Kowalski et al. World Allergy Organization Journal (2016) 9:33 DOI 10.1186/s40413-016-0122-3 WAO STATEMENT Open Access Risk and safety requirements for diagnostic and therapeutic procedures in allergology: World Allergy Organization Statement Marek L. Kowalski1*, Ignacio Ansotegui2, Werner Aberer3, Mona Al-Ahmad4, Mubeccel Akdis5, Barbara K. Ballmer-Weber6, Kirsten Beyer7, Miguel Blanca8, Simon Brown9, Chaweewan Bunnag10, Arnaldo Capriles Hulett11, Mariana Castells12, Hiok Hee Chng13, Frederic De Blay14, Motohiro Ebisawa15, Stanley Fineman16, David B. K. Golden17, Tari Haahtela18, Michael Kaliner19, Connie Katelaris20, Bee Wah Lee21, Joanna Makowska22, Ulrich Muller23, Joaquim Mullol24, John Oppenheimer25, Hae-Sim Park26, James Parkerson27, Giovanni Passalacqua28, Ruby Pawankar29, Harald Renz30, Franziska Rueff31, Mario Sanchez-Borges32, Joaquin Sastre33, Glenis Scadding34, Scott Sicherer35, Pongsakorn Tantilipikorn10, James Tracy36, Vera van Kempen37, Barbara Bohle38, G Walter Canonica39, Luis Caraballo40, Maximiliano Gomez41, Komei Ito42, Erika Jensen-Jarolim43, Mark Larche44, Giovanni Melioli45, Lars K. Poulsen46, Rudolf Valenta47 and Torsten Zuberbier48 Abstract One of the major concerns in the practice of allergy is related to the safety of procedures for the diagnosis and treatment of allergic disease. Management (diagnosis and treatment) of hypersensitivity disorders involves often intentional exposure to potentially allergenic substances (during skin testing), deliberate induction in the office of allergic symptoms to offending compounds (provocation tests) or intentional application of potentially dangerous substances (allergy vaccine) to sensitized patients. These situations may be associated with a significant risk of unwanted, excessive or even dangerous reactions, which in many instances cannot be completely avoided. However, adverse reactions can be minimized or even avoided if a physician is fully aware of potential risk and is prepared to appropriately handle the situation. Information on the risk of diagnostic and therapeutic procedures in allergic diseases has been accumulated in the medical literature for decades; however, except for allergen specific immunotherapy, it has never been presented in a systematic fashion. Up to now no single document addressed the risk of the most commonly used medical procedures in the allergy office nor attempted to present general requirements necessary to assure the safety of these procedures. Following review of available literature a group of allergy experts within the World Allergy Organization (WAO), representing various continents and areas of allergy expertise, presents this report on risk associated with diagnostic and therapeutic procedures in allergology and proposes a consensus on safety requirements for performing procedures in allergy offices. Optimal safety measures including appropriate location, type and required time of supervision, availability of safety equipment, access to specialized emergency services, etc. for various procedures have been recommended. This document should be useful for allergists with already established practices and experience as well as to other specialists taking care of patients with allergies. * Correspondence: kowalsml@csk.umed.lodz.pl 1 Department of Immunology, Rheumatology & Allergy, Medical University of Lodz, 251 Pomorska Str, 92-213 Lodz, Poland Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 2 of 42 Introduction safety equipment, access to specialized emergency ser- Over the last several decades allergy practice has been vices, etc.) for various procedures. expanding worldwide in parallel with the increasing An international group of experts collaborating within number of patients suffering from allergic diseases. It the World Allergy Organization (WAO) presents this has been widely accepted that appropriate training and consensus report assessing risk and proposing safety re- certification are necessary for the physician to correctly quirements for performing procedures in allergy offices. diagnose and manage allergic diseases. However, in some This document refers to available literature and also to countries the allergy specialty is still poorly developed or other documents and resources (e.g. local regulations) does not exist. Allergy practice, therefore, varies from available to experts. Since for the majority of reviewed country to country and according to local regulations or procedures no formal recommendations were available, traditions both trained allergists or physicians with other the experts had to reach the consensus with regard to specialties are performing allergy procedures such as proposed recommendations. As a result, optimal safety skin testing or immunotherapy. Furthermore, in several measures for various procedures have been proposed. regions of the world the increasing number of allergy This consensus, which is based on the recommenda- sufferers has not been matched by an appropriate supply tions of international experts, provides useful informa- of trained specialists; as a result, physicians without tion for allergy specialists and all doctors who diagnoses training in allergy including general practitioners and and treat allergy patients. Moreover, the consensus has pediatricians will be assisting allergic patients more and value for general allergy practice worldwide; thus WAO more. is an appropriate organization to provide it. Doctors dealing with allergic diseases (certified aller- The following grading of recommendations on the gists or other specialists trained in allergy) are employ- safety measures has been presented based on the con- ing, in the office, various diagnostic and therapeutic sensus reached by the expert panel: procedures which are associated with a significant risk of unwanted reactions for a patient. The reactions, de- A. Mandatory pending on the procedure, may vary from local discom- B. Recommended fort to severe anaphylaxis and death. Most unwanted C. Suggested reactions can be either avoided or the risk/symptom in- D. non-required tensity may be minimized if the procedures are per- formed in an appropriate manner. However, certain risk Recommendations reported in the sections below have of unwanted and or excessive reaction remains even if been summarized in Table 1 and 2. all precautions are respected. During some diagnostic procedures, called provocations (e.g. oral drug or food Diagnostic procedures challenges), the allergist deliberately aims at inducing Skin testing for inhalant and food allergens – Skin Prick adverse symptoms which are mimicking those occurring Test (SPT) and Intradermal Skin Test (IDST) at natural exposure and sometimes may be associated Skin testing with inhalant and food allergens with a significant discomfort and even with some risk to the patient. In such situations unpleasant or even poten- Definition and short technical description These in tially dangerous symptoms are inherent to the procedure vivo tests are used for the detection of allergen specific and cannot be completely avoided. Thus, it is critical IgE on the skin mast cells and confirmation of that well established inclusion/exclusion criteria for the sensitization to a specific allergen [1]. challenge are considered and the protocols of provoca- tions are strictly followed. Furthermore the patient Skin Prick Test (SPT) should be appropriately monitored by trained and expe- rienced medical staff not only during the whole proced- Skin prick testing relies on the introduction of a very ure but also for an appropriate time after its completion. small amount of allergen extract into the epidermis Such precautions usually allow for a significant reduc- using a disposable fine needle or lancet device, which is tion of risk of unwanted or excessive symptoms. changed with each test allergen [2]. Besides metal de- The literature on the risk of allergic procedures exists, vices, there are other varieties of commercially available but it has not been recently reviewed in a systematic skin prick devices. The incorporation of these devices way. Furthermore, there is no available consensus on into the protocol may require prior evaluation [3]. Skin safety requirements for performing specific diagnostic prick should be applied carefully, as insufficient prick procedures. Thus it is important to reach the consensus may produce false negative results, and induction of on optimal safety measures (e.g. appropriate location, bleeding (too deep) may produce false positive results type and required time of supervision, availability of and bear the risk of systemic reactions. Allergens should Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 3 of 42 Table 1 Summary of Safety Recommendations for Diagnostic Allergy Procedures (for details, see the text) Section subtitle Recommended Emergency Emergency staff (ICU) Duration of Comments site equipment availability supervised follow-up availability in the office after procedure Skin testing (SPT and IDST) With Inhalant and Both O and H (a) mandatory (c) not required 20 min Field skin testing (prick test only), for food allergens epidemiology studies, may also be carried out by trained medical personnel. Skin testing with Both O and H (a) mandatory (c) not required 20 min hymenoptera venoms Skin testing with O or H depending (a) mandatory available on site (a) or 20 min Patients at risk: Patients who are drugs on the risk Comment: not available within 30 min (b) tested for anaphylactic reactions, or assessment applicable for depending on the risk with a history of complicating patch testing assessment conditions such as asthma, mastocytosis and severe cardiac disease Skin testing with Both O and H (a) mandatory (c) not required 20 min occupational allergens Skin testing with Both O and H (a) mandatory (b) available within 30 min 20 min For some patients waiting time latex should be extended to 40 min Bronchial challenge Both O and Ha (a) mandatory (b) available within 30 min 7 h a although outpatient clinic is with allergen acceptable the hospital setting is recommended Bronchial challenge Both O and H (a) mandatory (b) available within 30 min 1 h with lysine aspirin (Lys ASA BPT) Nonspecific bronchial Both O and H (a) mandatory (c) not required not required provocation tests (NS-BPT) Nasal allergen Both O and H (a) mandatory (b) available within 30 min 30 min provocation tests Nasal aspirin Both O and H (a) mandatory (b) available within 30 min 30 min provocation tests Nasal endoscopy Both O and H (d) not required (c) not required not required unless complications occur Food challenges Both O and H (a) mandatory (a) available on site or (b) 1-2 h after negative available within 30 min, and 4 h after depending on risk positive food assessment challenge Oral drug O or H depending (a) mandatory (a) available within 5 min, at least 2 h; provocation test on risk assessment or (b) available within hospitalization is 30 min, depending on risk recommended after assessment severe reaction Insect sting challenge Both O and H (a) mandatory (b) available within 30 min at least 2 h until symptoms have disappeared O: Outpatient clinic (a) mandatory (b) recommended (c) suggested (d) not required H: Hospital setting (a) available on site (in less than 5 min) (b) available within 30 min (c) not required be placed at least 2 cm apart to avoid overlapping re- resulting weal is recorded in two dimensions (longest sponses between allergens tested. The results of skin and its orthogonal diameter). By convention, a positive prick testing are read at 15 min and the diameter of the test is one in which the mean of the two weal diameters Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 4 of 42 Table 2 Summary of Safety Recommendations for Therapeutic Allergy Procedures (for details, see the text) Section subtitle Recommended Emergency Emergency Staff (ICU) Availability Duration of supervised Comments site equipment follow-up in the office availability after procedure Subcutaneous Both O and H (a) mandatory (a) available on site (in less than 5 min), 30 min immunotherapy or (b) available within 30 min, depending with inhalant on risk assessment and the immunotherapy allergens protocol used Venom Both O and H (a) mandatory (b) should be available on site, (in less 30 min immunotherapy than 5 min) or within 30 min, depending on the risk assessment and the immunotherapy protocol used Drug O or H (a) mandatory (a) available on site (in less than 5 min) 30 min after acute Waiting time can be desensitization depending on reactions extended to 24-98 h procedures risk assessment for delayed reactions Oral Both O and H (a) mandatory available within 5 minutess (a) or 2h Currently not immunotherapy for available within 30 min (b) depending recommended for food allergy on risk assessment routine clinical use Treatment with (a) mandatory (b) available within 30 min 2 h for the first Anti-IgE and other administration;30 min biologicals for succesive administration Treatment with (a) mandatory (b) available within 30 min 30 min products from human plasma O: Outpatient clinic (a) mandatory (b) recommended (c) suggested (d) not required H: Hospital setting (a) available on site (in less than 5 min) (b) available within 30 min (c) not required is at least 3 mm greater than the negative control (sa- Clinical indications SPTs may be used for the evalu- line) [4]. Positive and negative controls are critical to en- ation of allergen-specific IgE to inhalants, foods, drugs able interpretation of test results. Ideally, the histamine and venom in the following conditions: respiratory/in- control is read at 10 min. The test is usually performed halant allergy, food allergy, venom allergy, drug on the volar aspect of the forearm but it is also per- allergy. formed on the back, especially in young children. There IDSTs have a very high non-specific reaction rate is a gradient of response when using the back – with lar- and are not recommended for testing with inhalants ger responses in the lower third compared to the upper or foods [6] and food allergens [7]. Moreover, intra- third [5]. Interpretation of results should consider the dermal tests carry a higher risk of adverse reactions following factors: the allergen extracts used (standard- than SPTs. ized when available), the type of lancet device, the skin site chosen for testing, the clinical state of the patient Age limitation Testing can be performed from infants and the medications used by the patient. to the elderly. Infants and the elderly have smaller SPT weal responses, and prominent flare responses [8]. Intradermal allergy testing (IDST) Description of adverse/unintended reactions associated Intradermal allergy testing is a procedure where a with the procedure SPT is considered a safe procedure, small amount of diluted allergen is injected into the der- with minimal discomfort. Adverse events can occur but mis. It increases the sensitivity but decreases the specifi- rarely. These are classified as allergic or non-allergic. city of the test and is carried out with allergen concentrations 100 to 1000 times less than that used for 1. Type and spectrum of unintended allergic reactions skin prick tests. It has no place in aeroallergen (other  Local: than for research) and food allergen testing. It is most In some patients with marked sensitivity late commonly used in testing for drug and venom allergy. phase local skin swelling (the IgE late phase Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 5 of 42 response) consisting of tender and painful – Vasovagal syncope [13]: swelling may occur (seen more commonly with – Female sex intradermal testing). Rarely, it could cause quite – Testing with multiple allergens marked swelling and discomfort, but does not usually last more than 36 h [9]. Institutional/organizational safety recommendations  Systemic: Several guidelines for performing skin tests have been Systemic reactions associated with SPTs, usually published: starting within 15 to 30 min, have been reported as case reports [10], in surveys and in prospective  Allergy diagnostic testing: an updated practice studies. Although systemic reactions may occur parameter (Bernstein et al, 2008) [18] in any individual undergoing skin testing (both  Skin Prick Testing for the diagnosis of allergic adults and children), specific risk factors should diseases – A manual for practitioners be taken into consideration when performing (Australasian Society of Clinical Immunology and these tests (see section III). Allergy, 2013) [9]  Fatal Reactions:  Allergic Rhinitis and its Impact on Asthma; Few fatal reactions as a result of skin testing have Practical guide to skin prick tests in allergy to been described in the literature [11, 12]. Based on aeroallergens. Allergy 2012;67:18-24 [19]. two large retrospective surveys by the American Academy of Allergy and Immunology in the US, WAO safety recommendations These recommenda- seven fatalities have been described involving tions are based on the rare occurrence of severe systemic older children and adults. Six of these deaths reactions reported in retrospective surveys, one pro- involved intradermal testing to inhalants and food spective study, and several case reports. Quality of evi- and one death involving skin prick testing dence is high regarding the rare occurrence of systemic performed with 90 allergens. life threatening and fatal (1 case in the literature with 2. Type and spectrum of non-allergic reactions. skin prick test without intradermal test) reactions justify These may include syncope (vasovagal syncope) the need for facilities offering skin prick testing to have and headache, Based on a prospective study in the following prerequisites for safety. There are no rec- children [13] and a retrospective survey [11], all ommendations for intradermal testing as they are not reported systemic and vasovagal syncope reactions indicated for inhalant and food testing [20]. related to skin testing occurred within 15 to 30 min of the test. 1. Site: 3. Prevalence and risk associated with the procedure.  Both a hospital and outpatient clinic setting The prevalence of systemic reactions related to skin  Field (skin prick test only), e.g. epidemiology prick testing with inhalant and food allergens is low studies, may also be carried out by trained but not absent. It was estimated to be less than medical personnel. 0,055 % [14, 15]. The rate of systemic reactions 2. Personnel: requiring epinephrine was reported as 20 per Can be performed by trained nurse/technician 100,000 SPT visits [16]. The prevalence in young under supervision of experienced physician children appears to be higher with a reported rate of 3. Emergency equipment availability: systemic reactions of 0.12 % [13] and 6.5 % in Should be available on site (mandatory) infants less than 6 months of age [17]. 4. Emergency staff (ICU) availability: 4. Risk factors for adverse/unintended reactions Not required  Systemic Reactions: [7, 9, 11, 12, 17] 5. Pretreatment: Not applicable – Infants especially <6 months 6. Duration of supervised follow up after the – Multiple allergens procedure: – Previous history of anaphylaxis to food when It is recommended that patients who have testing for incriminating food undergone skin prick testing and have positive – Testing with fresh food (non-commercial results, who have asthma or a history of anaphylaxis, extracts) should remain in the centre for at least 20 min – Testing with non-standardized latex extracts following completion of the skin prick test [9]. – Extensive eczema 7. Contra-indications: – Uncontrolled asthma Contraindications to skin prick testing may be – Intradermal Testing categorized into: Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 6 of 42  Clinical situations which interfere with the adults, and in more than 30 % of those who have been procedure or its interpretation. These include stung in the previous few months. A positive test in such absence of normal skin, including individuals creates the perception of risk even when the dermatographism, use of medication that might history might indicate low risk (<3 %) of anaphylaxis. inhibit skin prick responses. This is the case in people who have large local reactions  Relative contraindications related to safety/high to stings, in those with only cutaneous systemic reactions risk situations. These include severe or unstable to stings, and in patients who have completed a 5 year asthma and patients on beta-blockers. If SPT is course of venom immunotherapy. considered to carry a significant risk e.g. in a highly sensitized patient or in a woman with 1. Type and spectrum of adverse reactions unstable asthma in pregnancy then avoid  Local: performing the test. Local adverse reactions are very uncommon but 8. Other considerations: might cause delayed progressive swelling and In patients with a history of anaphylaxis, skin prick induration of the test site, with itching and tests should be initiated with several serial 10-fold possibly pain. dilutions of the usual test concentration.  Systemic: Systemic allergic reactions to venom skin tests Skin testing with hymenoptera venoms are rare, and near-fatal or fatal reactions are Definition and short technical description Immediate exceedingly rare. hypersensitivity skin testing is performed with standard 2. Prevalence and risk associated with the procedure: techniques and standard reporting of results. Venom Early studies of venom skin tests included small skin testing may begin with prick/puncture tests using a numbers of subjects. They were focused on venom concentration of 1,0- 100 mcg/ml, or with intra- diagnostic accuracy, and reported no significant dermal tests using venom concentration of 0.001 -1 adverse effects. The only large study reporting on mcg/ml. If the puncture test is negative, it is followed by the safety of venom skin tests was that of Lockey et an intradermal test using venom concentration of 0.01 al [20]. In that survey of 3236 patients, 64 (2 %) had mcg/ml. If the intradermal test using venom concentra- a systemic reaction during venom skin tests, 13 tion of 0.01 mcg/ml is negative, it is repeated using con- (0.4 %) of which were severe. Thirteen of 64 adverse centrations of 0.1 mcg/ml, and then if necessary 1.0 reactions (20 %) were possibly vasovagal, and six mcg/ml. A positive puncture test has a wheal diameter other subjects (9 %) demonstrated no symptoms of at least 3 mm larger than the diluent (negative) control. immediate-type hypersensitivity. Thus, 45 (1.4 %) of Intradermal tests should introduce sufficient volume to the 3236 subjects tested had a systemic reaction that give a 3–4 mm bleb (usually 0.02–0.03 ml). A positive was considered to be a reaction of hypersensitivity, intradermal test has a wheal diameter of at least 5 mm. of which eight reactions (0.25 %) were severe. 3. Risk factors for adverse/unintended reactions: Clinical indications Skin tests for venom allergy are in- The risk of severe anaphylaxis is always increased in dicated to confirm the presence of venom sensitization patients with a history of asthma. The severity of the in patients who have had systemic reactions to insect previous reaction to a sting is not a risk factor for stings (or repeated severe large local reactions) and are anaphylactic reaction to skin tests. In contrast to candidates for venom immunotherapy. Testing is also skin tests with inhalant allergens, the risk of useful to distinguish among different types of venom anaphylaxis is not increased when intradermal tests (bee, wasp, etc); are performed without initial prick/puncture tests. In fact, there are 2 studies of “accelerated” venom Age limitation No age limitation. skin tests that reported no increased risk of adverse reaction [21, 22]. Guidelines and Practice Parameters Description of adverse/unintended reactions associated in Europe and the United States do not recommend with the procedure Adverse events are very rare with any precautions for venom skin tests in patients who venom skin tests. Local itching and induration is a nor- are taking beta-blockers of ACEI medications. mal positive response, and may take hours to subside. Anaphylactic reaction to venom skin tests is extremely Institutional/organizational safety recommendations rare. Unintended consequences of venom skin tests can Guidelines and Practice Parameters in Europe and in the occur when the tests are performed in individuals who United States do not express any concern about safety of have no clear history of anaphylaxis to a sting. This is venom skin tests, and do not recommend any specific because venom skin tests can be positive in 15–20 % of precautions or safety measures [19, 18, 23]. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 7 of 42 WAO safety recommendations all the published and recommended test concentrations for any drug reported [28]. 1. Site: Both outpatient clinic and hospital setting Clinical indications Indications for SPT and IDST with 2. Personnel: drugs are immediate reactions manifested as erythema- Tests are performed by personnel who have tous eruptions/flushing, urticaria and angioedema, ana- undergone training and proficiency testing. A phylaxis, conjunctivitis, rhinitis and bronchospasm/ physician should be present. asthma. The most common use of patch testing with 3. Emergency equipment availability: drugs are maculopapular exanthemas, acute generalized Should be available on site (mandatory) exanthematous pustulosis (AGEP), and fixed drug erup- 4. Emergency staff (ICU) availability: tions [29, 30]. Other clinical entities where patch tests Not required are being used are delayed-appearing urticaria, photo- 5. Pretreatment: sensitivity, drug reactions with eosinophilia and systemic Not applicable symptoms (DRESS/DIHS), Abacavir hypersensitivity syn- 6. Duration of the supervised follow up after drome, Stevens-Johnson syndrome and toxic epidermal procedure: necrolysis (TEN) [31]. 20 min 7. Contra-indications: Age limitation Skin testing with drugs can be per- See contraindications for SPT in previous section formed at any age, although the experience in children is (inhalants) limited. 8. Other considerations: The results of venom skin tests must be reviewed Description and prevalence of adverse/unintended and interpreted by an experienced specialist in reactions associated with the procedure Skin testing allergology, in the context of the clinical history of with drugs is a safe diagnostic approach, if performed the patient and the natural history of the condition. according to the published guidelines [26, 28, 32, 33]. The pitfalls of diagnostic allergy testing have been However tests may be associated with some risk of ad- well-described [24]. verse local and also systemic reactions; a relapse of the previous reaction might be provoked with any skin test procedure. Skin testing with drugs 1. Type and spectrum of adverse reactions: Definition and short technical description Skin Prick-  Local: (SPT) and Intradermal Skin Tests (IDST) are the most SPT, IDST and patch tests may cause local useful modality for demonstrating an IgE-mediated irritation resembling (false-) positive reactions. mechanism underlying clinical symptoms [25], whereas Skin necrosis and scarring might result from epicutaneous patch testing (or SPT/IDST with delayed testing with toxic substances such as reading) is the logical first step in defining the relevant chemotherapeutic agents or when using non- drug in delayed cell-mediated hypersensitivity to system- physiological concentrations. ically administered drugs – and not only for contact  Systemic: dermatitis caused by topically applied drugs [26, 27]. Anaphylaxis after SPT with chymopapain, However, depending on factors such as the clinical type penicillin, tetanus toxoid, and other drugs, has of reaction, the drug suspected, the pathomechanism of been reported rarely, leading to the conclusion the reaction, the availability of qualified test substances that SPT is a safe diagnostic procedure, although and the existence of a valid test protocol, an individual a theoretical and remote risk in principle remains approach must be chosen for any specific situation, i.e. [10]. drug testing has to be performed in an individualized manner. – IDST, being more sensitive than SPT, is more Generally it is advised to perform the tests 6 weeks to likely to induce systemic reactions. Urticaria, and 6 months after the hypersensitivity reaction. SPT can be rarely anaphylaxis have been described almost done with any soluble drug, for the IDST sterility is im- exclusively with β-lactams [reviewed in 25]. portant. Patch tests can be performed with any form of – Systemic reactions associated with patch testing commercial drugs. In general, for most of the drugs are extremely rare. In a retrospective study that there is a lack of standardization of reagent concentra- evaluated 111 and 134 patients with a history of tions. Only recently a guideline has been released listing severe cutaneous adverse reactions to drugs no Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 8 of 42 severe side effects induced by the tests were Should be available on site (mandatory) – only for reported [27, 30]. patients who are tested for anaphylactic reactions, or for patients with a history of complicating  Flare-up reactions: conditions such as asthma, mastocytosis and severe Flare-up reactions might be mediated by IDST cardiac disease. and patch tests. A patch test-induced exfoliative For all other patients should be available within dermatitis was observed in a patient with an ad- 30 min verse reaction to carbamazepine [34]. A relapse 5. Pretreatment: of a pruritic rash occurred following a prick test Not applicable with pristinamycin [35]. The relapse of an 6. Duration of the supervised follow up for safety after AGEP has been provoked by patch testing with the procedure: acetaminophen (paracetamol) while these tests Should remain in the centre for at least 20 min after remained negative [36]. Thus, patch tests, SPT, completion of the procedure. After IDST in patients and IDST can induce a systemic reaction even with previously diagnosed asthma (due to the though their results were negative [26]. suspected drug itself or as an underlying disease)  Fatalities: supervised follow-up should be extended to 6 to The few fatalities associated with skin tests, 8 h [25]. reported from 1895 to 1980, were associated with 7. Contraindications: biologic products that are no longer used such as Drug-induced autoimmune diseases, severe horse serum-derived tetanus or diphtheria toxins exfoliative skin reactions and severe vasculitis or pneumococcal antiserum [reviewed in 29]. A syndromes for SPT and IDST [25]. There are no recent literature review on systemic reactions absolute contraindications for patch testing with from skin testing concluded that the occurrence drugs. of systemic reactions with inhalant allergens has See also contraindications for SPT in previous diminished over the last 30 years, whereas fresh section (inhalants) food, hymenoptera venom and antibiotic SPT still carry some risk [10].  Risk factors for adverse reactions: Skin testing with occupational allergens In general, patients with history of previous Definition and short technical description The tech- anaphylactic reactions, uncontrolled asthma or niques for skin test (ST) with occupational allergens are high degree of reactivity, small children or identical to ST with other (inhalant) allergens. As for pregnant women,, may be considered at higher risk other allergens, in routine the skin prick test (SPT) (i.e., they may react more readily and/or more should be preferred over the intradermal skin test severely to the minute test amounts applied [25]. (IDST), because it causes less pain and there is a lower risk of systemic reactions. Since there is no clear defin- Institutional/organizational safety recommendations ition of occupational allergens (also food and drugs are Several guidelines for performing drug skin tests have occupational allergens for some workers) for the purpose been published [26, 28, 32, 33]. of this document we looked for potential adverse reac- tions after skin testing in occupational exposed workers. WAO safety recommendations The following sensitizing substances most commonly 1. Site: cause occupational asthma and are used for skin testing: SPT and IDST with drugs should be performed in dust of cereal flours, enzymes, laboratory animals, farm- hospital settings of specialized centers. Since adverse ing (animals, cereals, hay, straw and storage mites), fish reactions to drug patch testing are rare and rather and seafood as well as low molecular substances such as not severe, tests can be applied at outpatient clinics. isocyanates, platinum salts and acid anhydrides [37, 38]. 2. Personnel: Natural rubber latex (hereinafter referred to as latex) is Trained technician or nurse under supervision of a discussed separately (see following section on skin test- physician. Personnel has to be prepared, trained and ing with latex). Due to the fact that occupational aller- equipped for serious events, especially anaphylactic gies in comparison to sensitizations to ubiquitous reactions. allergens are rare, often no standardized SPT solutions 3. Emergency equipment availability: are available. In these cases non-standardized patient- Should be available on site (mandatory) for SPT and tailored allergen preparations have to be used. If the pa- IDST. Not applicable for patch testing. tient shows a positive reaction to such a SPT solution, 4. Emergency staff (ICU) availability: control tests should be performed in a number of Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 9 of 42 healthy subjects in order to exclude an unspecific WAO safety recommendations Although allergy ST is reaction. considered a safe procedure, it is not without risk of sys- temic reaction Clinical indications For the diagnosis of occupational 1. Site: type I allergies, the common steps are a detailed case Both outpatient clinic and hospital setting history, skin testing, in vitro diagnosis (mostly specific 2. Personnel: IgE antibodies), and specific inhalation challenge. The Can be performed by trained nurse/technician under clinical indication for SPT with occupational allergens supervision of experienced physician (including latex) is to demonstrate IgE-mediated 3. Emergency equipment availability: sensitization to occupational allergens. However, in com- Should be available on site (mandatory) bination with work-related symptoms of the patient, SPT 4. Emergency staff (ICU) availability: with occupational allergens is also relevant for compensa- Not required tion and further socioeconomic consequences. 5. Pretreatment: Not applicable Age limitation In general, STs with occupational aller- 6. Duration of the supervised follow up after gens are performed only in working adults. procedure: Should remain in the centre for at least 20 min after completion of the procedure Description and prevalence of adverse/unintended 7. Contra-indications: reactions associated with the procedure Taking into Identical to ST with other (inhalant) allergens account, that skin tests with occupational allergens are 8. Other considerations: only performed in adults and that commercial ST solu- None tions for occupational allergens (other than latex) usually contain only small amounts of antigens and proteins Skin testing with latex [39] ST and especially SPT with occupational allergens Definition and short technical description Natural remains a safe diagnostic procedure. rubber latex (NRL), commonly referred to as latex, is a vital natural resource that is used in the manufacturing 1. Type and spectrum of adverse reactions of a wide variety of commercial products ranging from  Local: airplane tires to protective medical gloves. Ninety-nine If non-standardized patient-tailored allergen percent of latex comes from one source: the sap-like fluid preparations are used, local adverse reactions from the rubber tree Hevea brasiliensis. Sensitization to might be caused by irritation or toxic reaction latex, which is a potent allergen, affects people who are  Systemic: frequently exposed to products made of latex such as In general the risk of systemic reaction following health care and latex industry workers, patients with a his- ST with occupational allergens is low (lower with tory of multiple surgical procedures including children SPT than IDST). There exists one report about with spina bifida as well as specific food allergy patients. an anaphylactoid reaction (without cardiovascular Fourteen latex allergens have been identified and skin symptoms) after a scratch test with iridium test (ST) extracts have to contain especially NRL allergens chloride in an occupational exposed process Hev b 1, 2, 3, 4, 6.01, 7.01, and 1 and recombinant Hev b operator [40]. However, scratch tests have generally 5 (rHev b 5). Skin prick test (SPT) should be performed, been abandoned because of non-standardized intradermal tests are not recommended (Cabañes et al. procedure. 2012) [42]. SPT extracts to determine latex allergy in-  Fatal: cluded commercial extracts, latex glove extracts and hevea Out of 17 cases of anaphylaxis after SPT with leaves. Serial 10-fold dilutions of non-ammoniated latex various allergens listed by Liccardi [10] after (NAL, e.g. from Malaysian Hevea brasiliensis (clone 600) Medline research (1980-2005) none referred to sap (Greer Laboratories)) or newly introduced ammoni- occupational exposure. ated latex (AL, e.g. Bencard Laboratories, Mississauga, 2. Risk factors for adverse reactions: Ontario) allergens were employed in ST. Standardized ex- Unknown tracts can provide a sensitivity of 93 % with a specificity of 100 % [42]. Institutional /organizational safety recommendations Also ‘glove use tests’ are performed. Considerable dis- EAACI position paper: skin prick testing in the diagnosis parity exists between glove use protocols, with exposure of occupational type I allergies [41] times ranging from 15 min to 2 h. In general, the first Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 10 of 42 step involves placing a fingertip of the glove on a damp- operations or medical procedures involving latex prod- ened finger; if the result is negative, the complete pow- ucts, reactions induced by ingestion of fruits and dered glove is put on. A vinyl or nitrile glove is used on whether the patient belongs to a risk group. The com- the other hand as a negative control. The result is con- plementary diagnosis is based on STs and the determin- sidered positive if contact causes erythema, pruritus, ation of specific IgE [42]. blisters, or respiratory symptoms [42]. Age limitation SPTs with latex are performed both in Clinical indications Latex is a common component of adults and children. many medical supplies used in the hospital environment. Although latex is most often associated with disposable Description and prevalence of adverse reactions gloves, other items which may contain latex are breath- associated with the procedure Skin testing with latex ing tubes, infusion sets, syringes, stethoscopes, catheters, allergen is associated with a significant risk of adverse dressings and bandages. Frequent users of latex products systemic reactions may develop a latex allergy. Allergic rhinitis and asthma mainly affect individuals exposed via inhalation, such as 1. Type and spectrum of adverse reactions health care workers, lab workers, dentists, nurses, and In most cases, subjects with adverse reactions after physicians. latex SPT showed a variety of different symptoms. Patients at risk are also subjects with spina bifida and  Local: congenital genitourinary abnormalities who have under- There are no reports about isolated large local gone multiple procedures. While the incidence of latex reactions after latex SPT. One health care allergy in the general population is 1 % to 2 %, in spina worker in whom angioedema, hives and bifida (SB) patients, who are mostly children, incidence hypotension developed had no discernible of latex allergy ranges from 20 % to 70 % [43]. As well, wheal and flare reaction at the site of the SPT people who have certain food allergies, including ba- (Kelly et al. 1993) [44]. nana, avocado, chestnut, apricot, kiwi, papaya, passion  Systemic: fruit, pineapple, peach, nectarine, plum, cherry, melon, Several reports of anaphylaxis during SPT for latex fig, grape, potato, tomato and celery, may also have signs allergy have been published (Table 3). However, in of a latex allergy due to cross-reactivity. these former cases mostly non-standardized SPT Diagnosis of latex allergy is based on clinical suspicion. extracts prepared from powdered latex gloves or A good clinical history taken by an experienced allergol- crude latex preparations directly from Hevea brasi- ogist is very important. The history should record the liensis trees were used. In a study initiated with the presence or absence of other allergies, atopy, previous goal to establish an FDA (Food and Drug Table 3 Exemplary cases of systemic reactions during skin prick test (SPT) with latex Number Type of ST Culprit agent (type of latex) Symptoms/fatalities Reference Comments (e.g. setting, age etc.) of cases reported 1 SPT Liquid latex material Immediate flushing, tachycardia, Spaner et al. 1989 [260] 34 year old female Operating urticaria, light-headedness room nurse 1 SPT 10 % aqueous dispersion Cold, sweaty extremities, initial Bonnekoh and Merk 17 year old female dentist’s tachycardia, subsequent 1992 [261] assistance bradycardia, hypotension 1 SPT 100 HEP Hevea brasiliensis Dizziness, difficulty with breathing, Nicolaou and Johnston 39 year old female house wife wheezing, tachypnoea 2002 [262] 6 SPT extemporaneous extracts Signs of anaphylaxis in different Nettis et al. 2001 [48] 6 female patients with age (dilutions of 1:1000, 1:100, degrees ranging from 26-51 and 1:10) (n = 5), commercial SPT solution (n = 1) 9 SPT 1:100,000 dilution of latex Systemic reactions Kelly et al. 1993 [44] 9 of 107 patients: 85 children glove extract with spina bifida, 15 health care workers, 7 others 2 or 3a SPT 50 % glycerine, 0.23 mg/mL Pruritus, flushing, urticaria, Valyasevi et al. 1999 [15] 2 or 3a patients from a clinic out total protein from gloves angioedema, asthma, cough chest of 1316 tightness, wheezing, dyspnea, eye itching, nasal congestion a in one patient reason of anaphylactic reaction was not clear because he was also positive to aeroallergens Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 11 of 42 Administration) – licensed extract for use in the 4. Emergency staff (ICU) availability: United States an optimal diagnostic Should available within 30 min accuracy (SPT [IDST]: sensitivity 96 % [93 %], 5. Pretreatment: specificity 100 % [96 %]) without any systemic Not applicable or large local reactions was obtained in 59 latex 6. Duration of the supervised follow up after allergic adults with a non-ammoniated latex ex- procedure: tract (SPT 100 μg/ml, IDST 1 μg/ml) [44]. More Time of supervised follow-up should be extended up recently, the available standardized latex SPT to 40 min. reagents in Canada and Europe enable SPT with 7. Contra-indications: latex with a low risk of inducing systemic aller- Patients with a history of systemic reactions due to gic reactions [45, 46]. However, so far there is latex: no latex SPT or safety precautions essential no approved SPT solution for latex in the United 8. Other considerations: States [47]. Not only SPT with latex per se is In patients with a history of latex allergy with systemic mentioned to be a putative risk factor for ana- symptoms in-vitro tests should be performed before phylaxis during SPT but also a low age [9]. SPT. To reduce the likelihood of adverse reactions  Fatal: SPTs with latex allergen should be performed using The authors did not find reports that patients different dilutions (beginning with higher dilutions). died after latex SPT. However, in cases of See also contraindications for SPT in previous anaphylactic reactions emergency section (inhalants) pharmacologic intervention was necessary [48] and patients have been hospitalized for continued therapy [44]. Bronchial provocation tests (BPTs) 2. Prevalence and risk factors for adverse reactions Bronchial provocation tests with allergen Young patients with spina bifida may be at higher Definition and technical description Inhalation or risk of systemic reactions with latex SPT. As a rule, bronchial allergen challenge is a well-established and re- patients with a positive bronchial challenge test producible method to confirm sensitization to specific result presented the most severe reactions [48]. It allergen in the bronchi. Allergen-induced reaction mani- has been suggested that in patients with a history of fests as an early asthmatic response (EAR) and may or latex allergy with systemic symptoms in-vitro tests may not be followed by a more prolonged airway re- should be performed before SPT [44]. sponse (late asthmatic response; LAR). Two methods can be used: continuous generation of an aerosol by a nebulizer and inhaled by the subject via Institutional/organizational safety recommendations a facemask or inhalation of a standardized dose of an There are no published safety recommendations refer- aerosol by generating it intermittently. Any reproducible ring specifically to skin testing to latex allergens. The inhalation method can be used for either approach, the currently published position paper ‘Latex Allergy’ stated incremental allergen challenge usually employs 2-mins that standardized latex SPT extracts are considered safe, tidal breathing from a calibrated constant output nebulizer, although isolated cases of anaphylaxis have been reported. while the single bolus method usually uses a counted num- Intradermal tests are not recommended [42]. The diag- ber of deep breaths from a (breath-actuated, standard-dose) nostic algorithm for latex allergy which has been proposed dosimeter [49, 50]. Both methods produce comparable by Hamilton et al. [46] may decrease the risk of adverse airway responses. reactions during skin testing. The patient can also be challenged with allergen (e.g. wheat flour), with a use of a special/custom WAO safety recommendations Skin testing with latex chamber, by the allergen as such especially in exami- allergens in highly sensitive patients is considered to be nations for occupational asthma (e.g. baker’s asthma) associated with some risk of systemic reactions. [51] or in environmental exposure chambers for clin- ical research purposes. Bronchial response to allergen 1. Site: is either early, late or both and is verified by measur- Both hospital and outpatient setting ing lung volumes (FEV1) by flow-volume spirometry 2. Personnel: or peak expiratory flow (PEF) values. The patient is Should only be conducted by allergy specialists or closely followed for at least 6 to 8 h after the chal- equivalently trained medical nurse/technician lenge. In some centers segmental bronchial provoca- 3. Emergency equipment availability: tion techniques through fibro-optic bronchoscope Should be available on site (mandatory) have been employed. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 12 of 42 Clinical indications Allergen challenge is not a routine required repeated administration of an inhaled diagnostic procedure as patients are examined for their short-acting bronchodilator, while few (3 %, 95 % CI: asthma or asthma suspicion and asthma diagnosis is ob- 1–5 %) induced an asthmatic reaction that required tained by other means. BPT with allergen is primarily a re- additional oral or IV corticosteroids [55]. search tool in investigations on pathophysiology of asthma 3. Risk factors and on asthma controller therapy. However in some cen- Unstable asthma (FEV1 below 70 %, recent ters BPT with allergen is used to confirm sensitization hospitalization for asthma requiring oral corticosteroids). and/or explain discrepancy between the clinical history, The risk of moderate or severe reaction was and the sensitization (skin tests and specific IgE). increased when the subjects were challenged with a Allergen provocation is also done to explore the LMW agent and when they were using treatment causal relationship of allergen exposure at a work- with an inhaled corticosteroid [55]. place to patient’s actual symptoms (occupational asthma) [51]. For example, in the Finnish clinical rou- Institutional/organizational safety recommendation tine these tests are rarely performed and only in oc- Safety recommendations have been included in the state cupational settings. –of-the art documents published by the ERS/ATS, EAACI, or the French Society of Allergology [56]. Age limitation In clinical allergy practice inhalant aller- gen tests are seldom done to children or elderly, how- WAO safety recommendations ever no clear age limits have been established. Adults of 1. Site: working age are usually subjects of these tests, especially Hospital setting recommended. Outpatient clinic in occupational settings or research. There are centers setting could be acceptable. where children are challenged with allergen (e.g. house 2. Personnel: dust mite) [52, 53]. The provocation test can be performed by a trained nurse/technician but only under the surveillance of a Description of adverse/unintended reactions competent physician. 1. Type and spectrum 3. Emergency equipment availability:  Local: Should be available on site (mandatory) Bronchoconstriction is developing from few 4. Emergency staff (ICU) availability: minutes to 3 h and patient usually experiences Should be available within 30 min some cough, chest tightness and even wheezing. 5. Pretreatment: These symptoms are usually easily to control Is not necessary, but symptoms of positive reaction with bronchodilators. From 16 to 50 % of the should be immediately relieved by the inhalation patients, dyspnea may appear after 3 to 8 h as a of short-acting b2-agonist or by nebulization LAR [54]. (e.g. 2.5–5.0 mg of salbutamol). In case of more Severe asthma attack resulting in prolonged severe reactions oral or intravenous corticosteroids or exacerbation of asthma sometimes occur. Other epinephrine are administered. accompanying local symptoms may include 6. Duration of the supervised follow up after irritation of throat, trachea and bronchi, causing procedure: cough. The patient should be followed closely in a hospital  Systemic: setting for at least 7 h after provocation. The subject Exceptionally, severe anaphylactic reactions should never be left unattended during and caused by the allergen inhalation challenges can following the challenge procedure and FEV1 should occur. Such reactions usually develop within few be closely monitored for at least 7 h post-challenge. minutes and require epinephrine injection. After the last lung function measurement (usually  Fatal reactions: at ≥ 7 h post-challenge), subjects should receive One case of death caused by rapid, severe inhaled bronchodilators until the FEV1 returns bronchoconstriction and anaphylaxis have been within approx. 10 % from pre-allergen baseline. reported during exposure to isocyanate 30 years Only if this is achieved and the subject is clinically ago [53]. stable, subject can be sent home with the following 2. Prevalence precautions: secured transportation from research No systematic review is available on the occurrence center to home address, provided with rescue of unexpectedly strong bronchial responses or medications, preferably not left alone at home, and anaphylactic reactions. For occupational allergen emergency number(s) of on-call qualified physician inhalation challenge it is considered that 12 % who has been notified of the subject. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 13 of 42 7. Contra-indications for BPT with allergen aspirin or other NSAIDs in patients with cross-reactive,  Uncontrolled asthma and /or FEV1 < 70 % of respiratory type of hypersensitivity. It is an alternative to predicted oral aspirin challenge test which is the diagnostic gold  Recent hospital admission or asthma standard, but brings some risks of systemic reaction (see exacerbation section on Oral Drug Provocation Test). Inhalation test  Spirometry-induced bronchoconstriction (i.e., less with L-ASA is faster to perform than the oral test, but it than 2 baseline FEV1 measurements out of 8 is less sensitive and negative result of an inhalation test attempts within 15 %); does not exclude NSAIDs-hypersensitivity. The diagnos-  Recent major surgery; severe disease of the heart, tic value of L-ASA BPT has been documented only in brain, digestive tract, liver, kidney patients with a history of respiratory type of hypersensitiv-  Active, recent or chronic infections; ity to ASA/NSAIDs - called Aspirin Exacerbated Respira- immunological disorder; cancer, history of tory Disease (AERD) or NSAIDs Exacerbated Respiratory anaphylaxis Disease (NERD) - and is considered to be specific, repro-  Pregnancy ducible, and generally safe method for NERD confirm-  Use of systemic beta-blockers ation [61]. 8. Other considerations: Allergen preparations employed in the challenge Age limitation The test is usually performed in adults should be as standardized as possible. Furthermore, since NERD is rarely seen in children. However, a single to prevent sensitization and/ or bronchoconstriction study on L-ASA BPT challenges in children (aged 6–17 in sensitized investigators, an exhaust hood and/or years) reported, similar to adults, general safety of this (HEPA) filters should be used during allergen procedure [62]. Interestingly, in one child, urticarial nebulization. symptoms were reported following L-ASA bronchial Other GCP-based prerequisites relate to data quality challenge. and integrity, consist of: Description of adverse/unintended reactions associated  Adequate, well-ventilated challenge rooms with with the procedure standardized humidity conditions within an 1. Type and spectrum of adverse reactions irritant and smoke-free area, 1. Local:  Regularly calibrated and serviced equipment Typical and expected symptoms include dyspnea meeting ATS/ ERS criteria, and chest tightness accompanied with fall in  Standardized, validated SOPs, FEV1 developing within 10–30 min after positive  Qualified laboratory and pharmacy, complying to bronchial challenge. The symptoms can be easily locally required standards. relieved by inhaled/nebulized β2 agonist. In some patients an early prolonged reaction has been Bronchial provocation with lysine-aspirin observed (fall in FEV1 developing with 2–3 h) Definition and short technical description Bronchial [63], while in one study, several hours following challenge with a soluble form of aspirin (lysine – aspirin; lysine aspirin challenge the development of late L-ASA) is used to confirm a history of hypersensitivity bronchial symptoms was observed [64]. reactions induced by aspirin or other NSAIDs in patients 2. Systemic: with an underlying chronic airway respiratory disease Bronchial reaction induced by inhalation of (asthma/rhinosinusitis/nasal polyps) and manifesting pri- L-ASA may be accompanied by extrabronchial marily as bronchial obstruction, dyspnea and nasal con- (nasal and/or cutaneous) symptoms in almost gestion/rhinorrhea [57]. Incremental concentrations of half of ASA-hypersensitive patients, and in some L-ASA are administered by a dosimeter-controlled jet- patients, inhalation of L-ASA results in nebulizer in 30 min intervals and forced expiratory vol- development of isolated extrabronchial ume in 1 s is measured at 10, 20 and 30 min after each symptoms [65, 66]. Only a single case of severe, dose [58, 59]. The provocation is considered positive if systemic reaction has been described in a patient at least 20 % fall in FEV1 as compared with post saline with history of ibuprofen - induced dyspnea, but baseline value occurs [60]. Diagnostic inhalation chal- without typical asthma triad [67]. The reaction lenges with other NSAIDs (indomethacin, sulpyrine, alter LysASA BPT started with facial flush, and ketoprofen) have been also reported. generalized pruritus was followed by shortness of breath, cold sweating, and wheezing. Severe Clinical indications An inhalation provocation test with bronchoconstriction (75 % fall in FEV1) was lysine -aspirin is used to confirm hypersensitivity to associated with asphyxia and Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 14 of 42 hypotonia. The patient fully recovered after 7. Contra-indications: administration of epinephrine, oxygen, a short acting,  Uncontrolled asthma and/or FEV1 below 70 % bronchodilator by inhaler, methylprednisolone, and of predicted volume expander.  A history of very severe anaphylactic reactions 3. Fatal reaction: precipitated by aspirin or other NSAIDs No fatal reaction has been reported  Infection of respiratory tract within 4 weeks 2. Prevalence and risk associated with the procedure: prior to the challenge Although BPT with L-ASA is generally safe, it may be  Recent major surgery, severe disease of the associated with systemic reaction, thus precautions heart, brain, digestive tract, liver, kidney during the procedure are necessary. The major risk is  Pregnancy a significant bronchospasm, which however, can be  Use of systemic beta-blockers easily relieved by appropriate treatment [68]. 8. Other considerations 3. Risk factors for adverse reactions  Although associated with some risk of more Low basal FEV1 (below 70 % of predicted), severe reaction, Lys-ASA-BPT is generally uncontrolled asthma, inappropriate increasing of the considered safe, sensitive, specific and reliable dose of inhaled Lys-aspirin. diagnostics tool for confirming both AERD and NERD Institutional/organizational safety recommendations General safety recommendations has been presented by Nonspecific bronchial provocations the HANNA/ENDA guideline [57] Definitions and technical description During NS-BPT, a patient inhales under laboratory conditions increasing WAO safety recommendations The following WAO doses (concentrations) of a potentially bronchospasm- safety recommendations are proposed (Grade IV): inducing agent or is exposed to forced hyperventilation during exercise. After inhalation of each dose FEV1 is 1. Site: measured. A challenge is completed when a significant 4. Hospital or outpatient clinic setting fall in FEV1 occurs or a maximal cumulative dose (con- 2. Personnel: centration) is administrated. The stimuli used for non-  Physician should be responsible for supervising specific BPT can be classified as direct (methacholine, the L-ASA bronchial challenge procedure, which histamine, leukotrienes or prostaglandins), and indirect may be performed by a nurse. (e.g. exercise, eucapnic voluntary hyperpnea, hypertonic 3. Emergency equipment availability: saline, adenosine monophosphate, and mannitol) de-  Should be available on site (mandatory) pending if they act directly on a specific airway smooth 4. Emergency staff (ICU) availability: muscle receptor or release mediators from inflammatory  Should be available within 30 min cells [69–71]. 5. Pretreatment:  Is not necessary, but symptoms of positive reaction Clinical indications The test are used to confirm the should be immediately relieved by the inhalation presence or assess the degree of airway hyperrespon- of short-acting b2-agonist or by nebulization siveness, which is one of the main characteristics of (e.g. 2.5–5.0 mg of salbutamol). In case of more asthma, and its measurement, using different severe reactions oral or intravenous corticosteroids methods, is important in establishing a correct diag- or epinephrine are administered. nosis [72]. However, non-specific airway hyper re- 6. Duration of the supervised follow up after procedure: sponsiveness may be also present in other chronic  Patient should remain under observation in the respiratory conditions such as COPD, cystic fibrosis, office/hospital for at least 1 h after the or allergic rhinitis. These tests have been also used to completion of an aspirin inhalation challenge. monitor asthma treatment [73] and to monitor non- The FEV1 value should have returned to within specific bronchial hyperresponsiveness before and 10 % of the prechallenge baseline, before after bronchial challenges with specific occupational discharge from the hospital. The patient should and non-occupational agents [74]. be provided with a peak expiratory flow (PEF) meter and record the PEF values before leaving Age limitations Since change in FEV1 is the primary out- the hospital and every 2–3 h until late evening. In come measure for these tests, the ability to perform reliable the case of any respiratory symptoms and a 20 % spirometric maneuvers is the major limitation. Therefore, decline in PEF value, the patient should take the use of these testing methods is not recommended for short acting β2-mimetic and contact the center. those under the age of 6. There is no upper age limit to Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 15 of 42 perform NS- BPT. The use of impulse oscilometry, instead 3. Emergency equipment available: of spirometry, may expand the age groups able to perform Should be available on site (recommended) reliable spirometric maneuvers as it requires passive co- 4. Emergency staff (ICU) available: operation instead of active participation [75]. Not required 5. Pre-treatment: Description of unintended/adverse reactions associated No pre-treatment is necessary, however drugs with the procedure which may potentially affect the reactions (see 1. Type and spectrum of adverse reactions guidelines) should be withheld prior to the chal-  Local: lenge [80]. Cough is the most common side effect of these 6. Duration of supervised follow-up: protocols [71]. Less common side effects include Due to the characteristics of the agents used, oropharyngeal pain and irritation, chest late-phase reactions are not expected, except in rare discomfort, and dizziness. There are isolated cases after exercise tests. As a result, no special cases of angioedema and Vocal Cord Dysfunction follow-up is needed after recovering from reported in the literature. Clinical staff exposed to bronchospastic reactions. the bronchoprovocation agents are at increased 7. Contraindications: risk of bronchospasm if they have asthma.  Severe airflow limitation (FEV1, < 50 % predicted  Systemic: or < 1.0 L) (absolute contraindication) No systemic reactions except for cough or gag  Moderate airflow limitation (FEV1 < 60 % have been reported. predicted or <1.5 L(relative contraindication)  Fatal:  Uncontrolled asthma No fatal reactions following NS-BPT have been  Spirometry-induced bronchoconstriction (i.e., less reported. than 2 baseline FEV1 measurements out of 8 The NS-BPT procedures are considered to be attempts within 15 %); generally safe and adverse reactions are usually  Recent major surgery; severe disease of the heart, mild and fairly easy to control. Most patients re- brain, digestive tract, liver, kidney cover spontaneously after the challenge test or after  Active, recent or chronic infection receiving a standard dose of a bronchodilator. Dis-  Pregnancy tressed  Use of systemic beta-blockers patients respond very well to inhaled bronchodilators  Current use of cholinesterase inhibitor with or without oxygen supplementation. medication (for myasthenia gravis) for 2. Risk factors for adverse reactions/unintended reactions methacholine challenges The risk of excessive reaction may be increased in 8. Additional for exercise testing: individuals with low baseline lung function, if their The European Respiratory Society suggested [80]: asthma is not well controlled or during active  FEV1 greater than 75 % of the predicted normal respiratory infection. value  The patient with unstable cardiac ischemia or Institutional/organizational safety recommendations malignant arrhythmias should not be tested. Both European and America guidelines propose safety  Those with orthopedic limitation to exercise are measures and list contraindications for NS-BPTs [76–78]. unlikely to achieve exercise ventilation high enough to elicit airway narrowing. WAO safety recommendations and contraindications  For patients over 60 years of age, a 12-lead elec- 1. Site: trocardiogram (ECG) obtained within the past Hospital or outpatient clinic setting – These year should be available. procedures do not require hospital-based specialized 9. Other considerations: centers and hospital admission is not necessary for  Subjects should understand the procedure and the duration of the provocation [79]. be able to perform reliable spirometric 2. Personnel: maneuvers. The procedure can be performed by trained technician/nurse who is familiar with the guidelines Nasal provocation tests and knowledgeable about specific test procedures. Nasal allergen provocation tests Physicians who have expertise in the field should be Definition and short technical description Nasal aller- readily available to manage acute asthmatic reactions gen provocation test (NAPT) or nasal allergen challenge or other complications. test is the method by which the nasal mucosa is Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 16 of 42 challenged by instillation of allergen into the nasal cav- NAPT also carries a risk of a delayed reaction ities. NAPT assesses the nasal response to the suspected defined as the reappearance of nasal symptoms triggering allergen. 3–12 h after NAPT [86, 88, 89]. Some There are several methods by which NAPT is per- researchers have reported that the immediate formed. Some clinicians perform it by spraying the aller- and late phase response of NAPT was 63 % gen solution as aerosols into the nasal cavity, while and 37 %, respectively [90]. others apply a small allergen coated paper disk on the – Lower airway adverse reaction to NAPT inferior turbinate. Nebulization or instillation by pipette/ (bronchoconstriction) can occur when the dropper are other forms of NAPT. Yet another form of allergen enters directly into the lower allergen challenge is by using special challenge chambers respiratory tract via the larynx. The chance of with controlled environments and precise delivery of allergens directly entering the lower airways agents [81]. Therefore, there is no standardized uniform also depends on the method of NAPT used. method for performing NAPT, and so also for the pre-  Systemic: cise criteria for evaluating the positive response, and No systemic reactions following NPTs have been grading for the risk of adverse events [82, 83]. reported 2. Risk factors for adverse reactions Clinical indications NAPT is performed to confirm the The possibility of excessive/adverse events of NAPT diagnosis of AR in the situation of discrepancy between comes from either the use of excess allergen for the symptoms and the results of skin prick test (SPT) NAPT or deposition of the allergen from nose/ and/or serum specific immunoglobulin E (sIgE), to object- nasopharynx into the lower airways. ively assess disease severity and to monitor the response to pharmacologic treatment, for specific immunotherapy Institutional/organizational safety recommendations (SIT) in AR, to study the pathophysiological mechanisms Not available of allergic inflammation, and to diagnose occupational rhinitis [84]. Nasal provocation tests are necessary for the WAO safety recommendations diagnosis of local allergic rhinitis [85]. 1. Site: Outpatient clinic or hospital setting Age limitation NAPT can be done in both adults and 2. Personnel: children. Upper age limit depends on the presence of Technician/nurse with physician’s supervision contraindicating disease conditions. 3. Emergency equipment availability: Emergency equipment should be available on site Description and prevalence of excessive/adverse (mandatory) reactions associated with the procedure 4. Emergency staff (ICU) availability: 1. Type and spectrum of excessive/adverse reactions Should be available within 30 min  Local: 5. Pretreatment: – The chance of side effects is influenced by the Not applicable concentration of allergen and by the method 6. Duration of the supervised follow up after of allergen application. The appropriate dose procedure: of allergen for provocation can be estimated 30 min based on the dose of SPT. The dose of allergen 7. Contra-indications: that elicits a positive response (3 mm) of SPT  Intense nasal obstruction or septal perforation can be used for NAPT. The starting dose can  Current nasal symptoms be 1:1,000 then increased by either factor of 3  Within 4 weeks after viral or bacterial infection. or 10 [86, 87] NAPT performed by spraying  Not well-controlled asthma, severe asthma or severe allergen or applying a small disk on the inferior chronic obstructive pulmonary disease (COPD) turbinate carries a lower risk as compared to  Cardiopulmonary disease where epinephrine is the methods using nebulization or instillation of contraindicated allergen solution by a pipette/dropper. 8. Other considerations: – Adverse reactions from NAPT can be divided Proper cooperation of the patient when performing into those upper airway reactions (mainly NAPT (especially when performing by allergen nasal) and lower airway reactions nebulization or pipetting/dropping) is mandatory. (bronchoconstriction). An excessive reaction The patient should hold one’s breath during allergen of the upper airway due to NAPT is a severe instillation to prevent the leaking of the allergen into nasal blockage or excessive nasal discharge. the lower airways [91, 92]. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 17 of 42 Nasal aspirin provocation desensitization, intranasal ketorolac and modified Definition/description Nasal challenge with lysine as- aspirin challenge significantly attenuated the mean pirin or ketorolac (United States) can be used to diag- percentage decrease in FEV(1) values (8.5 % vs nose aspirin exacerbated respiratory disease (AERD). 13.4 %; P = .01) and decreased the percentage of Baseline symptoms and measurements of the upper and extrapulmonary reactions (23 % vs 45 %; P = .002), lower airway are made and then incremental doses of particularly laryngospasm (7 % vs19%; P = .02) and the aspirin or NSAID are applied internally to the nose, gastrointestinal reactions (12 % vs 33 %; P = .001). as drops or spray with close monitoring of symptoms This protocol was significantly shorter, lasting an and airway measurements. The timing of response differs average of 1.9 vs 2.6 days (P = <.001). In fact, 83 % of from allergen challenge- so 45 min is allowed between ap- the patients completed the new protocol in less than plication and measurement. An increase in nasal symp- 48 h compared with only 20 % in the oral challenge toms (obstruction, rhinorrhea, sneezing, itching) plus an control group (P < .001) [93]. objective decrease in the upper airway of >25 % minimal 5. Risk factors for excessive reactions: cross sectional area or volume 0–12 cm on acoustic rhi-  Laryngospasm to aspirin-challenge inadvisable nometry is a positive response [60, 93].  Failure to monitor nasal airway objectively If negative after a total of 150 mg lysine aspirin an oral  Dose miscalculation challenge should be undertaken. Institutional/organizational safety recommendations Clinical indications Used to assess aspirin sensitivity in EAACI/GA2LEN guideline: aspirin provocation tests for patients with rhinitis and/or polypoid rhinosinusitis, and/ diagnosis of aspirin hypersensitivity [60]. or asthma. WAO safety recommendations Age limitation Usually done in adults since AERD is 1. Site: uncommon in children. Upper age limit depends on Both hospital and outpatient clinic setting health status, particularly spirometry- see below. Avoid 2. Personnel: in pregnancy. Technician/nurse supervised by physician 3. Emergency equipment availability: Description of adverse/unintended reactions associated Should be available on site (suggested). with the procedure 4. Emergency staff (ICU) availability: 1. Local: Available within 30 min Since topical aspirin is applied to possibly sensitive 5. Pretreatment: tissue the reaction usually involves the upper airway Pre-treatment with all usual asthma therapy on day first with predominant symptoms being nasal of study permitted; nasal therapy stopped one week obstruction, rhinorrhoea, sometimes sneezing, beforehand. itching. The lower airway may become involved, 6. Duration of the supervised follow up after with asthma symptoms, but this is less frequent than procedure: with oral challenge and rarely severe. Laryngospasm 30 min reported following ketorolac challenge. About 5–10 % 7. Contra-indications: of subjects experience mild gastric irritation. History of anaphylactic to NSAIDs Other 2. Systemic: contraindications as listed in previous section (NPT) Very rarely skin reactions such as urticaria and 8. Other considerations: angioedema can occur, again less commonly than  Informed consent is mandatory. with oral challenge where some 25 % are affected.  In very severe aspirin hypersensitivity, for safety 3. Fatal: reasons start with lowest dose. No fatalities have been reported using nasal aspirin  Use of acoustic rhinometry to monitor nasal challenge airway is recommended (Nasal Inspiratory 4. Risk: PeakFlow is less sensitive) [95]. Using nasal lysine aspirin the challenge dose can be very accurately controlled. 6 % of 131 subjects Nasal endoscopy developed asthma symptoms, only 1.5 % showed a Definition and short technical description significant >20 % decrease in FEV1. Skin reactions Nasal endoscopy is the gold standard and the most valuable occurred in 5.3 %, mainly urticaria, one patient tool in the clinic to afford the diagnosis (presence, severity, developed facial angioedema [94]. Compared with etiology, and follow-up) of the majority of rhinologic the standard oral aspirin challenge and pathologies [96–98]. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 18 of 42 Nasal endoscopy is performed by a flexible or rigid Description of adverse/unintended reactions associated scope attached to a light source by glass fiber. For diag- with the procedure nostic examination, a scope with an optic angle from 1. Type and spectrum of adverse reactions: 0–45° is used with a caliber of 2,5–4 mm. Other optics Nasal endoscopy adverse reactions are mainly local. (45–70°, 4 mm) are mostly used in surgery. Nasal en- When exploring the nasal cavities a very mild doscopy may eventually be preceded by local adminis- discomfort with sensation of foreign body, nasal tration of anaesthetic and/or decongestive drugs. First, itching, and sneezing is quite common. Contact of the bottom of the nose through the nasopharynx is to endoscope head with the nasal mucosa, mainly be inspected with an evaluation of the nasal septum, linked to some unexpected patient head sudden the lower turbinate and meatus, the choanae and the movement, can induce some burning or pain nasopharyx. Afterwards, the scope follows the edge of sensation and rarely minor epistaxis. Although the middle turbinate towards the rostrum sphenoidale, possible, vasovagal reactions are very uncommon. with examination of the middle and upper turbinates, When exploring the throat with flexible scopes, a the mucus drainage from the sinuses, possible accessory nausea sensation can also be induced. There is no ostia from the maxillary sinus, and the aperture of the data in the literature reporting prevalence and risks sphenoidal sinus. At last, to get a view of the ostiomeatal associated with the nasal examination using nasal complex, the ethmoidal bulla, the access to the frontal endoscopy. sinus, and the olfactory cleft must be attempted. 2. Risk factors for unintended reactions: Non-compliant patients, mainly children, and Clinical indications patients with significant nasal septum deviations The following reasons for nasal endoscopy can be con- and/or risk of epistaxis constitute the relative risk sidered in allergy practice: factors for these adverse reaction.  The physical examination of the nasal cavities and Institutional/organizational safety recommendations paranasal sinuses. The different structures of the nose Both European (European Rhinologic Society [ERS], can be evaluated: nasal septum, upper, middle and European Academy of Allergology and Clinical Immun- lower turbinates and meati, ostiomeatal complex, ology [EAACI]) and American (American Academy of cavum, nasopharynx, and olfactory cleft. Even Otolaryngology, Head and Neck Surgery [AAOHNS], oropharynx and larynx can also be examined using American Academy of Allergy Asthma and Immunology flexible endoscopy. Although subjective in nature [AAAAI]) scientific societies have produced a number of (physician interpretation) it can provide an objective position papers which include the efficacy, safety, and evaluation of nasal signed (i.e. nasal congestion, main technical recommendations for the use of nasal en- rhinorrhea/postnasal drip). Despite being more doscopy in daily practice, clinical trials, and sinonasal difficult to perform, rigid nasal endoscopy usually and skull base surgery [99, 103, 104]. provides a better examination view than flexible endoscopy and anterior rhinoscopy [99]. WAO safety recommendations  To assess severity, and to follow-up (after medical or 1. Site: surgical treatment) of nasal and sinusal diseases Both hospital and outpatient clinics [97, 98, 100, 101]: 2. Personnel:  For differential diagnosis of sinus diseases e.g. Nasal endoscopic, either rigid or flexible, should be – Structural abnormalities: septal deviation, performed by a well-trained physician, either turbinate hypertrophy, choanal atresia, or otorhinolaringologist or not (allergologist, adenoid hypertrophy. pneumonologist, pediatrician, or even general – Nasal vasculitis, granulomatosis, or bleeding diseases. practitioner). – Benign tumors and malignancies (unilateral 3. Emergency equipment availability: versus bilateral) Not required  To obtain biopsies (i.e. nasal mucosa, nasal polyps, Comment: For potential minor epistaxis, a wet tumors) and microbiological samples for both gauze or merocel pack as well as silver nitrate sticks disease diagnosis and translational research [99]. for cauterization of potential minor nasal bleedings should be available. For unusual but potential Age limitation (children, adults, elderly) vasovagal adverse reactions, a reclining chair or a Nasal endoscopy is possible in all ages, including chil- litter should be available in the clinic. dren [99, 102]. The only relative limitation is the lack of 4. Emergency staff (ICU) availability: patient’s collaboration. Not required Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 19 of 42 5. Pretreatment: least prone to patient and observer bias and is therefore In general, no pretreatment is mandatory. If considered the “gold standard” [107, 111]. Testing is per- examination is difficult to perform, bothersome formed when the patient is in good general health and and/or painful, local anesthesia (lidocaine, without flares of atopic disease, has eliminated the food cocaine) may be used [105]. A nasal decongestant from their diet, is not using medications that interfere may also be useful mainly in the presence of with interpretation of the test (for example antihista- nasal deviation, turbinate hypertrophy or swollen mines), or medications interfering with gastric digestion mucosa. Both local nasal anesthesia and nasal and threshold levels such as anti-ulcer drugs [112]. Pa- decongestion may help the physician to have a tients are observed throughout the OFC, and the feeding better view of nasal cavities, turbinates, middle proceeds unless the clinician diagnoses an allergic re- meatus, and nasopharynx as well as to make the sponse. If a typical serving size of the food is ingested patient feel more comfortable during the without symptoms, tolerance is diagnosed. This may re- endoscopic examination. quire an open feeding of a larger amount following a 6. Duration of the supervised follow-up after nasal masked feeding. If a reaction is elicited, treatments may be endoscopy: administered to reverse the allergic reaction, and the con- After nasal endoscopy, patients do not need a clusion is that the patient is allergic. The time required for special follow-up supervision. Only in the case of feeding the test substances (test food and placebo), and minor complications (nasal bleeding, vasovagal observing for reactions, varies depending upon specific reaction) the patient may remain in observation in protocol and the anticipated outcomes, e.g., immediate or the clinic as needed (usually less than one hour). delayed reactions, but usually takes several hours. 7. Contraindications: There are no major contraindications for nasal Clinical indications endoscopy. Minor contraindications may be severe An OFC is indicated to confirm that an allergic or other nasal hyperreactivity (can be solved by using local adverse reaction to a food exists [105–108, 113]. The anesthesia), non-collaborative patients, and test is recommended as a diagnostic procedure because, predisposition to nasal bleeding (nasal vasculitis or in contrast to a positive allergy skin or serum sIgE test granulomatosis, Rendu-Osler syndrome). that indicates sensitization but is not solely indicative of 8. Other considerations: allergy, the OFC may verify or exclude clinical allergy The presence of nasal deviations, turbinate and [111, 114, 115]. An OFC is typically administered when adenoid hypertrophy and chronic rhinosinusitis with other tests, including the medical history, skin testing or without nasal polyps are usually considered as and/or serum tests are inconclusive, and there is motiv- exclusion criteria in clinical trials investigating the ation to add the food to the diet or clarify the existence of effect of medications in allergic rhinitis. Since the allergy [105]. Typical circumstances warranting an posterior nasal deviation and small size nasal polyps OFC include: suspicion of an allergy because of a possible are not easily visualized using anterior rhinoscopy, a allergic reaction, but having inconclusive supporting tests; number of patients with this concomitant problems no exposure to the food but having positive tests, or evalu- (10–15 % of general population has CRS and 4 % ating if an allergy has resolved when other tests remain in- nasal polyps) may be wrongly included in such conclusive. The OFC test can detect immediate or delayed clinical trials. allergic and even non-immunologic reactions. An OFC may also be indicated for research purposes, or to deter- Food provocation tests mine an individual’s threshold of reactivity [107]. When Definition and short technical description making the decision to perform an OFC, the clinician The oral food challenge (OFC) test involves having a pa- should also consider the: risk of reaction (based on history tient ingest a food gradually, in incrementally increasing and prior tests), potential severity of a reaction (may relate doses, under medical supervision to determine if there is to the food tested, history, presence of asthma in the pa- allergy or tolerance [105–109]. The food may be pre- tient, test results), patient or family preferences, nutri- pared and presented in the manner in which it is typic- tional importance of the food, social aspects of being able ally consumed, or its taste and texture may be masked to advance the diet, and emotional consequences should by mixing it with other foods. When the food is pre- the food not be tolerated. sented in its natural form, the test is considered an “open” feeding. An open OFC is commonly used in clin- Age limitation (children, adults, elderly) ical practice [110], but may introduce bias. The food is The test may be conducted at any age. The test can in- masked for single-blind or double-blind, placebo- duce anaphylaxis; therefore, the physician should be controlled OFCs, the latter format being considered the confident in recognizing and treating anaphylaxis in the Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 20 of 42 age group being tested, and understand the health issues systematically studied [105, 107, 125]. Reactions, that may increase adverse reaction risks or present con- including severe ones, may occur on the first dose of traindications in the age group tested (e.g., heart disease, an OFC [119, 121]. Very slow and gradual dosing obstructive lung disease, pregnancy, etc.) [107, 108]. does not necessarily reduce the risk of allergic reaction severity [107, 125]. Using capsules to mask Description of adverse/unintended reactions associated the food allergen is not generally recommended. The with the procedure use of capsules may result in more severe or 1. Type and spectrum of adverse reactions uncontrolled reactions because they may release A physician-supervised OFC may induce allergic allergen in an unpredictable fashion and also oral reactions that could range from mild to severe, symptoms are bypassed [126]. including anaphylaxis. Food-induced anaphylaxis can be fatal [116]. Although severe reactions have been Institutional/organizational safety recommendations documented [117, 118], fatal reactions during A number of safety recommendations have been pro- supervised OFCs have not been reported. mulgated by various organizations, expert panels and au- Nonetheless, fatal reactions can occur. Symptoms thors [105, 107, 113, 114]. in the event of a reaction, which are expected and should be anticipated, most commonly affect the WAO safety recommendations skin, followed by gastrointestinal and respiratory 1. Site: symptoms [118, 119]. Cardiovascular symptoms Both hospital and outpatient clinic setting are uncommon but must be anticipated, especially 2. Personnel: in adults. Delayed and biphasic reactions are Trained personnel, including a physician, with possible, but also uncommon [120]. experience in the procedure and skill 2. Prevalence and risk associated with the procedure 3. Emergency equipment availability: The likelihood of having a reaction and the Should be available on site (mandatory) severity of a reaction is not accurately predictable 4. Emergency staff (ICU) availability: by current tests [105–107, 109, 121, 122]. Data Should be available on site (in less than 5 min) or regarding risk assessment is limited by biases within 30 min depending on the risk assessment introduced by patient selection and other factors 5. Pretreatment (if any): (foods tested, age, clinical approach, definition of Not applicable a positive test, etc.). Variability in patient 6. Duration of the supervised follow up after selection likely accounts for the large range of procedure: OFC outcomes; for example studies in children Observation periods should be determined based on report reaction rates of 19–48 % [111, 118, 120, clinical circumstances, but generally a 1–2 h 123]. The emotional impact, for example observation is suggested for patients who tolerate increasing anxiety, is also not predictable. the full food dose during the OFC and at least 4 h Reactions are most often managed with when a significant reaction occurs; discharge antihistamines, but epinephrine, including more instructions should include the possibility of late than one dose, may be needed [120]. Epinephrine is reactions (patients understand how to identify and administered, in general, for under 10 % of challenges treat); (overall challenges, including those without reactions) 7. Contra-indications: [111, 120, 124]. Additional treatments may be The test should not be performed when the food has required (e.g., oxygen, intravenous fluids, recently caused a life-threatening reaction or if the bronchodilators, etc.). patient has a chronic medical condition that would 3. Risk factors for adverse/unintended reactions pose a health threat in the event of anaphylaxis It is presumed that risk factors for reactions include (angina, cardiac disease, pregnancy, severe chronic increasingly positive test results, the food tested, lung disease, use of beta-blockers, etc.). personal sensitivity and target organ reactivity (e.g., 8. Other considerations: asthma) [105, 123]. Clinical decisions about stopping Recording a peak flow or spirometry may be an OFC, for example continuing dosing if a reaction considered and intravenous access should be has not clearly occurred, but is suspected, may also secured if anaphylaxis or severe reactions such as introduce increased risk that must be weighed enterocolitis [127] are likely, or if emergency against benefits of confirming the allergy [105, 106]. intravenous access would be deemed difficult. Dosing amount, and frequency between doses, may Monitoring of the blood pressure may be play a role in outcomes, but this has not been necessary. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 21 of 42 It is important to select a starting dose that is likely Description of adverse/unintended reactions associated below the patient’s reaction threshold. Upon positive with the procedure food challenge the patient should be advised in The intention of the DPT is to evoke a hypersensitivity regard to dietary restriction through trained reaction, however the magnitude of the reaction should personnel (e.g., dietician) and equipped with emergency be limited to the minimum. Thus the major task is to medications (e.g., self-injectable epinephrine) for minimize the potential risk of development of general- allergic reactions upon accidental exposure. Patients ized and/or severe reaction should be encouraged to eat the food on a regular basis after a negative test. 1. Type and spectrum of adverse/unintended reactions Adverse reaction is anticipated to be similar in manifestations to those occurring in the Oral drug provocation test hypersensitivity reaction, with a similar time kinetic Definition and short technical description but usually milder and of shorter duration. In Oral drug provocation test (DPT) is the controlled ad- practice it may vary from mild, local and transient ministration of a drug to diagnose immune-mediated to generalized and severe and in some instances (allergy) and non-immune-mediated drug hypersensitiv- potentially fatal. ity reactions. Incremental doses of the drug are adminis- 2. Prevalence and risk associated with the procedure tered with the aim of inducing symptoms emulating The prevalence and risk of adverse reaction is those reported by the patient but at a very low scale and dependent on the correct assessment of causality of in a safe and controlled manner. DPT should be per- the hypersensitivity reaction, risk-benefit evaluation formed placebo-controlled, single blinded, and, in situa- of the patient undergoing DPT, assessment of the tions where psychological factors may be present, even general health of the patient on day of procedure, double-blind. The rational approach is provided in dif- and compliance with the technical requirements of ferent reviews [128–130] and protocols are published DPT [122, 124]. for several drugs but these have not been standardized 3. Risk factors for adverse/unintended reactions [57, 61, 129, 131–135]. Patients with severe co-morbidities such as uncontrolled asthma, cardiac, hepatic, renal or other organ specific or systemic diseases which can be Clinical indications worsened or activated if the hypersensitivity reaction DPT are usually performed if other less dangerous test- is provoked would be at higher risk. In such ing methods are not available or do not allow a firm instances, DPT is considered only if the drug under conclusion, and the outcome is of clinical relevance to suspicion is essential for the patient. the patient. DPT may be carried out in the following situations: Institutional/organizational safety recommendations The most comprehensive safety guideline on DPT is from  To confirm the presence of hypersensitivity in a the European Network for Drug Allergy (ENDA) [57]. patient with equivocal history Other guidelines are on the general aspect of the diagnosis  To exclude hypersensitivity, when clinical history and management of drug allergy [18, 62, 136–138]. suggests it may not be the culprit drug, when the reaction does not appear to be drug hypersensitivity WAO safety recommendations reaction, and when skin tests or in-vitro tests are General statement All DPT must be preceded by an in- not available. dividual risk-benefit assessment [139].  To assess cross-reactivity to related drugs (e.g. an alternative betalactam antibiotic or another COX-1 1. Site: inhibitor in hypersensitivity to NSAID)  Both hospital and outpatient clinic setting  To certify tolerance to an alternative drug  DPT can be done in the clinic setting if previous reaction was mild [140]. Patients with more severe reactions should be hospitalized for DPT Age limitation [128]. There is no data on the age limit for DPT. In general, 2. Personnel: the procedure is limited by the ability to objectively as- DPT should only be carried out by a trained nurse/ sess the supposed hypersensitivity reaction that may be technician under the direct supervision of the elicited and the risk to the patient when the reaction is allergist. provoked. 3. Emergency equipment availability Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 22 of 42 Should be available on site (mandatory) the attending allergist). The patient’s health status 4. Emergency staff (ICU) availability should be good, without any sign of allergy or Should be available on site (within 5 min) or within viral infection. Blood pressure, pulse rate, peak less than 30 min reach depending on the risk flow meter reading (in asthmatics or when assessment. bronchospasm is anticipated), and intravenous 5. Pretreatment cannula inserted (if the initial reaction was  There should not be any pre-treatment that may suggestive of a systemic reaction/anaphylaxis). mask early signs of a reaction.  Prior to each incremental provocation dose,  H1-antihistamines should be discontinued blood pressure, pulse rate, peak flow meter (duration depending on the half-life of the reading (in asthmatics or if bronchospasm preparation) before the procedure. Corticosteroids, anticipated), and any new symptom/sign must be anti-leukotrienes and tricyclic antidepressants clearly recorded. may modify response to the challenge and should be reviewed. Medications that may cause problems if emergency treatment becomes essential e.g. ß- Insect sting challenge blocking agents have to be reviewed and decision Definition and short technical description made on whether to stop the drug prior to DPT Sting challenge (SC) is the ultimate standard for the [141]. diagnosis of insect venom allergy [144, 145]. During this 6. Duration of the supervised follow up after procedure procedure patient is deliberately stung by a living insect The duration of supervised follow-up after procedure of the culprit species. Before SC the respective insect is dependent on the expected time latency between needs to be entomologically classified. drug ingestion and reaction onset based on the In general, a blinded, placebo-controlled procedure is previous hypersensitivity episode. In general, not possible and incremental doses of culprit venom immediate-type reactions need a short observation cannot be applied, making the SC test less controllable period, whereas delayed-type reactions in the history compared to other challenge tests in allergic patients. A may necessitate similarly long observation periods thorough patient work-up and the evaluation of contra- after procedure. If a mild reaction has occurred indications are, therefore, of eminent importance. during DPT, observation after stabilization is recommended for at least 2 h. After severe reactions, Clinical indications hospitalization is mandatory because of the possibility Depending on the individual risk profile and culprit, in- of biphasic episodes that can be lethal if not sect venom immunotherapy (VIT) may not be effective recognized early and treated adequately [142]. It is in 5–20 % of the patients. SC aims to identify those indi- recommended that before going home, all patients viduals on maintenance VIT to assess effectiveness and are given an action plan that stresses when to seek who are not protected after 3–5 years of VIT. Although medical attention and a number to call in case of the standard management of insect venom hypersensi- emergency. tivity does not include SC in the United States [25, 146], 7. Contraindications: the results of SC tests may help physicians to decide on DPT should not be carried out when the whether VIT should be performed with a higher venom hypersensitivity reaction is serious and potentially dose and are an invaluable research tool. If standard VIT life-threatening including: anaphylaxis, drug is not effective (systemic allergic reaction at SC despite hypersensitivity syndromes/drug reaction with VIT), a higher maintenance venom dose will be used eosinophilia and systemic symptoms, acute generalised (usually 200 μg venom). Later on, VIT effectiveness may exanthematous pustulosis, exfoliative dermatitis, be re-evaluated by a subsequent, second SC (after the erythema multiforme major/Stevens-Johnson higher maintenance dose has been reached). Syndrome or toxic epidermal necrolysis, generalised Additionally, results of SC may improve patient quality bullous eruptions, vasculitis and other drug-induced of life if it can be demonstrated that one does not de- autoimmune disease, or specific major organ velop an allergic reaction to a sting of the culprit insect involvement such as cytopenia. Pregnancy is (i.e., less anxiety about future sting reactions). considered a contraindication for DPT unless the drug is essential during pregnancy or delivery [128, 137, 143]. 8. Other considerations: Age limitation  On the morning of the DPT, the patient should There is no age limit for SC. However, in patients who are have had only a light breakfast and morning not capable of understanding the procedure, and who can- medications taken or omitted (as instructed by not give their informed consent SC cannot be done. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 23 of 42 Description of unintended/excessive reactions associated venom [151]. Duration of VIT is inversely with the procedure correlated with the risk for a systemic allergic 1. Type and spectrum of unintended/excessive reaction during SC [151]. Severe systemic allergic reactions at sting challenge: reactions which have been observed before SC Adverse reactions include pain at sting site, and during the build-up or maintenance phase of VIT local reactions which may be large. In case of are also associated with an increased risk for a VIT failure, systemic allergic reactions may occur systemic allergic reaction during SC [151, 154–156]. varying between minor and very severe, and In addition, certain underlying diseases (mastocytosis) affecting respiratory and/or cardio-circulatory increase the risk for systemic reactions at SC function. [151, 157]. 2. Prevalence and risk associated with the procedure:  Factors, which influence the severity grade of a Pain at sting site, and a minor local reaction (wheal, sting reaction, have not been systematically erythema, and swelling) is undesirable but is viewed investigated. However, mastocytosis is a clear risk as a normal sting reaction. Large local reactions with factor for very severe sting reactions [157]. a diameter of more than 10 cm, and/or local Finally, the severity of systemic allergic reaction reactions of a duration of up to several days are will increase if the patient presents with severe very rare. According to pooled data of co-morbidities such as asthma or cardiovascular observational or randomized studies systemic diseases. allergic reactions may occur in 18.0 % (range 0–59 %) of bee honeybee venom allergic patients Institutional/organizational safety recommendations and in 4.3 % (range 0–12.3 %) of yellow jacket Guidance on how to perform SC has been described, (vespid) venom allergic patients [146]. The vast and a guideline was published by the Interest Group on majority of systemic reactions are mild to Insect Venom Allergy of the EAACI [144, 158]. moderate; however, cases of severe systemic allergic reactions and in the absence of an early efficient emergency therapy, even a fatal WAO safety recommendations anaphylactic reaction have been described. The patient must be screened for any contraindication 3. Risk factors for unintended/excessive reactions: to SC; risks, benefits and alternatives of the procedure  Systemic reactions need to be accepted in order shall be discussed with the patient, and written informed to identify treatment failure [147]. The general consent for the procedure must be obtained. If the pa- risk for the patient in terms of a life-threatening tient is unstable (in case of an organ dysfunction), or if reaction is significantly lower in a medical setting the patient requires a medication possibly disposing him when adequate treatment of symptoms is started to a higher risk, SC shall be postponed until conditions immediately after first onset of symptoms, than at have been improved. field sting. In patients on VIT, several factors Drugs, which might ease symptoms of an allergic reac- determine the overall risk for a systemic allergic tion (thereby evoking falsely negative results at SC) reaction at SC (thereby indicating VIT failure). should be discontinued before SC. These drugs may in- Patients allergic to honeybee venom are at a clude corticosteroids, H1-antihistamines, or anti-IgE higher risk for systemic allergic reactions than antibodies. The respective half-life of the medication has patients allergic to vespid venom [148–151]. to be considered when planning a SC. If an ACE- Systemic allergic reactions during SC are also inhibitor therapy is indispensable it should not be dis- more likely in patients who are on ACE continued just because a SC is planned. ß-blocking (angiotensin converting enzyme)-inhibitor therapy agents should be stopped prior to SC if possible. [53–150, 152, 153]. The rate of systemic allergic Before SC, treatment protocols (indicating venom reactions at SC depends on the venom doses doses of at least 100 μg, and adherence to injection applied during VIT with higher therapeutic venom intervals) should be requested from patients who have doses (individual or cumulative) decreasing this been treated elsewhere. Patients should remain fasted rate [148, 151, 154]. The risk-lowering effect of a for at least six hours before SC, and should not be on a higher therapeutic venom dose is not specific for medication potentially interfering with anaesthesia. the type of Hymenoptera venom used for VIT. Chronic diseases like asthma or arterial hypertension Thus, during SC, the magnitude of risk reduction should be stable and the patient should not suffer from is the same irrespective whether the patient has any relevant acute disease. Blood pressure, pulse rate, received a double VIT (standard dose of two and, in asthmatics, pulmonary peak flow or FEV1 should different venoms), or a double dose of the same be measured. Before SC, a peripheral intravenous Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 24 of 42 cannula with a large bore should be inserted into all Therapeutic procedures patients. Subcutaneous Allergen Specific Immunotherapy (SCIT) Definition and technical description of the procedure (SCIT) 1. Site: Since the beginning of the twentieth century, allergenic  Both hospital or outpatient clinic setting vaccines were administered subcutaneously (SCIT). The  After SC, some patients will require a subsequent favorable clinical results obtained in the early empirical in-hospital surveillance or treatment. Therefore, attempts, rapidly lead to a widespread use of SCIT, which SC should be performed at a site which is remained for decades the only form of allergen immuno- sufficiently close to a hospital specialized on therapy. Some clinicians occasionally attempted to use emergency treatment. routes different from the subcutaneous one [159–161], 2. Personnel: but the alternatives to SCIT remained of very limited The insect can be put onto the patients’ skin and interest for many years [162]. can be motivated to sting by a trained nurse or by SIT is started by increasing subcutaneous injections of other assistance personnel. SC shall be done under allergen up to a maintenance dose. Several protocols of direct supervision of an allergist. SCIT administration (mainly regarding the modality to 3. Emergency equipment availability: achieve the maintenance dose) have subsequently been Should be available on site (mandatory) proposed and used in clinical practice, such as the “rush”, 4. Emergency staff (ICU) availability: ultra-rush or the “cluster” [163, 164]. Should be available within 30 min After reaching the maintenance dose, the interval be- 5. Pretreatment: tween injections is usually increased to monthly, and No specific pretreatment is necessary. continued for 3 to 5 years. For hymenoptera venom al- Cardiovascular or bronchial diseases, which might lergy, the interval between maintenance doses can be de- represent a specific risk in the context of SC, should layed to every 4 months [165], and performed life-long be treated to reach a stable situation. especially in patients with significant risk factors such as 6. Duration of the supervised follow up after procedure: mastocytosis or previous severe sting reactions. Monitoring of all subjective or objective signs and symptoms is required during and after SC. After SC Indications to SCIT the patient should be monitored for at least two Allergen-specific immunotherapy (SIT) is a “biological hours or longer, depending on the patient’s history response modifier” that affects the immune response to- and on the outcome of SC. After severe systemic wards allergens at different levels. For this reason, SIT is allergic reactions, hospitalization is mandatory until currently considered a cornerstone of the management complete recovery (minimum duration 24 h). of allergic respiratory diseases (allergic rhinitis/asthma) 7. Contraindications: and of Hymenoptera venom allergy. SC should not be done in patients who already had a systemic allergic reaction after a field sting Age limitation while still being in the maintenance phase of VIT. Usually SCIT is considered in children 5 years and older. In patients with repeated side effects during the maintenance phase of VIT, SC should not be Description of adverse/unintended reactions associated performed unless a tolerance of VIT has been with SCIT reached. Severe or poorly controlled cardiovascular/respiratory diseases (FEV1-value ≤ 1. Type and spectrum of adverse events (AEs) 70 %) as well as pregnancy are contraindications After the earliest descriptions of AEs due to SCIT for SC. [165] these are generally classified according to a If medications which might lower the risk for system introduced in Europe since the 1990s [166] systemic allergic reactions at SC cannot be safely (largely based on the Mueller’s classification for withdrawn, they shall be continued. However, results hymenoptera venom reactions) [167] and up-dated of subsequent SCs must be interpreted with caution by the World Allergy Organization and other since there is an increased chance for falsely organizations [168, 169]. Nonetheless, other classifi- negative results, and the reaction to a later field cations have been repeatedly proposed (for review sting may differ from that observed after SC. see 174), always distinguishing between local and sys- 8. Other considerations: temic reactions, grading systemic reactions according For patients with mastocytosis and other risk factors to their severity and the number of organs involved, an alleviated maintenance dose should be given from and distinguishing between early (<30 min) and delayed the start. reactions [162, 163, 168, 170]. Local reactions are Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 25 of 42 limited to the site of injection and include itching, population-based surveys have been conducted swelling, pain or induration. among the European Countries, and the data from Systemic reactions include rhinoconjunctivitis, clinical trials are largely incomplete [185]. To date, bronchospasm, urticaria/angioedema, generalized the largest safety survey on SCIT was conducted in itching, abdominal cramps sometimes ending as Italy [186], which analyzed over 1,700 patients, show- respiratory failure or shock. Other reactions are ing a 3.3 % of systemic reaction rate with no fatalities. considered nonspecific (headache, tiredness, general 3. Risk factors for adverse reactions malaise). Also vaso-vagal reactions due to the Based on the available data derived from the large USA injection (nausea, vomiting, bradycardia, surveys as well as European data reports, severe and hypotension, sweating) may occur. This again uncontrolled asthma seems to represent the most proposes the distinction between “generic” systemic prominent risk factor for severe side effects [177–179]. adverse events and overt anaphylaxis [171], since the Other factors indicated in the official position papers definition of anaphylaxis itself has been repeatedly have to be considered as relative contraindications and changed during the last years. In general the should be considered individually [168]. This is involvement of more than one organ/system strongly especially true for children below the age of 5, where suggests anaphylaxis, as well as a clinically relevant severe AEs are more difficult to recognize and to treat drop in blood pressure, loss of consciousness or [168]. Another well recognized risk factor is human respiratory compromise [171, 172]. The more recent error, including wrong dosing administration, injection classification of systemic AEs, has been proposed by into vessels, and lack of emergency measures the World Allergy Organization [172]. The majority immediately available [187]. Although in the past it was of the AEs are immediate (i.e. within 30 min) and reported that large local reactions are more frequently therefore are presumed to be due to specific IgE, but described in those patients who experience systemic delayed reactions may also occur. reactions, it is now well accepted that on an individual 2. Prevalence of adverse reactions and risk associated basis large local reactions are poor predictors of future with procedure systemic reactions [188]. The fact that the injection of allergens in atopic Finally, it has been sometimes suggested that SIT can subjects could cause AEs including severe reactions induce autoimmune diseases. Recently published data, and even death, had been recognized and published however, demonstrate no increase in autoimmune since the early 1980s [173–175]. The rate of disease, and thus recommendations state that it systemic reactions with SCIT largely depends on the should not be considered a contraindication to the administration schedule, the type of allergen and the treatment [189]. Recent data have also shown no need survey method (e.g. controlled trial VS to avoid its use in well controlled HIV infection [190, questionnaire-based surveys). When evaluating the 191]. Pregnancy seems not to be a significant risk data from literature, it has to be noticed that the factor for SIT [191, 192]. Although a hypothetical risk practice of SCIT largely differs between USA and can exist, based on pathophysiologic considerations, Europe. In USA, allergen mixtures are commonly there is no evidence that the use of betablockers used, and the extracts are at higher concentrations (especially the cardioselective ones) or angiotensin [176], whereas in Europe, the usual attitude is to inhibitors enhance the risk of adverse events in vaccinate with few (1 to 3) allergens. On the other patients taking SCIT [193, 194]. hand, the improved manufacturing procedures and quality of extracts, the improved standardization of Institutional/organizational safety recommendations allergen extracts, and the divulgation/education ef- EAACI, Immunotherapy Task Force. Standards for practical forts [163, 164, 168], have probably contributed to allergen-specific immunotherapy (2006 Alvarez-Cuesta E) the decline of severe/fatal reactions. [163] The majority of data on the safety of SCIT come Allergen immunotherapy: a practice parameter third from the USA surveys that have been regularly update (2011 Cox L et al) [164] conducted over the past 40 years. According to past Sublingual immunotherapy: World Allergy Organization and more recent surveys the occurrence of fatal position paper 2013 update [195] adverse events is less than 1 per 2,500,000 injections [177–181], although the occurrence of fatal or near WAO safety recommendations for SCIT fatal events has progressively declined over the years These WAO recommendations refer to subcutaneous [179, 182–184]. The occurrence of systemic AEs form immunotherapy (SCIT) only. Sublingual immuno- with SCIT is approximately 0.05–0.6 % of doses therapy (SLIT) has not been included in this document administered. On the other hand, no large since the vaccine (drops or tablets) is NOT administered Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 26 of 42 in a medically supervised setting. Although the first dose 7. Contraindications: of allergen vaccine may be administered at the allergist’s Pregnancy has been always prudently suggested as a office, it has never been a formal requirement. potential contraindication to SIT, and to SCIT in general, although no evidence was present in the 1. Site: literature. A recent survey demonstrated that the SCIT treatment may be started and continued in an use of SIT in pregnancy, when clearly indicated, outpatient setting does not increase the risk of perinatal or foetal 2. Personnel: adverse events [191, 192]. The suggestion of not Only trained allergist may initiate and supervise starting SCIT during pregnancy, and not stopping SCIT. The injections can be made by a nurse under an already ongoing SIT remains valid, based on physician supervision. common sense. 3. Emergency equipment availability: 8. Other safety considerations: Should be available on site (mandatory) Safety of maintenance of SCIT may be improved by 4. Emergency staff (ICU) availability: monitoring of symptoms, appropriate adjustment of Should be available on site (in less than 5 min) or vaccine dosing etc. within 30 min, depending on the risk assessment 5. Pretreatment: Venom immunotherapy The use of premedication with oral Definition and technical description of the procedure (VIT) antihistamines/oral antileukotrienes still remains a Venom immunotherapy (VIT) is so far the only ef- matter of debate. On one hand it has been fective treatment that prevents anaphylaxis and im- claimed that premedication may delay or mask proves quality of life in patients with venom allergy systemic reactions. On the other hand, it has been [23, 196–198]. Several protocols of VIT have been de- reported that premedication could reduce the scribed and used in clinical practice: Conventional frequency and severity of AEs. The strength of protocols are started with weekly injections of in- recommendation on this matter is still weak, thus creasing venom doses from 0.01 to 100 μg over its employment largely remains in the hands of 2 months. In rush protocols the increase to the main- the physician. tenance dose is reached by daily increasing doses of 6. Precautions and duration of the supervised follow up venom for 2 to 3 days. In ultrarush protocols the in- after procedure: crease to a total dose of 100 μg is reached by injec- Although some of the adverse events of SCIT can be tions every 30 min in 3.5 h (Table 1) [196]. After avoided, others occur unpredictably and without reaching maintenance dose the interval of injections explanation. Immunotherapy should be administered is increased from weekly to monthly, and 6–8 weeks with a 26- to 27-gauge syringe, and the injection from the second year. The recommended duration of should be given subcutaneously in the lateral/posterior VIT is 3 to 5 years, in patients with risk factors like portion of the arm. The skin should be pinched and mastocytosis or previous severe sting reactions, VIT lifted off of the muscles to avoid intramuscular or may be continued indefinitely or as long as the risk intravenous injection and the skin should be wiped of accidental stings remains. The maintenance dose of with disinfectant before giving the injection. 100 μg protects over 95 % of wasp and ant venom al- It is well known that some fundamental precautions lergic and 80–90 % of bee venom allergic patients can be taken to reduce the risk of severe/fatal AEs. from systemic allergic reaction (SAR) when re-stung First, the correct administration (i.e., patient’s name, [148, 196, 197]. In case of a SAR to a re-sting during batch, and allergen) has to be verified and recorded. VIT an increase of the maintenance dose to 200 μg As recommended in all guidelines it is essential that protects most of these patients from further SAR the patient have a careful examination and medical [196]. history taken [168–172, 174–187]. These include the objective assessment of current respiratory symptoms/signs (e.g. asthma/rhinitis), the evaluation Indications for VIT of previous systemic reactions to SCIT (immediate US guidelines recommend VIT in all patients with a his- or delayed), and the presence of any concomitant tory of SAR and positive diagnostic tests – skin tests acute respiratory illness. When feasible, a Peak and/or venom specific serum IgE. Excepted are children Expiratory Flow evaluation should be done, with only cutaneous reactions [23]. European guidelines considering a value of less than 70 % of best predicted [196] do not recommend VIT also in adults with only a warning signal [162, 163, 167]. After each injection cutaneous reactions, unless there are special risk factors the patient should be observed for at least 30 min. or a severe reduction of QOL [198]. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 27 of 42 Age limitation 2. Personnel: technician/nurse/physician VIT may be given to children including those of pre-school The treating physician should recommend and age [23, 196], although the balance between discomforts supervise VIT. The injections can be made by a versus benefits of treatment should be considered on an in- nurse under physician supervision. dividual basis. In general, it is best to wait until a child is 3. Emergency equipment availability old enough to understand and accept the treatment. Elderly Should be available on site (mandatory) patients have an increased risk of very severe SAR to acci- 4. Emergency staff (ICU) availability dental stings with lasting morbidity, e.g. myocardial infarc- Should be available on site (in less than 5 min) or tion, cerebral infarction or even fatal outcome [199, 200], within 30 min, depending on the risk assessment which may be prevented by VIT. Although older age and and the immunotherapy protocol used. comorbidities also increase the risk of reactions to VIT it- 5. Pretreatment self, these are usually milder and easier to manage than a Pre-treatment with oral antihistamines during the field sting. Therefore, there is no upper age limit for VIT. dose build-up phase reduces the risk of SAR during VIT, and does not impact on the overall efficacy of Adverse reactions associated with VIT VIT [208]. 1. Type and spectrum of adverse reactions 6. Precautions and duration of the supervised follow up Local reactions at the injection site are common, after procedure and may be large (>5 cm in diameter) or last more  xPrior to each VIT injection, the patient should than 24 h. Immediate-type adverse reactions are be asked about: (i) reactions or unexpected common during VIT. The majority of these are mild symptoms following the last visit or injection, skin-only reactions, but some may be severe. and; (ii) any new health problems including newly 2. Prevalence of adverse reactions and risk associated prescribed medications. Blood pressure and pulse with procedure rate should be routinely measured before every The reported proportions of patients experiencing one or injection is given. Issues identified may lead to more significant reactions requiring medical intervention modifications as follows: are 10–20 % for bee and Myrmecia ant VIT, and 5 % for – Reactions on previous visits or injections Vespula VIT [23, 148]. Fatal reactions to VIT have not consider reduced VIT dose been reported. Rush and ultrarush protocols (Table 1) – Intercurrent illness consider delaying protect most patients more rapidly but may increase the treatment number of SAR side effects [196, 201]. – Newly prescribed antihypertensive medications 3. Risk factors for adverse reactions consider temporarily withholding In addition to the species of venom used, risk factors antihypertensive medications for 24–48 h for SAR due to VIT include older age, coexisting prior to each visit for VIT. cardiovascular or pulmonary disease, – Poorly controlled blood pressure or new onset antihypertensive medications, elevated baseline (or worsening) of possible cardiac or lung serum tryptase and mastocytosis [200–204]. disease (e.g. angina, asthma) consider pausing Intercurrent illnesses (e.g. fever, infection) may also VIT until further investigations and/or increase the risk of an adverse reaction. Dialysed stabilisation of condition. aqueous venom and Aluminium hydroxide depot  After each injection the patient should be extracts have somewhat lower risks of SAR [205, 206]. observed for at least 30 min.  If there is no SAR the next injection can be given Institutional/organizational safety recommendations or the patient can be discharged after 30 min of The most recent international guidelines addressing observation. the issue of VIT safety are: The guidelines of the 7. Contraindications EAACI [195]. The practice parameter update 2011 of Contraindications for VIT are concomitant active the AAAAI [23] and the WAO anaphylaxis guidelines neoplastic and auto-immune diseases [194]. VIT 2013 [207]. should not be started during pregnancy but can be continued if well tolerated before pregnancy. WAO safety recommendations 8. Other safety considerations  Safety of maintenance VIT may be improved by 1. Site: careful monitoring of symptoms and appropriate  Both hospital and outpatient clinic settings adjustment of vaccine dosing.  VIT treatment may be started and continued  After an SAR the next injection dose should be either at a hospital or in the office decreased. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 28 of 42  Discharge may be considered 1 h after complete Description of adverse reactions associated with the regression of all symptoms, but after a severe procedure reaction (hypotension or hypoxemia), observation 1. Type and spectrum of adverse reactions for a longer period should be considered. The most common adverse reactions are local, e.g.,  If there are repeated SAR due to VIT, pre-treatment oral pruritus, or gastrointestinal, e.g., abdominal with oral antihistamines on the evening before and pain. More severe adverse reactions affect the 1 h before the following VIT injections should be respiratory tract, e.g., wheezing or multisystem considered [208]. reactions  Other options are to switch to a conventional [210–212]. The development of allergic eosinophilic protocol using dialysed aqueous or Aluminium esophagitis has been described [216]. hydroxide depot preparations [205, 206], and 2. Prevalence of adverse reactions and risk associated pretreatment with Omalizumab [209]. with the procedure. Currently OIT is only recommended in controlled Oral Immunotherapy for Food Allergy (OIT) clinical studies until the short- and long-term safety Definition and short technical description profile is better known and understood [215]. Oral immunotherapy is a promising concept for the 3. Risk factor for adverse reactions treatment of food allergy. The majority of clinical trials Augmentation factors, e.g., infection, menses and focused on peanut, cow’s milk, and hen’s egg allergy exercise seem to be risk factors for adverse [210, 211]. Meta-analysis revealed a substantially lower reactions. risk of reactions to the relevant food allergen in those receiving OIT [211]. There are several protocols for OIT Institutional / organizational safety recommendations used throughout the world [212]. In general, OIT starts EAACI food allergy and anaphylaxis guidelines: diagno- with oral administration of very low doses of food pro- sis and management of food allergy [215]. tein, e.g. 2 mg of peanut protein [213], which is given on a daily basis. The doses are progressively increased over WAO safety recommendations time. Regular dose increments, e.g. biweekly, are per- 1. Site: formed mostly under medical supervision [212]. When a  Both hospital and outpatient clinic settings; defined target dose is reached, this maintenance dose, however, OIT is currently not recommended for e.g. 800 mg peanut protein [213] is continuously admin- routine clinical use [214, 215]. istered on a daily basis and continued for several years. 2. Personnel: technician / nurse / physicians: However, it is important to note that, in fact, mainten-  Physicians experienced with food allergy and ance dose ranged among various centers from 400 to specific immunotherapy should recommend and 8000 mg of peanut protein [214]. Moreover, to date supervise OIT. During the build-up phase food there is no recommended duration for OIT as long-term should be administered by a nurse under studies are still missing [211]. physician’s supervision. 3. Emergency equipment availability:  Should be available on site (mandatory) Clinical indications 4. Emergency staff (ICU) availability: OIT is a promising treatment approach, but it is associ-  Should be available on site (in less than 5 min) or ated with risk of adverse reactions, including anaphyl- within 30 min, depending on the risk assessment. axis; it is therefore not currently recommended for 5. Pretreatment: routine clinical use [215]. Patients with peanut or tree  Antihistamines or omalizumab can be considered nut allergy might especially benefit from OIT, as natural 6. Precautions and duration of the supervised follow-up tolerance is rare. In addition, patients with persistent after procedure: cow’s milk or hen’s egg allergy will be candidates. The  During the build-up phase, doses are progressively objective of OIT is to achieve first a clinical desensitization, increased over time, e.g. biweekly, under medical which means the tolerance to a certain amount of the supervision [212, 213]. After each dose the patient allergen with an ongoing therapy, and later a long-term should be observed for at least 2 h. The same dose tolerance, which means the permanent loss of reactivity is given at home daily until the next increase. In also after stopping OIT [212]. the maintenance phase the tolerated dose is given daily at home [212, 213]. Age limitations 7. Contraindications: OIT could be performed at all ages; however, most OIT  Commonly, OIT is not performed in patients trials have been performed in children [210, 211]. with unstable asthma or in pregnancy. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 29 of 42 8. Other safety considerations: severe delayed reactions are candidates for slow desen-  Doses should be adjusted during infection as this sitizations [218]. has been described as an important augmentation factor. Clinical indications for drug desensitization Rapid and slow drug desensitizations are indicated: Drug desensitization Definition and short technical description 1. If the drug is considered first line therapy (e.g. The term desensitization is used for procedures inducing patients with platin-sensitive recurrent ovarian clinical tolerance or tolerization to drugs eliciting hyper- cancer, cystic fibrosis patients with antibiotics sensitivity reactions [217, 218]. Rapid desensitization allergy, patients with NSAIDS intolerance in need of protocols are used for type I IgE/mast cell-mediated al- dual antiplatelet therapy). lergic reactions and slow desensitization protocols are 2. If the drug is more effective than the alternatives. used for type IV delayed drug hypersensitivity reactions 3. If non-cross reacting therapeutic agents are [218] and other hypersensitivity reactions such as aspirin unavailable. exacerbated respiratory disease (AERD) [138]. 4. The drug administrated after desensitization has a Desensitization procedures are based on protocols in unique therapeutic effect (aspirin in patients with which suboptimal doses of the drug allergens are re- NSAIDs – exacerbated respiratory disease introduced, starting at 1/100 to 1/1000 the target dose complicated with nasal polyps). or lower for patients presenting severe reactions, and in- creasing at fixed time intervals by doubling or higher in- Age limitation crements until reaching the target dose. These protocols Most published protocols assess clinical efficacy of introduce the sensitizing medication in few hours up to desensitization in adult populations. There are several 6–8 h. Desensitization protocols allow allergic patients published desensitization protocols for children to receive their first line therapeutic agents to treat in- (desensitization protocols to antibiotics [227] and fections, cancer or chronic inflammatory diseases. The chemotherapy [228]). The success rate of adult and induction of clinical tolerance is temporary and largely pediatric desensitization protocols is similar with a depends on the half-life of the medication. The range from 50 to 100 %. desensitization state persists from few hours, in the case of antibiotics administered every 6 to 8 h to several days Adverse/unintended reactions associated with the drug in the case of aspirin. It is generally accepted that once desensitization more than two half-lives of the medication have spanned In 30 to 50 % of all desensitization procedures mild symp- the patient is no longer desensitized and will need re- toms occur and there are no reported deaths resulting desensitization. Successful desensitization can be from a desensitization protocol. Anti-histamines are used achieved in patients with IgE/mast cell mediated hyper- commonly as pre-medications and some protocols are sensitivity reactions (allergy to beta lactams or other an- modified once patients have presented reactions to subse- tibiotics) [219] and platinium salts [220, 221] who quent desensitizations [228]. present symptoms including urticaria, angioedema, wheezing, laryngeal edema, nausea, vomiting, diarrhea 1. Type and spectrum of adverse reactions or hypotension. Anaphylaxis in which tryptase levels are Most of the desensitization protocols are well found elevated in serum is not a contraindication for tolerated by the majority of patients. However, rapid desensitization. Other hypersensitivity reactions reintroduction of a drug to an allergic patient carries (patients with aspirin exacerbated respiratory disease high risk including anaphylaxis. [222], non-beta lactam antibiotics [223], sulfonamides Reactions during rapid desensitization protocols can [224] and other chemotherapeutics including mono- occur in minutes and can range from flushing and clonal antibodies [221]) have been successfully desensi- urticaria to hypotension and oxygen desaturation. tized with different and slow protocols, some of them During aspirin desensitization in patients with involving several days. Patients with chronic urticaria Aspirin Exacerbated Respiratory Disease (AERD) the exacerbated by aspirin and other NSAIDs (named tolerant state is achieved by repeating the provoking NSAIDs Exacerbated Cutaneous Disease-NECD) may dose of aspirin so that aspirin sensitivity has to be be refractory to desensitizations [225] with few suc- demonstrated during the procedure. Thus, except cessful cases [226]. There are few standardized proto- for so called “silent desensitization” adverse reaction cols for delayed reactions and caution has to be taken (respiratory or cutaneous) are intentionally evoked to avoid desensitization in patients with severe cutane- during the procedure, but the magnitude is ous or systemic reactions. Only patients with non- controlled and limited by rapid administration of Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 30 of 42 reliever drugs. These reactions can appear at every desensitizations are those performed on step of desensitization protocols. In patients patients with initial grade 3 anaphylactic desensitized to aspirin, breakthrough reactions reactions associated with hypotension and/or usually occur after the oral dose of 45–60 mg of oxygen desaturation, patients with severe/ aspirin [229] but it can be seen at higher doses. unstable cardiovascular diseases and/or on Protocols for rapid desensitization to aspirin in beta blockers and patients with FEV1 < 70 %. patients with cutaneous symptoms differ from the – Once high risk patients have presented a AERD protocols [225, 230] in which the prevalence successful desensitization in the intensive care of adverse reactions is only up to 19 %. unit repeated desensitizations can be done in During intravenous rapid desensitization protocols the outpatient setting provided resuscitation most of the adverse reactions are seen when the medications including epinephrine, oxygen and drug is infused at the maximal concentration and intubation materials are available. during the last step of the protocol [221]. – Patients with hypersensitivity reactions 2. Prevalence and risk associated with the procedure: involving the skin and/or two organs without Side effects may complicate 12 to 52 % of changes in vital signs can be desensitized for desensitizations to antibiotics and from 4–33 % of the first time in the outpatient setting with desensitizations to chemotherapeutics and 29 % trained staff and emergency equipment desensitizations to monoclonal antibodies [220, 221]. available on site (see below). In repeated desensitizations the rate of adverse – In patients requiring repeated desensitizations reactions decreases to less than 10 % with over 6–10 (desensitizations to chemotherapy, monoclonal desensitizations [221] and the spectrum of reactions antibodies), after an initial successful ranges from cutaneous reactions [228] to desensitization, subsequent procedures can be anaphylactic shock [220]. performed in outpatient settings. 3. Risk factors for adverse/unintended reactions – For patients with delayed drug hypersensitivity The severity of the initial hypersensitivity reaction is slow desensitization protocols can also be the most important risk factor, but other factors done as outpatient procedures based on the such as the time course of the HS reaction (in patients severity of the initial reaction and the disease with delayed HSR it is most reasonable to hospitalize being treated (allopurinol desensitization for gout) patients for longer time), the concomitant use of other 2. Personnel: medications such as beta-blockers and ACE inhibitors Desensitization should be supervised by and the severity of the underlying disease need to be well-trained, experienced allergists and nurses. One taken into consideration. on one nursing should be available for each For patients desensitized to chemotherapy and desensitized patient and an allergist should be monoclonal antibodies the presence of atopy, a available on site at less than 3 min of the previous severe reaction and the presence of severe desensitization procedure. cardiovascular disease are risk factor for severe 3. Emergency equipment availability: reactions. In addition patients on beta blockers and Should be available on site (mandatory) on ACE inhibitors are at risk for severe hypotension 4. Emergency staff availability and cardiovascular collapse during desensitization. Should be available on the site Risk factors for severe or moderate reaction during 5. Pretreatment aspirin desensitization include: age: 30–40, duration Pretreatment with systemic steroids is not of AERD less 10 years, FEV1 < 80 %, uncontrolled recommended unless required by current guidelines asthma, previous asthma –related ED visits and lack for cancer treatment (dexamethasone for taxanes of antileukotriene pretreatment [229]. administration) [231]. Pretreatment with H1 and H2 antihistamines is recommended for rapid Institutional/organizational safety recommendations desensitization for chemotherapy, monoclonals and Not available antibiotics but no controlled studies have been done comparing outcomes of desensitizations with and WAO safety recommendations without pre-medications [221, 232]. Whitaker et al. 1. Site: [233] indicated that pretreatment with antihistamines  Both hospital and outpatient clinic settings alone or with glucocorticosteroids did not reduce the  Comment: risk of reactions in desensitized patients. Leukotriene – All high risk desensitizations should be done receptor blockade with montelukast and prostaglandin in the intensive care unit. High risk inhibition with aspirin have provided excellent Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 31 of 42 protection against severe reactions in patients – Cutaneous and systemic vasculitis desensitized to chemotherapy and monoclonals – Drug induced autoimmune disorders [234, 235]. In early trials with paclitaxel and docetaxel – Drug induced organ involvement (hepatitis, approximately 30 % of patients presented acute nephritis, cytopenias, pneumonitis) infusion reaction and pretreatment with antihistamines – Immune complex disorders (serum sickness and glucocorticosteroids and slower infusion rate disease) reduced the rate of adverse reactions to 10 % [236].  Relative contraindications Based on these results many current chemotherapy – Treatment with beta blockers and ACE regimens include pretreatment with corticosteroids, inhibitors antihistamines and proton-pump inhibitors. – Unstable underlying disease (asthma, coronary Although some authors [217] do not recommend heart disease) pretreatment with antihistamines as it may mask Maculo-papular rashes are not contraindications for early signs of hypersensitivity reaction [138], current desensitization and slow protocols are generally studies in populations of desensitized patients without successful. pre-medications are lacking and no recommendations 8. Other considerations: can be made. Treatment of chronic disease should be continued, Leukotriene receptor antagonists may alleviate but drugs that can influence the course of reaction symptoms of breakthrough reactions in aspirin like beta blockers and ACE inhibitors should be hypersensitive patients [237] by shifting reaction discontinued at least 24 h prior to desensitization to from bronchial to naso-ocular symptoms and these avoid prolonged and intractable hypotension during pre-medications are strongly recommended at the anaphylaxis induced by the desensitization procedure. present time for all patients desensitized to aspirin. 6. Precautions and duration of the supervised follow up Treatment with Anti-IgE and other biologicals after procedure Definition and short technical description The severity of the initial hypersensitivity reaction is Omalizumab is a humanized monoclonal antibody di- the most important risk factor, but other factors such rected against human IgE. It prevents binding of soluble as the time course of the HS reaction (in patients with IgE to the IgE receptor. This is currently the only mono- delayed HSR it is most reasonable to hospitalize clonal antibody directed against IgE which is licensed. patients for longer time), the concomitant use of other medications such as beta-blockers and ACE Indication inhibitors and the severity of the underlying disease Omalizumab is indicated for adults and adolescent and need to be taken into consideration. children (6 years of age and above) with moderate to se- Patients should be in stable condition (FEV1 > 70 % vere persistent asthma, who have a positive skin test or in patients with asthma) before the start of the in-vitro reactivity to a perennial aeroallergen and whose desensitization. In patients with cystic fibrosis the symptoms are inadequately controlled with inhaled cor- baseline FEV1 may be substantially lower and risk ticosteroids [238–244]. Although new clinical data sug- assessment should be done but low FEV1 is not gest that there are also other patient populations with considered a formal contraindication for asthma or other allergy or atopy related conditions, who desensitization. would benefit from with Omalizumab, the clinical indi- Duration of the supervision depends on the initial cation is currently limited to the above described patient hypersensitivity reactions. In case of immediate group. More recently omalizumab has been approved reactions, rapid desensitized patients to for use in chronic idiopathic urticaria [245]. chemotherapy, monoclonal and antibiotics are supervised for 30 min in the hospital for acute post Age limitations desensitization reactions and then for the next Anti-IgE is indicated for adults and adolescence (12 years 24–48 h for delayed post desensitization reactions. of age and above). 7. Contra-indications The contra-indications to drug desensitization may Description of adverse reactions be absolute or relative, when the risk /benefit 1. Anaphylaxis evaluation is performed.  Absolute contraindications The frequency of anaphylaxis attributed to Omalizumab – Previous severe/life threatening cutaneous is estimated to be at least 0.2 % of patients, based on an drug induced disease (SJS/TEN, DHS/DIHS/ estimated exposure of about 57,300 patients from June DRESS, AGEP) 2003 through December 2006. Anaphylaxis has occurred Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 32 of 42 as early as after the first dose of Omalizumab, but also oc- 2. Personnel: curs beyond 1 year after beginning of regularly scheduled treatment [246]. Omalizumab has received a box warning All personnel, supervising the patient during and after label by the FDA [247–249]. the injection, should be trained to handle anaphylactic reactions. 2. Malignancy 3. Emergency equipment availability Although malignant neoplasms were observed in 20 of 4,127 (0.5 %) Omalizumab-treated patients compared to Should be available on site (mandatory) 5 of 2,236 (0.2 %) control patients in clinical studies, the direct relationship between this treatment and the devel- 4. Emergency staff availability opment of malignancies is completely unclear. The observed malignancies in Omalizumab-treated patients Should be available on site (in less than 5 min) included a variety of different types, including breast, non-melanoma skin, prostate, melanoma, and others 5. Pretreatment [238]. However, the impact of longer exposure to Omalizumab, or the use in patients at higher risk for No pretreatment malignancies, is not known and the application of omalizumab in patients with preexisting malignancies 6. Precautions and duration of the supervised follow up contradicted [239]. after procedure 3. Eosinophilic conditions Following immediate reaction and intervention in the rare case that anaphylaxis occurs, the patient should be In rare cases, patients with asthma on therapy with further followed up in an appropriate emergency setting. Omalizumab presented a serious systemic eosinophilia, Consider in-office waiting time – 2 h for the first injec- sometimes presenting with clinical features of vasculitis, tion of omalizumab and then 30 min after each subsequent consistent with Churg-Strauss syndrome. dose. Patient should have an epinephrine autoinjector available [250]. 4. Fever, arthralgia, rush 7. Contraindications Some patients have experienced a constellation of signs and symptoms including arthritis, arthralgia, rush, The use of Omalizumab is contraindicated in the fever and lymphadenopathy with an onset 1 to 5 days patients with a history of severe hypersensitivity reac- after the first of subsequent injections. tions to Omalizumab or any of the preparation’s ingredients. Furthermore Omalizumab should not be 5. Parasitic infection used to treat acute bronchospasm or status asthmaticus. It is not clear if treatment with omalizumab may be associated with increased morbidity attributable to para- sitic infections [240]. Treatment with products from human plasma Definition and short technical description 6. Immunogenicity Products made from human plasma are increasingly being used also in the field of allergy and asthma treatment. Omalizumab does not seem to be associated with de- They include preparations of human immunoglobulins velopment of immunogenicity [243]. [251, 252], used for subcutaneous and intravenous admin- istration. More recently, also other plasma components have been isolated and made available in commercial Institutional/organizational safety recommendations preparations, which can be used for various other Not available conditions. A prominent example is the C1 esterase inhibitor [253]. C1 esterase inhibitor is manufactured WAO safety recommendations from human plasma, purified by a combination of fil- 1. Setting: tration and chromatographic procedures. Several pre- cautions have been implemented to reduce the risk of Both hospital and outpatient clinic setting viral transmission, since this factor, as well as Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 33 of 42 immunoglobulin preparations in general, are being de- Institutional safety recommendations rived from a large pool of donors. Not available. Indication WAO safety recommendations Indications for the use of human immunoglobulin prepa- 1. Site: rations are the treatment of primary humoral immuno- Both hospital and outpatients clinic settings deficiencies, chronic immune thrombocytopenic purpura, 2. Personnel: and others [251, 252, 254, 255]. All personnel in direct contact to the patient must C1 esterase inhibitor is indicated for routine prophylaxis be experienced in handling hypersensitivity against angioedema attacks in patients with Hereditary reactions. Angioedema (HAE) [254]. 3. Emergency equipment availability: Should be available on site (mandatory) Age limitations 4. Emergency staff availability: Immunoglobulins are available for all ages, but some C1 Should be available on site (in less than 5 min) inhibitor preparations have limited recommendations in 5. Pretreatment: children. Pretreatment regimen including analgesics, antihistamines, and/or anti-inflammatory medications, Description of adverse reactions steroids, hydration may be indicated in some patients All adverse reactions are related to direct or indirect ef- to avoid or diminish common adverse effects fects and mechanisms, known to occur by human im- 6. Precautions during the supervised follow up after munoglobulins and plasma preparations [256]. These are procedure: particularly: Based on the individual risk of the patient (see above), special precautions have to be taken before  Hypersensitivity reactions administering these preparations. They may include,  Renal dysfunction and renal failure but are not limited to: Periodic monitoring of renal  Thrombotic events function and urine output, assessment of blood  Hyperproteinemia, increased serum viscosity, and viscosity, analysis of signs and symptoms of hyponatraemia hemolysis, and the presence of anti-neutrophil anti-  Aseptic meningitis syndrome (AMS) bodies and anti-HLA antibodies in both, the product  Hemolysis and patient serum. These should be obtained in case  Transfusion related acute lung injury of an increased index of suspicion.  Volume overload 7. Contraindications:  Transmissible infectious agents Immunoglobulin preparations are contraindicated in  Interference with laboratory tests, due to the patients who have a history of anaphylactic or severe passively transferred antibodies in immunoglobulin systemic hypersensitivity reactions to the administration preparations of human immunoglobulin. Administration is also contraindicated in IgA-deficient patients with The following risk factors have been identified for the antibodies to IgA and a history of hypersensitivity. development of thrombosis: Anaphylaxis has been reported with the intravenous use of immunoglobulin preparations and is theoretic-  Advanced age, prolonged immobilization, ally possible following subcutaneous administration. hypercoagulable conditions, history of venous or arterial The C1 esterase inhibitor is contraindicated in thrombosis, use of estrogens, indwelling vascular patients who have manifested life-threatening catheters, hyperviscosity and cardiovascular risk factors. immediate hypersensitivity reactions, including  Patients predisposed to renal dysfunction, including anaphylaxis to the product. those with any degree of pre-existing renal 8. Other considerations: insufficiency, diabetes mellitus, age > 65, volume In case of hypersensitivity reactions stop infusion of depletion, sepsis, paraproteinaemia, or patients injection immediately. Have epinephrine receiving no nephrotoxic drugs. immediately available for treatment.  The only serious adverse reaction observed in clinical studies with C1 esterase inhibitor was Management of emergencies in allergy practice cerebrovascular accident. The most common All medical staff involved in either diagnostic or therapeutic adverse reactions observed have been headache, allergy procedures should be trained in the recognition and nausea, rash and vomiting. management of allergic emergencies including anaphylaxis. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 34 of 42 Recommended equipment and medications itchy, watery eyes, allergy eye drops may be The following equipment is necessary at the allergy sufficient. office performing diagnostic allergy procedures:  Difficulty breathing or wheezing related to e.g. inhaled allergen or oral food challenge should be Equipment assessed by measurement of respiratory function 1. Trolley for patient to lie flat if needed (spirometry) and could be relieved by inhalation 2. Oxygen and suction equipment, including tubing, of 2 puffs of albuterol or other beta2-agonist from masks etc. an MDI 3. Airway management equipment according to skill  If other symptoms like swollen lips, tongue, level (basic essentials are oral and nasopharyngeal tightness in the throat, hoarseness or trouble airways, bag-valve-mask for ventilation) speaking occur they should be consider as 4. Intravenous access cannulae (20-16G) and giving potential developing laryngeal edema and sets; needles and syringes. injection of adrenaline should be considered. 5. Manual blood pressure cuff Similarly, symptoms such as nausea, abdominal 6. Nebulizer mask (for inhaled/nebulized pain, vomiting, tachycardia, anxiety or dizziness epinephrine) may herald development of anaphylaxis and Note: In a hospital setting it is recommended that should be treated accordingly. there also be immediate access to ECG, pulse  The patient even with mild symptoms related to oximetry and non-invasive blood pressure monitoring the procedure should be observed continuously equipment, advanced airway management devices for and any worsening of symptoms should be intubation and cricothyrotomy, and an intravenous assessed as potential signs of anaphylaxis. infusion pump. 2. Severe allergic reactions If criteria for a diagnosis of anaphylaxis are met Drugs and fluids (that is, involvement of two or more organ 1. Epinephrine (2 packs of 5 ampoules of 1 mg/1 ml) systems, or the onset of cardiovascular collapse/ 2. Corticosteroid for intravenous injection hypotension, an appropriate treatment protocol 3. Antihistamines for oral or intravenous use (Table 4) should be initiated. The reaction 4. Two 1 L bags of normal saline (although rarely) may not respond to a single Note: In a hospital setting, it is recommended intramuscular dose of epinephrine, thus the that there also be immediate access to (a) smaller supervising doctor should be prepared to escalate bags of saline for setting up an epinephrine treatment. Reactions limited to the skin may infusion according to local hospital protocol and settle without treatment and/or be managed (b) a second line vasoconstrictor (metaraminol or symptomatically with oral antihistamines. vasopressin) Parenteral antihistamines should generally be avoided as there is no proof of benefit and they Management of adverse reactions may themselves trigger the onset of hypotension. Algorithms for management of allergic emergencies have The efficacy of steroids is unknown and so their been described by several state- of- the-art documents use is not recommended as a routine. available [206, 207, 257–259]. Management of excessive or emerging adverse reaction should be prompt, but must be preceded by assessment of the situation and Summary and recommendations should involve careful clinical assessment of a patient. Diagnosis of allergic disorders may require intentional Any intervention should be tailored to the type and se- exposure of patients to potentially allergenic or irritating verity of symptoms and vital signs. substances and sometimes involves deliberate induction of allergic symptoms to offending compounds during 1. Local/Mild reactions provocation tests. Intentional application to a sensitized  Allergy skin testing or allergen injection during patient of potentially dangerous substances (allergy vac- immunotherapy which are associated with cines) is also a part of routine management of allergic development of local redness, edema and pain diseases. Unwanted, excessive or even dangerous reac- can be relieve by local application of cold tions associated with these procedures can be minimized compresses followed by oral antihistamine. For or even avoided if the procedure is performed in appro- mild allergy symptoms, such as hay fever or priate manner and setting, medical personnel are aware hives, an oral antihistamine may be sufficient. For of its potential risk and are prepared to appropriately stuffy nose, decongestant can be given and for handle the situation. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 35 of 42 Table 4 Standard protocol for anaphylaxis management The general recommendations include: 1. Initial steps 1. Procedures for the diagnosis and treatment of • Call for assistance allergic diseases should be performed by medical • Give epinephrine 1:1000 at a dose of 0.01 mg/kg IM in the lateral personnel (physician/nurse/technician) fully aware of thigh (maximum 0.5 mg) risks associated with the procedure and trained in • Lie patient flat with legs elevated unless this causes increased respiratory distress, in which case the patient may prefer to sit up. the recognition and management of allergic However, return to supine position if there is any deterioration in emergencies, including anaphylaxis. conscious state 2. Some procedures can be performed by trained • Airway management (according to skills and equipment) if required • Document a simple systolic BP by palpation (radial/ brachial pulse) nurse/technician, but always under close supervision and then deflate the cuff to just below systolic pressure as a of the allergist. tourniquet and gain IV access. If equipment is available, start 3. Although most procedures can be done in both physiological monitoring (ECG, oxygen saturations, 5 minutely noninvasive BP) and give oxygen if severe respiratory distress and/or outpatient and hospital settings availability of hypotension. appropriate rescue service should be secured. If the patient is hypotensive, also: 4. Basic emergency equipment and rescue medications b. Give IV normal saline bolus 20 mL/kg c. Gain additional wide bore IV access (14G or 16G in adults) and should be available on site during each allergy prepare to give additional fluid and/or adrenaline infusion if the procedure. patient does not respond to initial management 5. Depending on the type of procedure emergency staff For upper airway obstruction/stridor, also: d. Continuous nebulization of epinephrine (5 mL of 1mg/ml) (ICU) should be available on site or should be reached within a specified time. 2. If there is inadequate response, an immediate life-threatening situation or deterioration 6. Before a procedure is initiated, contra-indications should be considered and risk/benefit ratio for each • Repeat IM epinephrine injection every 3–5 min as needed or start an IV epinephrine infusion as per hospital guidelines/protocol. procedure should be assessed. Monitor BP closely. Nausea, vomiting, shaking, tachycardia or 7. The patient should receive full information on the arrhythmias in the setting of normal or raised BP is likely to purpose and potential adverse effects associated with represent adrenaline toxicity rather than worsening anaphylaxis If the patient remains hypotensive, also: each procedure and for some procedures should be • Further N/saline fluid boluses (up to 50 mL/kg in total) may be asked to sign an informed consent. required in the first 20 min 8. If anaphylaxis or severe reactions are likely, • In the hospital setting, consider adding a selective vasoconstrictor (see Table 1). intravenous access should be secured before the When indicated at any time, prepare to initiate cardiopulmonary procedure is started. resuscitation (CPR) including standard IV adrenaline dosing if the patient 9. Continuous monitoring of patient by authorized goes into cardiac arrest. Prolonged CPR is indicated because the arrest is usually sudden (no preceding hypoxia) and potentially reversible personnel during is the procedure necessary to 3. Disposition secure safety of performed procedure. 10. After the procedure is completed the patient should • Consider to use systemic corticosteroids to prevent potential late phase reaction remain under close supervision for a specified period Severe reactions should be monitored for a minimum 4 h after the last of time. dose of adrenaline 11. Before the patient is released, she or he should be provided with appropriate instruction in how to Following review of available literature the group of handle potential adverse symptoms and what to do WAO allergy experts, representing various continents in case of an emergency. and areas of allergy expertise, reports on risk associated 12. Medical personnel who have asthma or had a prior with diagnostic and therapeutic procedures in allergy reaction to a testing agent should take precautions to practice. Based on known/expected risk and taking into minimize exposure (adequate ventilation, exhalation account existing allergy guidelines/recommendations a filters, hoods or closed chambers) or avoid performing set of safety requirements for performing allergy proce- these tests. dures have been proposed. The consensus on safety requirements for performing specific procedures recom- Acknowledgements mends appropriate qualifications of personnel, optimal The authors would like to thank the Executive Committee Officers and Board of Directors of the World Allergy Organization for support for setting where the procedure should be performed, this project. necessary availability of safety equipment, access to specialized emergency service and required time of Funding medical supervision. The group proposes also general Not applicable. recommendations which should be followed in allergy practice, regardless of the type of diagnostic/therapeutic Availability of data and materials procedure. Not applicable. Kowalski et al. World Allergy Organization Journal (2016) 9:33 Page 36 of 42 Authors’ contributions and Medical Center, Aichi, Japan. 43Messerli Research Institute, Medical MLK led the development of the paper. Each author contributed to the University Vienna, University Vienna, Vienna, Austria. 44Department of development of one or more sections in the paper. All authors reviewed and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, approved the paper. The development of this paper has been a project of Canada. 45Istituto Giannina Gaslini, Genoa, Italy. 46Gentofte University the WAO Committee on Allergy Diagnosis and Molecular Allergy, 2012-2013 Hospital, Lab for Allergology, Allergy Clinic, Hellerup, Denmark. 47Department term, and 2014-2015 term. of Pathophysiology, AKH, Wien, Austria. 48Campus Charite Mitte, Klinik fur Dermatologie & Allergologie, Berlin, Germany. Competing interests WA, MA-A, ACH, BKBW, BB, CB, GWC, ACH, LC, MC, HHC, ME, SF, DBKG, MG, Received: 12 March 2016 Accepted: 19 August 2016 TH, BWL, UM, JM, JO, JP, GP, MSB, JS, GS, SS, JT, VVK, TZ have no conflicts of interest to declare related to this paper. References Consent for publication 1. Pepys J. 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