom, in whom a subsequent allergic reaction may be more severe or even fatal, VIT has an elective indication even if there has been a myocardial infarction or a severe ventricular arrhythmia

Suggest VIT in cardiopathic venom allergic patients when a systemic reaction occurred

I20, I21

 VIT16

[28]

VIT should be taken into consideration in older adults, even if they have experienced a non-severe systemic reaction, provided that they have risk factors such as: concomitant vascular diseases, treatment with ACE inhibitors and/or beta-blockers, severe COPD pictures, reduced quality of life due to the previous anaphylactic event

Suggest VIT in older adults, even in case of non-severe systemic reaction, when they present risk factors for severe reactions at re-sting, such as vascular diseases, treatment with ACE-inhibitors and/or β-blockers, severe COPD

I1, I12, I20

 VIT17

[8]

For the majority of patients, VIT with one venom may be recommended as sufficient for protection. In patients with a history of systemic sting reactions to different insects or with severe initial reactions and clearly double positive tests, VIT with two venoms (i.e. Apis mellifera and Vespula or Vespula and Polistes) is recommended

Suggest VIT with two venoms in patients with a history of systemic sting reaction by not-identified insect or with severe initial reaction and double positive diagnostic tests, in the absence of second and third level diagnostic tests

I20, I21

 VIT18

[8]

VIT can be recommended in adults with recurrent, troublesome LLR to reduce the duration and size of future LLR

Take into consideration VIT in adults with recurrent, troublesome late local reactions

I20, I22

 VIT19

[8]

VIT is not recommended in individuals with incidentally detected sensitization to insect venom and no clinical symptoms

Do not recommend VIT in individuals with Hymenoptera venom sensitization and no clinical symptoms (asymptomatic sensitization)

I22

 VIT20

[8]

VIT may be recommended in patients with underlying systemic mastocytosis as it is safe and effective

Recommend VIT in patients with Hymenoptera venom allergy with underlying systemic mastocytosis

I15, I17, I20

 VIT21

[26]

VIT in mastocytosis patients should be performed by experienced allergy centers due to the risk of severe side-effects, including anaphylaxis, and the need for dosage adjustments and concomitant treatments

In patients with systemic mastocytosis perform VIT in experienced allergy centers

I21

 VIT22

[28]

Status of cardiovascular disease, its pharmacological treatment and the risk of anaphylaxis with consequent adrenaline administration should be carefully evaluated on an individual basis, preferably in concert with the consulting cardiologist, before starting VIT

Evaluate on individual basis, preferably with the consulting cardiologist, the status of the cardiovascular disease and the pharmacological treatment (especially β-blockers or ACE-inhibitors) before starting VIT for the possible future use of adrenaline

I19, I20, I22

 VIT23

[8]

VIT can be recommended in patients with cardiovascular disease but the underlying disease should be stabilized before initiation

Stabilize an underlying cardiovascular disease before starting VIT

I20

 VIT24

[8]

Beta-blocker therapy may be continued during VIT but the patient should be informed about possible risks

Inform the patients about the possible risks of a beta-blocker therapy

I20, I21, I22

 VIT25

[8]

ACE inhibitor therapy may be continued during VIT but the patient should be informed about possible risks

Inform the patients about the possible risks of ACE-inhibitor therapy during VIT, particularly about the possible reduced efficacy of VIT

I20, I21, I22

 VIT26

[8]

Treatment with MAOIs is not a contraindication for VIT but caution is recommended with the use of adrenaline

Recommend caution in using adrenaline during VIT in patients in MAO-inhibitory treatment

I20, I19

 VIT27

[28]

In patients allergic to Hymenoptera venom with a high risk of severe reactions to subsequent stings (e.g. previous life-threatening reaction or clonal mast cell diseases), VIT appears to prevent fatal events even in the presence of neoplasia

Suggest VIT to patients with neoplasia, stable or in remission, and high risk of severe reactions to subsequent sting or clonal mast cell diseases

I20

 VIT28

[28]

VIT is not generally indicated in unusual reactions (i.e. serum-like sickness manifestations, manifestations of central nervous system, hematological, muscle and renal reactions)

Do not prescribe VIT in unusual reactions, not IgE-mediated

I20

 VIT29

[28]

Immunotherapy should not be started during pregnancy. However, VIT should not be interrupted in case of pregnancy if patients are already undertaking and well tolerating VIT, considering the low risk of side effects

Do not start VIT during pregnancy, however a well tolerated VIT should not be interrupted in case of pregnancy

I20, I21

 VIT30

[28]

VIT cannot be recommended in patients with active, multisystem autoimmune disorders

Do not administer VIT in patients with active multisystem autoimmune disorders

I20

 VIT31

[28]

VIT is not contraindicated in patients with organ-specific autoimmune diseases (e.g. diabetes mellitus, Hashimoto’s thyroiditis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis), provided the disease is stabilized before starting treatment

Start VIT in patients with organ-specific autoimmune disease when the disease is stabilized

I20

 VIT32

[28]

HIV infection is a relative contraindication to VIT that can be assessed on an individual basis

Assess VIT on an individual basis in patients with HIV infection

I20

 VIT33

[28]

AIDS with a confirmed category C disease (according to CDC 1993 Atlanta Classification) is an absolute contraindication to VIT

Do not perform VIT in patients with AIDS with a confirmed category C disease (according to CDC 1993)

I20

 VIT34

[28]

In patients without specific risk factors VIT should be continued for 5 years

In patients without risk factors VIT should be continued for 5 years

I20, I21

 VIT35

[8]

It may be recommended to give injections every 4 weeks in the first year of treatment, every 6 weeks in the second year, and in case of a 5 year treatment every 8 weeks from year 3–5

Administer VIT every 4 weeks in the first year of treatment, every 6 weeks in the second year, and every 8 weeks from year 3 to 5

I21, I22

 VIT36

[8]

In the case of lifelong therapy, 12-week intervals may be still safe and effective

In case of a VIT prolonged over 5 years a progressively increased maintenance interval till to 12 weeks con be applied

I21

 VIT37

[28]

The panel of experts suggests that VIT duration should be at least 5 years also in pediatric patients

Suggest a VIT duration of 5 years in pediatric patients

I20, I21

 VIT38

[17]

Encourage continuation of VIT for an extended time, or indefinitely, in patients with high-risk factors, such as very severe reaction before VIT (syncope, hypotension, severe respiratory distress), systemic reaction during VIT, honeybee allergy, and increased basal serum tryptase levels

Encourage VIT for an extended time (more than 5 years) or indefinitely in patients with high risk factors for relapse

I21, I22

 VIT39

[17]

Consider continuation of VIT for more than 5 years in patients with other high-risk factors for recurrent or severe sting reactions, such as underlying cardiovascular or respiratory conditions, select antihypertensive medications, frequent exposure, and limitation of activity due to anxiety about unexpected stings

As for VIT38

 VIT40

[26]

Patients with IgE-mediated anaphylaxis to Hymenoptera should be offered venom immunotherapy (VIT) to honeybee or wasp or both and should be performed life-long in patients with mastocytosis

Suggest life-long VIT in patients with mastocytosis

I20, I16

 VIT41

[28]

Since workers highly exposed to stings have a higher risk of relapse after VIT discontinuation, some experts recommend to continue the treatment until the profession risk is maintained

Continue VIT until the profession at risk of frequent stings is maintained

I20, I21, I22

 VIT42

[8]

Lifelong VIT may be recommended in patients who relapsed after stopping VIT

Start again and continue lifelong VIT in patients who relapsed after stopping VIT

I21

 VIT43

[3]

From a practical point of view, regardless of the tryptase value, we would suggest an accurate hematologic workup be performed before stopping immunotherapy in those patients with very severe reactions with hypotension and without urticaria and angioedema to exclude CMD

Before stopping VIT in patients with very severe reactions with hypotension and without urticaria/angioedema, perform an accurate hematologic workup to exclude clonal mast cell disorders

I15, I17, I21, I22

 VIT44

[21]

Patients with HVA-induced anaphylaxis who lose protection after a proper course of VIT should be investigated for mastocytosis

Perform an accurate hematologic workup to exclude clonal mast cell disorders in patients with Hymenoptera venom allergy who lost protection after stopping VIT

I15, I17, I22

 VIT45

[8]

If no sting challenge can be performed, it may be recommended to record outcomes of field stings to evaluate effectiveness of VIT

Record outcomes of field stings to evaluate effectiveness of VIT

I21, I22

 VIT46

[8]

It may not be recommended to determine venom specific IgE, IgG levels, BAT response and allergen blocking capacity to estimate the individual risk for relapse

Do not use specific IgE and IgG levels, BAT response and CAP inhibition to estimate the individual risk for relapse

I13, I22

 VIT47

[28]

Patients at risk of multiple stings or with risk factors for relapse after VIT interruption: follow up visit in case of re-sting and anamnestic history collection at each re-order of adrenaline including a refresh in the training on device use

After stopping VIT, perform follow-up visit in case of re-sting, collecting clinical history especially in patients at risk for multiple stings or with risk factors for relapse; at each re-order of adrenaline include a refresh in the training on device use

I22

Mastocytosis (M)

 M1

[27]

The European Competence Network on Mastocytosis recommends using the REMA score as a clinically useful tool to predict for the presence of clonal MCs prior to a BM study; the REMA score is based only on demographic data (gender), the symptoms and signs observed during the acute episodes, and serum baseline tryptase levels. A REMA score of at least 2 predicts with a high sensitivity and specificity for ISMs- (or c-MCAS), whereas a REMA score of less than 2 usually indicates non-clonal disease. The REMA score is a particularly helpful tool since it is based on clinical data and can be used on a routine clinical basis, it is associated with rather low costs, and it avoids unnecessary BM studies

Use REMA score to predict a clonal mast cell disease before submitting the patients to bone marrow biopsy

I15, I17

 M2

[24]

Subjects with anaphylaxis after wasp or bee stings and negative allergy test results might have unrecognized mastocytosis. In these subjects, investigations for major and minor SM criteria are recommended, regardless of Serum baseline tryptase (sBT) level or the presence of skin lesions

Perform an accurate hematologic workup to detect major and minor criteria of systemic mastocytosis in patients with Hymenoptera venom anaphylaxis and negative diagnostic tests

I13, I15, I17

 M3

[21]

In cases with a clearly raised SBT level (> 25 ng/mL), BM biopsy is usually recommended, whereas in patients with systemic HVA reactions and borderline or normal tryptase, the scoring system proposed by REMA (score) can be useful to decide whether patients should undergo BM biopsy

Perform a bone marrow biopsy in case of clearly raised serum basal tryptase (> 25 ng/mL). In patients with systemic Hymenoptera venom reaction and borderline or normal serum basal tryptase level, use REMA score to decide whether patients should undergo bone marrow biopsy

I15, I17

 M4

[24]

In the presence of a very low BM MC burden, KIT D816V mutation analysis should be performed with very sensitive techniques, such as quantitative RT-PCR

Diagnose systemic mastocytosis performing KIT D816VT mutation analysis with a very sensitive technique, such as RT-PCR, in the presence of a very low bone marrow mast cell burden (major criterion)

I15, I17

 M5

[24]

Assessment of sBT levels is an inexpensive, reliable, and simple screening test for mastocytosis in subjects with a positive history of a systemic reaction to hymenoptera stings

Determine basal serum tryptase level in all the patients with positive history of hymenoptera sting systemic reaction

I13, I15, I17

 M6

[26]

In the follow-up and monitoring of patients with mastocytosis s-tryptase is a widely used marker of MC burden

Use serum basal tryptase levels as a marker of mast cells burden to follow-up patients with mastocytosis

I22

 M7

[3]

In these patients, it is very important to use a highly sensitive multiparameter flow cytometry approach to stain BM cells, using a combination of five monoclonal antibodies—CD45, CD117, CD34, CD25, and CD2—and with at least 1 to 3 million events acquired to detect atypical MC in these patients who have a very low MC burden

In patients with systemic mastocytosis, use a highly sensitive multiparameter flow cytometry with a combination of five monoclonal antibodies (CD45, CD117, CD34, CD25 e CD2)

I15, I17

 M8

[22]

It is important to confirm the diagnosis of c-MCAS in patients with HVA: (i) before to decide to stop VIT because, in patients with a diagnosis of c-MCAS, VIT must be continued lifelong. (ii) in order to give them a proper advice on the use of adrenaline. (iii) to investigate and manage other manifestations of c-MCAS, such as osteoporosis

Confirm the diagnosis of c-MCAS in Hymenoptera venom allergic patients to decide VIT duration, adrenaline autoinjector prescription as well as the evaluation of other clinical manifestation associated to systemic mastocytosis

I15, I16, I17, I19, I21

 M9

[26]

Of note, s-tryptase is not disease-specific for mastocytosis and may be elevated in healthy individuals, and in other conditions, such as chronic urticaria, kidney failure, chronic helminth infections, or other myeloid haematological diseases

A similar, step-wise approach, including KIT D816V testing in the algorithm is recommended by the ECNM (European Competence Network on Mastocytosis)

Diagnose systemic mastocytosis with other tests in addition to basal serum tryptase among which KIT D816VT mutation analysis

I15, I17

 M10

[26]

In general, these centres recommend and perform a thorough BM examination in order to exclude or to establish the diagnosis of SM, to assess the BM MC burden, and to rule out or demonstrate the presence of another (associated) hematological disease

Perform a thorough bone marrow biopsy to exclude or confirm the diagnosis of systemic mastocytosis, to evaluate the mast cells burden, and to exclude or detect another hematological associated disease

I15, I17

 M11

[22]

The diagnosis of SM is made upon the presence of the major criterion (histological finding of at least 15 multifocal dense MC infiltrates in BM or other extracutaneous organs) plus 1 minor criterion, or at least 3 out of 4 minor criteria (abnormal morphology of extracutaneous MC; serum tryptase > 20 ng/m; expression of CD2 and/or CD25 on BM MC; detection of a mutation at codon 816 of the KIT gene in extracutaneous organs). Clinical features associated with MC burden (B findings) or aggressiveness of disease (C findings) are also applied to subclassify patients with SM

Diagnose systemic mastocytosis upon the presence of a major plus a minor criterion, or at least three minor criteria. Subclassify systemic mastocytosis in indolent, smoldering or aggressive on the basis of the presence of B and/or C findings presence

I15, I17

 M12

[22]

MCAS can be diagnosed when patients have recurrent systemic, usually severe, symptoms of MC activation, and involvement of MC can be documented preferably by demonstrating a transient increase of serum tryptase or another established MC mediator during (or shortly after) an event; moreover, symptoms need to respond to anti-mediator-type or MC-stabilizing medications. All these criteria should be fulfilled in order to confirm the diagnosis of MCAS

To confirm the MCAS diagnosis, all the established criteria need to be satisfied: recurrent systemic symptoms responsive to anti-mediator therapy or to mast cell stabilizing medications, transient increase of serum tryptase or another established mast cell mediator during an event

I15, I16, I17

 M13

[26]

In children the diagnosis of CM is largely clinical and a BM examination is not warranted or recommended except for the very rare situation where the child does not thrive and, in addition, shows persistently high and rising s-tryptase levels, abnormal blood count, or hepato/splenomegaly

Diagnose cutaneous mastocytosis in the children by clinical examination; bone marrow biopsy is not warrant nor recommended except for very rare situations.

I15, I17

 M14

[26]

In all adult patients and all childhood patients, a precise and complete physical examination is standard

When suspect systemic mastocytosis carry out a complete physical examination in all the patients, both children and adults

I12, I15, I17

 M15

[26]

Elevated baseline serum tryptase is characteristically found in SM, although a normal serum tryptase level does not rule out the presence of mastocytosis

Do not exclude the diagnosis of systemic mastocytosis on the basis of normal basal serum tryptase levels

I15, I17

 M16

[24]

The characteristics of severe HVA episodes with hypotension in the absence of urticaria/angioedema might represent the most relevant factor to identify those patients with HVA and CMDs, regardless of baseline tryptase levels. In such patients, who are indeed very rare, a proper and adequate diagnosis should be offered without delay

Perform an accurate diagnostic workup for mastocytosis in patients with a history of severe anaphylaxis and absence of urticaria/angioedema; furthermore do not exclude systemic mastocytosis on the basis of normal basal serum tryptase levels

I15, I16, I17