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Acta Dermatovenerol Croat 2009;17(1):54-69 REVIEW

Nonallergic to Nonsteroidal Antiinflammatory Drugs, Angiotensin-Converting Enzyme Inhibitors, Radiocontrast Media, Local Anesthetics, Volume Substitutes and Medications used in General Anesthesia

Ružica Jurakić Tončić, Branka Marinović, Jasna Lipozenčić

University Department of Dermatology and Venereology, Zagreb University Hospital Center and School of Medicine, Zagreb, Croatia

Corresponding author: Summary Urticaria and angioedema are common allergic manifestations Professor Jasna Lipozenčić, MD, PhD and medications are one of common triggering factors. The most severe immediate drug reaction is . Apart from the well established University Department of Dermatology IgE-mediated immediate type hypersensitivity reactions, the pathogenesis and Venereology of drug-induced urticaria, angioedema and anaphylaxis often remains ob- Zagreb University Hospital Center scure. In this article, emphasis is put on nonallergic reactions to the most commonly used drug groups of nonsteroidal antiinflammatory drugs, an- and School of Medicine giotensin-converting enzyme inhibitors, radiocontrast media, volume ex- Šalata 4 panders and drugs used in general anesthesia. Urticaria is the second HR-10000 Zagreb most common drug eruption after maculopapular exanthema. The mecha- nisms of acute urticarial reactions are multiple, mostly IgE mediated, but Croatia some drugs can induce reactions and activate comple- [email protected] ment cascade, while others can induce direct activation of mast cells and degranulation or activation of complement by non-immune mechanisms. Received: December 20, 2008 With different types of medications different pathomechanisms are in- volved. Non-steroid anti-inflammatory drugs are thought to cause reaction Accepted: February 20, 2009 due to cyclooxygenase-1 inhibition and overproduction of leukotrienes, blamed for cutaneous and respiratory symptoms. Angiotensin-converting enzyme inhibitors can cause fatal angioedema, which is partially explained with bradykinin excess and impairment of aminopeptidase P and dipepti- dyl peptidase IV that are involved in the metabolism of substance P and bradykinin. It remains unknown what additional mechanisms are involved. Radiocontrast media and local anesthetics mostly cause nonallergic hy- persensitivity reaction, but in rare cases true allergic reaction can occur. Dextran is known to cause IgG mediated, immune complex anaphylaxis and it is recommended to use human serum albumin as the safest colloid.

Key words: pseudoallergy, nonallergic hypersensitivity, drug intoler- ance, drug hypersensitivity, anaphylactoid reaction, -like reactions

Introduction Specific intolerance reactions to medications described in 1901 by Hirschberg and was termed are not based on sensitization of the immune sys- „idiosyncrasy“. This term is today frequently used tem. For the first time, intolerance to aspirin was for similar reactions to local anesthetics, contrast

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media, natural and artificial food ingredients. Sev- delivery of drugs (6). Nanoparticulate vehicle sys- eral terms have been used such as idiosyncrasy, tems are very useful but also imply a high risk of intolerance, pseudoallergy and nonallergic hy- acute hypersensitive reactions that are not IgE persensitivity. According to revised terminology mediated. These reactions are called nonallergic from 2003, The European Academy of Allergol- hypersensitivity, are distinguished from type I re- ogy and Clinical Immunology has suggested that action by Coombs and Gell and have been termed each condition should be categorized as allergic “complement activation-related pseudoallergy” or nonallergic, and terms that are no longer in use (CARPA) (Table 1). Medications that can cause are idiosyncrasy (now hypersensitivity), pseudoal- CARPA are radiocontrast media, some liposomal lergy (now nonallergic hypersensitivity), and ana- drugs (Doxil, Ambisome and DaunoXome) and mi- phylactoid reaction (now nonallergic anaphylaxis) cellar solvents containing amphiphilic lipids (Cre- (1,2). mophor EL, the vehicle of Taxol). These agents Pseudoallergy or nonallergic hypersensitivity is activate complement system through the classic a nonimmune hypersensitivity reaction that mim- and the alternative pathways, giving rise to C3a ics allergic reaction (3). Two types of pseudoaller- and C5a anaphylatoxins, triggering mast cells and gy have been traditionally defined: intolerance and basophils for secretory response. As a result, there idiosyncratic reaction. The pathogenesis of these is an excessive amount of C3 and C5 anaphyla- reactions includes pseudoallergy, idiosyncratic re- toxins in the circulation, which can have dramatic actions, IgE mediated hypersensitivity, and also cardiovascular sequels (6,7). A new proposal has elevated IgG antibodies. Pseudoallergy is some- been given in recent literature to fit CARPA in the times called drug intolerance. Clinical symptoms classic scheme of hypersensitivity reactions, ac- are practically identical to IgE-mediated immedi- cording to the basic mechanism of mast cell and ate type symptoms and include angioedema, ur- basophil activation. There are direct and receptor- ticaria, bronchospasm, gastrointestinal signs and mediated reactions and therefore there are true anaphylaxis (previously called anaphylactoid re- IgE-mediated allergy, anaphylatoxin-mediated action). Probably the same effector mechanisms CARPA and IgE plus anaphylatoxin double trig- and cells (basophils and mast cells) are involved. gered reactions (6,7). However, since there is no evidence for induction Such reactions are primarily caused by 1) cer- of specific immunologic parameters, skin tests tain liposomal formulations of intravenous drugs and antibody determinations are typically negative and imaging agents; 2) infusion liquids contain- (3). The most common nonallergic reactions are ing micelle-forming amphiphilic lipids or synthetic to nonsteroidal antiinflammatory drugs (NSAIDs) block-copolymer emulsifiers; and 3) iodinated ra- and hypersensitivity to angiotensin-converting en- diocontrast media with limited solubility in water. zyme (ACE) inhibitors. Some reactions to drugs According to recent literature data, intravenous are due to an enzyme defect or deficiency. This application of some liposomal drugs, radiographic is observed in severe hypersensitivity reactions to agents used in diagnostic procedures, micelles or sulfonamides and aromatic anticonvulsants (4,5). other types of lipid-based nanoparticles can cause Drug intolerance is a condition encountered in acute hypersensitivity reaction in up to 45% of pa- patients that are unable to metabolize a drug due tients. The mechanism of these reactions is acti- to a defect or lack of the normal enzyme involved vation of the complement system on the surface of in the respective drug pharmacology; this results lipid particles. in an unexpected reaction to a specific drug. An example of intolerance is deficiency of glucose-6- Table 1. Three different groups of medications with phosphate dehydrogenase and methemoglobin- capacity of causing complement-activation related emia as the result of the use of dapsone. nonallergic hypersensitivity reaction (according to Today, there are new insights in the pathomecha- Szebeni et al.) nisms of these reactions, and some of them have Complement-activated nonallergic hypersensitivity been more or less clarified. reactions 1) Liposomal formulations of intravenous drugs and Types of drug reactions imaging agents Modern pharmacotechnology has made great 2) Infusion liquids with micelle-forming amphiphilic lipids or synthetic block-copolymer emulsifiers effort to increase therapeutic index of drugs by us- 3) Iodinated radiocontrast media with limited water ing nanoparticulate vehicle systems. These sys- solubility tems are used to provide slow release or targeted

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These acute reactions manifest with severe he- bation with human plasma (9). Recent literature modynamic, respiratory and cutaneous changes data point to the role of lipoproteins in complement (8). For example, a drug named paclitaxel (Taxol®) activation-related nonallergic hypersensitivity activates complement system in human serum in caused by amphiphilic drug carriers (10). Comple- vitro, due to fact that dilution of the injection con- ment activation requires multiple complement and centrate in aquagenous solvents resulted in mi- other immune proteins on the activator surface. As celle formation and needle like structures with final mentioned above, Cremophor EL micelles or po- result of complement activation (9). loxamer 188 individual molecules when exposed Cremophor EL is the main component of mi- to plasma cause de novo formation of abnormally celles and is used as a nonionic emulsifier. These large lipoprotein-like structures. Therefore, this micelles were shown to be 8-22 nm in diameter lipoprotein transformation may be the key event when analyzed, but de novo formation of micro- in complement activation caused by amphiphi- droplets sized 50-300 nm occurred following incu- lic emulsifiers. Lipoproteins also have a negative

Table 2. Groups of medications, suspected pathomechanism involved, possibility of cross-reactions, safe alternative medication, recommended diagnostic procedure and management, and possible prevention Group of Suspected Known cross- Safe alternative Diagnostic work- Management and medication pathomechanism reactivity up prevention NSAIDs True allergic reaction Possible Acetaminophen In vivo provocation Avoidance of and nonallergic reaction with all in single dose tests: oral, nasal nonselective reaction where drugs in group <1000 mg and inhalation NSAIDs, COX-1 inhibition test, scratch test, usage of COX- causes shunting TTL, ITDBG, 2 inhibitors, towards leukotriene CAST-ELISA test avoidance overproduction, and combined of artificial flowcytometry) and natural and decrease in the basophil salicylates in food anti-inflammatory activation test prostaglandin PGE2 with leukotriene determination ACE-inhibitors Nonallergic Complete Diuretics, calcium None available Immediate pathomechanism; cross-reactivity antagonists, discontinuation role of bradykinin among all beta-blocking of the drug, and substance P, ACEIs, possible agents possible surgical and impairment of reaction with procedure aminopeptidase angiotensin II (tracheotomy) in P and dipeptidyl inhibitors case of severe peptidase IV angioedema Radiocontrast Nonallergic reactions Cross-reaction In vitro testing Prick, intradermal Premedication media called among can identify non- skin test, TTL, with iodinated cross reacting ITDBG, specific corticosteroids CARPA reaction due contrast media radiocontrast IgE, patch test and to high osmolarity media antihistamines and water insolubility, (efficacy?) activation of complement occurs and C5a causes tryptase activation Allergic reaction caused by - iodinated proteins - specific IgE - T-cell reaction (delayed hypersensitivity reactions)

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Local Majority nonallergic Group cross- Based on skin Prick, scratch anesthetics reactions, reactivity can tests and IgE test, TTL, ITDBG, occur in the determination, patch test, only 1% true allergy, same group of cross reactive and mostly presented in vivo exposure anesthetics/ agents should be as type IV reaction test, IgE amide or ester determined determination type Volume Human serum Not observed Human albumin Specific dextran- expanders albumin is considered IgG or IgM to be the safest - non-specific volume expander reaction to protein aggregates, in some cases specific immune response to caprylate-modifiate human serum albumin Dextran Hapten inhibition by low molecular - immune complex dextran- mediated anaphylaxis dextran 1 is - presence of high infused before IgG (IgM) Dextran 40 or 70 - dextran reactive antibody and reduction of C1q complement feedback control on complement activation. Lipo- mune-mediated pathogenesis has been identified proteins play a complex modulatory role in CARPA for some of these drugs. nonallergic hypersensitivity caused by amphiphilic drug solvents and carriers (10). NonsteroidAL anti- It was experimentally shown that intravenous inflammatory drugs application of liposomes can cause significant pul- The prevalence of hypersensitivity to NSAIDs monary hypertension in pigs and this represents a manifested as angioedema and urticaria is in- model for vasoconstrictive response in the lungs creasing, ranging from 0.1% to 0.3% (13). The observed as cardiopulmonary distress in humans reason why some people react to NSAIDs is not caused by few liposomal drugs. quite explained, and the exact pathogenesis is not The size, composition and administration of li- clear for all entities, but it is believed that an im- posomes are of great importance, having a strik- balance in the arachidonic acid cascade, inhibition ing and different impact on pulmonary vessels and of prostaglandin synthesis and increase in leukot- outcome of drug administration varying from mini- rienes may play a crucial role (Table 2). Hyper- mal impact to lethal outcome (8,11). sensitivity to NSAIDs manifesting in the airways It is well known that allergic-like reactions are very (rhinosinusitis, polyps, ) or skin (urticaria, common upon vaccination. In the majority of cas- angioedema) is considered to be the second es, there is absence of immediate hypersensitivity most common drug reaction (14). There are two to the vaccine, which can be confirmed by prick- types of cyclooxygenase (COX) enzymes, COX- test and intradermal tests with immediate reading 1 and COX-2 (15,16). COX-1 is constitutionally (12). expressed in most tissues such as kidneys and Apart from NSAIDs and ACE inhibitors, some gastrointestinal tract, and is held responsible for other drug classes have been traditionally clas- the classic pharmacologic side effects of NSAIDs sified as elicitors of nonallergic hypersensitivity such as renal failure, bleeding and gastric ulcers. reactions, such as radiocontrast media, muscle COX-2 is present in brain tissue and is induced relaxants and local anesthetics. Recently, the im- by proinflammatory factors such as cytokines and

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endotoxin. COX-1 inhibition results in shunting of of arachidonic acid metabolism in response to arachidonic acid metabolism towards the 5-lipo- NSAIDs. This leads to leukotriene overproduc- oxygenase pathway and results in increased syn- tion and a decrease in the anti-inflammatory thesis and release of cysteinyl leukotrienes (13) prostaglandin PGE2 (20). Various aspects of (Table 2). Selective COX-2 inhibitors are well tol- this syndrome such as its clinical features, the erated by most patients with a history of sensitivity cell types and mediators involved, the role of against classic NSAIDs, but cutaneous reactions underlying chronic inflammatory processes, the to highly selective COX-2 inhibitors have also patterns of cross-reactivity between NSAIDs, been described (12,13). the major role of LTC4 and of some other me- However, it is worthy mentioning that NSAIDs diators such as PGE2 and C5a are described in by pharmacological mechanism involving the ara- recent literature. chidonic acid mechanism can cause exacerbation 2. Group of patients with chronic or chronic recur- of or trigger chronic urticaria. About 4% of patients rent urticaria or angioedema that experience with previous reaction to aspirin may have reac- aggravation of symptoms if NSAIDs are used. tion to COX-2 selective NSAIDs, especially in the Dyspneic feeling can be present but usually group of patients with aspirin sensitive asthma. there is no bronchial hyperreactivity or asthma. This group of patients should be advised not to The reaction is characteristic of acetylsalicylic take acetaminophen in a dosage higher than 1000 acid and other NSAIDs (3). mg in a single dose due to the fact that acetamino- 3. Group of otherwise healthy individuals may have phen is a weak inhibitor of COX-1 enzyme (17). anaphylactoid reactions to only one chemically Facial (periorbital) angioedema is the most distinct group of NSAIDs such as a pyrazolone common clinical presentation and one third of pa- derivative, diclofenac, or others (3). tients have a mixture of cutaneous (urticaria and/or However, cases with bronchial, cutaneous angioedema) and respiratory symptoms (13). Re- symptoms and severe anaphylactic reaction have spiratory symptoms include edema of the upper been described and patients have reacted to dif- respiratory tract, rhinorrhea, cough, breathless- ferent NSAIDs, including paracetamol (acetamin- ness and tearing. The stimulation of leukotrienes ophen) (21-23). Some kind of genetic predisposi- such as LTC4, LTD4 and LTE4 causes respiratory tion is found in patients with anaphylaxis to pyr- symptoms (3). azolones, with a significantly higher frequency of Three different patient groups are distinguished HLA-DQ7 as compared to controls (3,24), and in according to clinical appearance of nonallergic hy- patients with nonallergic anaphylaxis to different persensitivity to NSAIDs (3) (Table 3): classes of NSAID such as pyrazolones, aspirin 1. Patients with the aspirin or salicylate triad called and others, where an association with HLA-DR11 Fernand-Widal syndrome (Table 4). This syn- has been found as compared to subjects tolerant drome includes intrinsic asthma, nasal polyps, to the respective drugs (3,25). often serum and tissue eosinophilia, and in some Also, a distinct entity of NSAID nonallergic cases chronic rhinosinusitis. There are no cuta- hypersensitivity has been observed in atopic pa- neous symptoms but life-threatening aggrava- tients sensitized to house dust mites. They suffer tion of asthmatic and rhinitic symptoms can oc- from , severe anaphylactic reactions cur when acetylsalicylic acid or other NSAID is upon ingestion of mite-contaminated flour, and administered (2,18-19). Aspirin nasal challenge mostly periorbital angioedema to several NSAIDs is a very safe test with moderate sensitivity and (3,26,27). high specificity, and can be used in the diagno- Some special features of NSAID nonallergic sis of aspirin hypersensitivity. The similarities hypersensitivity have been described in a pediat- in the reaction between the nose and airways in aspirin-sensitive patients provide compelling Table 3. Nonallergic hypersensitivity to non-ste- evidence for common pathogenic mechanisms roid antiinflammatory drugs for nasal polyps, chronic rhinosinusitis, and (NSAIDs) bronchial asthma (19). The pathogenic mecha- Patient groups according to clinical presentation of nism of Widal syndrome now appears to involve nonallergic hypersensitivity to NSAIDs the combined effects of chronic inflammation 1) Fernand-Widal syndrome – ‘salicylate’ triad (causing nonspecific cellular hyperreactivity, 2) Worsening of chronic urticaria particularly of mast cells, basophils and eo- 3) Nonallergic anaphylaxis to one NSAID sinophils), and a pharmacogenetic abnormality

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The release of sulfidoleukotrienesin vitro is de- Table 4. Fernand-Widal syndrome (‘salicylate’ or tectable by the CAST ELISA test (34). The assay ‘aspirin’ triad) is based on the detection of LTC4, LTD4 and LTE4 1) Intrinsic asthma by a monoclonal antibody using cellular antigen 2) Nasal polyps and chronic rhinosinusitis stimulation test (CAST). The sensitivity of CAST 3) Tissue and serum eosinophilia was found to range from 62.5% to 80%, while the specificity was 70%-100% (34,35). ric group of patients (28). According to these data, Also, basophil activation test is useful for in vi- the prevalence is low in children aged less than tro diagnosis of NSAID hypersensitivity because 10 years, but has been estimated to 10% in the of its good specificity and positive predictive value group of patients aged 10-20 years. Two theories in NSAID hypersensitivity (35,36). of aspirin-sensitive asthma are described, i.e. the already mentioned theory of cyclooxygenase path- Combined test with flowcytometry basophil ac- way and the viral theory explaining the inhibition tivation and determination of leukotrienes is useful of cytotoxic lymphocytes by prostaglandin produc- for in vitro diagnosis of hypersensitivity to aspirin tion. Therefore, NSAIDs block PGE2 production and other NSAIDs. NSAIDs induce blood basophil and cause the release of cytotoxic lymphocytes. activation in vitro in aspirin- and NSAID-hyper- Five different clinical entities have been described: sensitive patients, and this can be detected by a respiratory disease with aspirin sensitivity, aspirin flowcytometry technique using the CD63 marker, induced urticaria, allergic reaction to aspirin and to flowcytometry basophil activation test (FAST) as- NSAIDs, aseptic pneumonitis, and meningitis due say, in addition to CAST as a leukotriene release to hypersensitivity. The latter are only mentioned test. According to the authors, FAST shows a high as exceptional, as case reports, have never been percentage of positive reactions, up to 60%-70% directly correlated to NSAIDs, and were only de- when four NSAIDs are tested and even 88% if the scribed in patients on long-term therapy. test is performed within 1 month of the last clinical drug exposure and reaction. The test has a high According to the authors, nonallergic hyper- specificity, above 90%. The addition of leukotri- sensitivity to NSAIDs was found in 13%-50% of enes determinations yields additional information pediatric patients with allergic-like reactions and in a few isolated cases (35). risk factors, personal and age over 8 years. Most children with NSAID nonallergic hypersensi- tivity tolerate acetaminophen (29). Angiotensin-converting enzyme In cases of aspirin-induced asthma it has been inhibitors (ACEIs) shown that the leukotriene antagonists montelu- Angiotensin-converting enzyme inhibitors kast and zafirlukast may prevent aspirin-induced (ACEIs) have been used in the treatment of vari- bronchospasm (3,30). The authors describe a ous cardiovascular diseases. Despite therapeu- failure of the leukotriene antagonist zafirlukast to tic benefits of ACEIs, there are several reported prevent anaphylaxis to ibuprofen in one patient side effects, including chronic cough, angioedema (3,31), and a patient with aspirin triad treated with and nonallergic anaphylaxis. ACEIs may cause a montelukast developed a life-threatening broncho- range of adverse cutaneous reactions (37). These spasm to diclofenac (3,32). The role of leukotriene reactions are caused by a combination of factors modifiers is not established and requires further involved in the synthesis, metabolism and pharma- investigations before they are recommended for cological activity of bradykinin and des-arginine9- this group of patients (18). bradykinin (37,38). According to the authors, half The management of these patients includes of the patients with angioedema have an enzyme avoidance of aspirin and all non-selective NSAIDs, defect involved in des-arginine9-bradykinin, which use of COX-2 inhibitors, and use of acetaminophen leads to its accumulation (38). in a dosage less than 1000 mg per dose (18). Captopril is most commonly involved. Capto- Thorough history data are obligatory. The only pril has a thiol-group and urticarial, exanthematic, reliable test of the eliciting drug and cross-reactivity bullous and photosensitivity reactions have been is oral provocation test that should be done under described (39,40). close medical supervision (3). Several diagnostic The most common adverse reactions are cough provocation tests can be used, i.e. oral (26,33), and angioedema typically presented without urti- inhaled or nasal (19) provocation tests. Besides caria. It is estimated that 0.1% to 0.5%, accord- provocation tests, in vitro tests are also available. ing to some data even up to 0.7% of the patients

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experience angioedema during ACEI therapy The degradation half-life of substance P corre- (41,42). lates inversely with dipeptidyl peptidase IV antigen Data from emergency wards on angioedema during ACE inhibition. Various factors that reduce indicate the percentage of ACEI induced cases to dipeptidyl peptidase IV activity may predispose range from 25% (43) to 38% (44), with the highest individuals to angioedema. Dipeptidyl peptidase prevalence of angioedema recorded in the group IV deficiency predisposes to peritracheal edema of African-American women. when ACE is inhibited through a neurokinin recep- tor-dependent mechanism (55,56). Angioedema is typically observed within the first weeks of treatment, most patients experience Recurrent isolated AE of the tongue is an ex- reaction in the first two months, but it may be de- tremely rare variant of ACEI-induced edema layed for months or even years (45). A late onset (46,50,51). Risk factors for ACEI-induced angio- of angioedema after enalapril is described after edema are previous angioedema of any origin and 4 months. Late onset of angioedema is often un- C1 esterase inhibitor deficiency (57), and use of recognized. Lip and tongue swelling was the most antibiotics and local anesthetics (58). Surgery and common airway manifestation. The attacks may local anesthesia can further aggravate angioede- occur at irregular, unpredictable intervals under ma (58). ongoing treatment (46). As in angioedema of other The above mentioned drugs do not elicit reac- origins, the face and oral mucosa (47-49) are most tion when used without ACEI. ACEIs may also ag- often affected but isolated visceral angioedema gravate anaphylactic and nonallergic anaphylactic has also been reported (50-52). reaction (59). The pathogenesis cannot be explained only by Since the pathogenesis is not quite explained, the vasodilatory effect (38). Angioedema caused the diagnosis can only be made based on the clini- by ACEIs is not immune mediated, and is due to cal finding and medical history; specific diagnostic the pharmacological effect of ACE inhibition. Bra- tests are not available. Oral provocation tests are dykinin is a potent vasodilator and is thought to ethically not acceptable because the severity of play a major role in the pathogenesis due to the the reaction is not predictable, and fatal outcome decreased degradation of bradykinin by ACE-inhi- of laryngeal angioedema has been reported (60). bition. During the attack, plasma bradykinin levels ACEI-induced angioedema shows class-effect, are elevated suggesting that this mediator does therefore, there is complete cross-reactivity among play a crucial role (53), but also other factors are all ACEIs (61). Diuretics, calcium antagonists and playing the role since angioedema does not occur b-blocking agents are relatively safe alternative regularly after the drug intake and in every patient for ACEI. Angiotensin II receptor antagonists (AT (46). According to the authors, half of the patients II blockers) such as losartan potassium are a class had an enzyme defect involved in the des-argi- of antihypertensives developed in part to eliminate nine9-metabolism (38). Bradykinin may lead to cough and angioedema associated with ACEIs the activation of proinflammatory peptides and lo- and to act by selective binding to angiotensin II cal release of , inducing a cough reflex sites. These drugs do not affect local and system- hypersensitivity. ic bradykinin levels. A small percentage of patients Preliminary studies have shown that patients with ACEI-related angioedema experience the with a history of developing these side effects same problems when switched to angiotensin II have a lower activity of an enzyme called amino- blockers. Until the exact cause of both ACEI- and peptidase-P. This enzyme is involved in bradykinin angiotensin II blocker-induced angioedema is de- degradation. This defect in enzymatic activity can termined, angiotensin II blockers should be used be partially explained by genetic variation (54,55). with extreme caution in patients with a prior his- Bradykinin and substance P, which are substrates tory of angioedema of any origin. Three cases of of ACE, cause an increase in vascular permeabil- angiotensin II blocker-induced angioedema have ity and cause tissue edema in animals. Studies been described (60-62). Losartan was not discon- indicate that amino-terminal degradation of these tinued after the first episode and resulted in sev- peptides by aminopeptidase P and dipeptidyl pep- eral episodes of angioedema; one severe episode tidase IV may be impaired in individuals with ACEI- required tracheotomy. The incidence of angioten- associated angioedema. Dipeptidyl peptidase IV sin II blocker-induced angioedema questions the activity is depressed in individuals with hyperten- theory on the etiology of angioedema and the role sion during acute ACEI-associated angioedema. of bradykinin in its pathogenesis (62-65).

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When the reaction occurs, drug should be im- ment activation could be the consequence of trypt- mediately discontinued, even when the first epi- ase release rather than histamine release (70). sode is mild. Life-threatening angioedema of the The responsible antigen in the presence of io- larynx due to continuation of the drug after dis- dinated contrast medium could be iodinated se- crete angioedemas of the face and the tongue rum proteins (71), and in case of drugs with low that occurred months and years before has been molecular weight different parts of the molecule reported. Some patients may experience severe responsible for different patterns of IgE binding. mucosal angioedema and intubation might be Recently, papers showing evidence for positive necessary in order to prevent fatal outcome. One specific IgE and correlation between histamine re- case report describes a favorable therapeutic ef- lease and reaction severity have been published fect of C1 inhibitor concentrate administration. (67,72). According to data, 2.4% to 3.1% of cases Hereditary angioedema is caused by excess of had positive IgE-RIA (72). bradykinin formation as a result of C1 inhibitor The low osmolality iodinated contrast media deficiency, and usually reverses angioedema by can be subdivided into nonionic monomers (io- C1 inhibitor in less than half an hour. Patients with hexol, iopamidol), ionic dimers (ioxaglate) and ACEI-induced angioedema have normal C1 inhibi- nonionic dimers (iodixanol) (67,68). tor values, excess bradykinin is probably impor- tant since angiotensin-converting enzyme breaks Contrast media are generally well tolerated; down bradykinin. The authors conclude that C1 only 0.1%-0.4% of patients receiving high-os- inhibitor was effective in reversing the ACE inhibi- molar ionic and 0.02%-0.04% of those receiving tor-induced angioedema (66). low-osmolar non-ionic contrast media will develop severe hypersensitivity reaction (67). The inci- Radiocontrast media dence of mild and moderate reaction is higher in high osmolarity media, but the incidence of severe All currently used iodinated contrast media are reactions is equal (68). Nonallergic anaphylactic composed of one (monomers) or two (dimers) tri- reactions are more common with high osmolarity iodinated benzene rings (67,68). Benzene is a tox- media, and cardiovascular decompensation with ic water-insoluble liquid. Addition of iodine gives low osmolarity media. several characteristics: high contrast density, firm Reactions are more frequent with ionic than binding to benzene molecule and low toxicity. with nonionic material (67,72,73). Reactions after Based on their physical and chemical characteris- the administration of nonionic contrast media are tics, contrast media are classified into ionic high- usually less severe (67). osmolality and low-osmolality contrast media. Risk factors for nonallergic hypersensitivity re- It was considered for years that the pathomech- actions include asthma (5 times), previous reac- anism of severe immediate reactions cannot be tion (4-6 times), renal and cardiovascular disease, explained by any of the four Coombs and Gell re- and beta-blocker intake. Reaction usually occurs actions, and reactions were mostly considered as within 20 minutes and can be mild (skin rash, nonallergic anaphylaxis and involving mast cells, itching, nasal discharge, nausea and vomiting), basophil histamine and/or vasoactive mediator re- moderate (facial or laryngeal edema, broncho- lease mechanisms. Histamine is released in vivo, spasm, dyspnea, tachycardia or bradycardia), and with the peak concentration correlating with the severe (arrhythmias, hypotension, laryngeal and reaction severity (69,70). Complement activation pulmonary edema, seizure, syncope and death) has been shown in vivo and in vitro in patients (68). that have the reaction and in those with no reac- tion. Although clinical signs suggest a major role According to literature data, the risk of adverse of histamine, it is still a matter of debate (70). In event is 4%-12% with ionic contrast medium and vivo histamine release could be an effect of hy- 1%-3% with nonionic material (73). The risk of perosmolarity, chemical toxicity of the molecule severe adverse reaction is 0.16% with ionic con- administered, complement activation by anaphyl- trast medium and 0.03% with nonionic material. atoxins, or immune mechanism mediated by im- Death rate is almost equal for both groups, and munoglobulins. Histamine is released from mast is 1-3/100 000 contrast administration (72,73). In cells and/or basophils (70). Mast cells also par- pediatric population, 80% of nonallergic hyper- ticipate through tryptase release (69,70). Tryptase sensitivity reactions are mild, 5% moderate and has been shown to activate complement system in 15% severe (74). Nonallergic hypersensitivity to vitro, resulting in C5 activation; therefore comple- low-osmolality contrast media in children are rare

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and according to published data occur in 0.18% of a history of allergy, IL-2 treatment and being of patients receiving contrast media (74). Japanese descent. The pathogenesis of these More than 90% of immediate reactions after delayed reactions is still unclear but a significant the administration of nonionic contrast media are proportion of these reactions seem to be T-cell non-IgE mediated reactions, therefore investiga- mediated (78,80-82). The involvement of T cells is tions are usually not performed (67,73). Contrast suggested by positive skin test as well as positive media are typically thought to induce urticaria and proliferative responses to the drugs in vitro. A high angioedema by a nonallergic pathomechanism. degree of cross-reactivity was observed with other As mentioned above, in some patients IgE-anti- iodinated contrast media. Moreover, 50% of these body-mediated mechanisms have been identified patients reported another drug hypersensitivity, (72,75). Therefore, the ENDA/EAACI group has suggesting a predisposition to immune reactivity recently established the value of skin tests in order in some patients (81). The management of these to look for IgE-mediated reactions (67). reactions is symptomatic and most of these reac- Since nowadays nonionic contrast media are tions have a self-limited course (78). widespread, severe adverse reactions are less There is a possibility of immune cross-reactivity frequently seen (73,76). in the group of iodinated contrast media, and due All iodinated contrast media may elicit immedi- to this fact all contrast media are usually avoided. ate type hypersensitivity reaction (within 5-10 min- Evaluation of patients with contrast medium-as- utes of administration) or delayed type that occurs sociated exanthema should always include patch, more than 1 hour after the application (76,77). prick and intradermal skin testing in order to en- Late adverse reactions to iodinated contrast me- sure that patients with delayed type are not missed dia have been reported in 2% to 5% of patients (76,83). Cross-reactivity among iodinated contrast exposed to these media. media results from the presence of contrast me- dium specific T cells that show a broad cross-re- Late adverse reactions are defined as reactions activity pattern (83). In vitro testing can identify occurring 1 h to 1 week after contrast medium in- non-cross reacting contrast media (83). Studies jection (78). The prevalence of these reactions is have also demonstrated that patients may receive still uncertain and their pathophysiology is not fully alternative iodinated contrast medium despite a understood. Late reactions appear to be more fre- history of contrast medium-induced exanthema quent when nonionic dimers are used (78). (76,83). An interesting observation of a patient The so-called “late reactions” can present as with urticaria that had a non-immediate positive in- maculopapular exanthema, hypersensitivity syn- tradermal test has been recently published; it was drome with exanthema, eosinophilia and fever, explained by the fact that immediate reactions are flu-like disease, headaches, gastrointestinal dis- mostly IgE mediated, but also require collabora- turbances (nausea, vomiting), musculoskeletal tion of activated T cells, as previously observed in pain, and are mainly not immune mediated (3). penicillin allergy. T cells participate in immediate They should be neither confused with the clearly reaction and are documented with positive lym- defined “late phase” of the IgE-mediated allergy phocyte transformation test (67,84). nor with mediated “delayed type” allergy. Delayed type hypersensitivity with maculopapular Skin tests, both prick and intradermal test, have febrile exanthemas has been reported (79). been used and positive tests are rarely reported, mostly in patients with severe reactions (85,86). Delayed hypersensitivity reactions occur more False-negative results of testing could be due to than 1 h after contrast medium administration. De- low molecular weight of iodinated contrast media layed reactions to iodinated contrast media are and a theoretical need for haptenization to be- most likely caused by immune reactions to drugs. come complete allergens (67). They have been reported in 0.5%-2% of recipients, mainly as mild to moderate skin reactions that can Classic approach to previous iodinated contrast elicit different clinical features such as maculo- medium reactors is premedication with corticoste- papular exanthematous and urticarial/angioede- roids and antihistamines and use of low osmolality matous types. Most of the reactions appear after iodinated contrast media (67,68,85,86). a latency of 3 h to 2 days and disappear within 1 The American College of Radiology recom- week. The incidence of more severe reactions is mends administration of prednisolone 50 mg extremely low. Major risk factors for delayed re- orally (0.5-0.7 mg/kg orally for children) 13 h, 7 actions are previous contrast medium reaction, h and 1 h before contrast medium administration,

62 ACTA DERMATOVENEROLOGICA CROATICA Jurakić Tončić et al. Acta Dermatovenerol Croat Nonallergic hypersensitivity to different drugs 2009;17(1):54-69

and diphenhydramine 1 h before in a dosage of 50 anaphylaxis), occurring during general anesthesia mg orally (1.25 mg/kg orally for children) (74). The remain a major cause of concern for anesthesiolo- efficacy of premedication is debated. It is recom- gists, since these reactions remain usually unpre- mended to exclude true allergic reaction (87). dictable and may be potentially life-threatening, even when appropriately treated. Local anesthetics The incidence of anaphylactic reactions in gen- Local anesthetics are divided into ester type and eral anesthesia is between 1:5000 and 1:25000 an- amide type. Adverse reactions to local anesthetics esthetics. During anaphylactic reaction, mast cells are relatively common, but true IgE-mediated hy- release proteases such as tryptase, histamine and persensitivity is extremely rare, particularly to the vasoactive mediators. Nonallergic reactions can more commonly used amide group. The majority be caused directly by the release of histamine and of adverse reactions have a nonallergic pathogen- other mediators from mast cells and basophils, and esis (88,89). Allergic reactions are extremely rare they do not depend on the interaction of IgE antibod- (about 1% of adverse reactions) and are mostly ies with the antigen. The most frequent agents that presented as type IV allergic reaction, more com- cause reactions during anesthesia are neuromus- mon with ester-type anesthetics (90-94). There cular blocking agents (among them most frequently are only few reports on cases of documented true rocuronium and succinylcholine), some general an- IgE mediated reactions to local anesthetics (90- esthetics, antibiotics, blood and blood products, opi- 94). Skin tests offer a reliable method for exploring oids and latex. Increased tryptase concentration in immediate allergy to confirm or rule out immedi- serum is a marker for systemic mast cell activation ate allergy to local anesthetics (90-94). In cases (100). Apart from latex, muscle relaxants are one of true allergic reaction to amide type, diagnostic of the major causes of anaphylaxis during general test should be done because cross-reactivity can anesthesia (101). IgE-antibodies directed against occur in the same group of anesthetics (93,94). quaternary ammonium ions have been identified Although some reports documented immediate (102). Based on skin tests and IgE determinations, IgE reaction to amide type anesthetics, it is little cross-reactive patterns could be identified and pa- known about cross-reactivity in this group (95,96). tients were successfully treated with test-negative Prick testing should be done (97). agents. Few attempts have been made to induce tolerance in sensitized patients (103). Type IV reaction is predominantly observed to ester-type anesthetics, but it can also occur to According to published data, the majority (ac- amide type (93-94); there are only few cases of cording to authors, 10 of 18 patients) experienced such reactions to amide derivatives resulting in in- an IgE-mediated anaphylactic reaction to neuro- filtrated plaques. muscular blocking drugs during anesthesia, later verified by detection of specific IgE and elevated Local anesthetics are known to elicit T-cell re- levels of mast cell tryptase (104,105). Rocuronium actions after epicutaneous application, namely is one of the most frequently involved agents (105- contact dermatitis. In addition, adverse reactions 107). like urticaria and angioedema are rather common after submucosal or subcutaneous injection. The pathogenesis of these side effects, which appear Volume expanders frequently hours after application, is unknown, but All colloid volume expanders have the risk of is thought not to be IgE-mediated, since immediate causing nonallergic hypersensitivity reactions and skin tests are mostly negative. Delayed appearance nonallergic anaphylaxis. Currently used colloids of urticaria and angioedema after subcutaneous are albumin, hydroxyethyl starch (HES), dextran application of local anesthetics may be related to and gelatin. T cell- mediated sensitization, which might be de- Albumin is a 69 kDa protein purified from hu- tected by patch testing or lymphocyte transforma- man plasma. HES is synthesized by partial hydro- tion test (98). Nonallergic anaphylaxis during spinal lysis of amylopectin plant starch and hydroxyethyl- anesthesia was observed with dibucaine (99). ation of glucose molecules. Dextran is composed of glucose polymers. Gelatine is synthesized by Medications used in general hydrolysis of bovine collagen. All artificial colloids anesthesia are polydispersed molecules in a range of sizes. Hypersensitivity reactions, whether IgE-mediat- Human serum albumin is considered to be a ed (anaphylaxis) or non-IgE-mediated (nonallergic relatively safe volume expander since nonallergic

ACTA DERMATOVENEROLOGICA CROATICA 63 Jurakić Tončić et al. Acta Dermatovenerol Croat Nonallergic hypersensitivity to different drugs 2009;17(1).54-69

anaphylactic reactions have been reported much Conclusions less than with artificial colloids (108,109). As re- Several daily used drugs can elicit drug reac- ported, recent data were analyzed, with albumin tions including non-immune mediated reactions as the reference volume expander; the incidence that may often be mistaken for allergic reactions in of nonallergic anaphylactic reactions was 4.51 daily life. The severity of these reactions can range after hydroxyethyl starch administration, 2.32 from mild to life-threatening severe reactions such after dextran, and 12.4 after gelatin (109,110) as angioedema and anaphylaxis. These reactions (Table 5). are most commonly caused by NSAIDs, ACE inhibitors, radiocontrast media, local anesthet- Table 5. Incidence of hypersensitivity reactions to ics, plasma expanders and several agents used different types of volume expanders in general anesthesia. The pathomechanisms of Type of volume Incidence of hypersensitivity these reactions have not yet been fully under- expander reactions (human serum stood for every incriminated agent, but it has been albumin as reference colloid) shown that the same mediators found in allergic (%) reactions can be responsible and are involved in Human serum albumin 1 non-immune mediated hypersensitivity reactions, Hydroxyethyl starch 4.51 e.g., histamine, mast cells, tryptase and comple- Dextran 2.32 ment system. Gelatin 12.4 Detailed history data, in vivo and in vitro testing should be performed to exclude allergic reaction. According to literature data, nonallergic anaphy- Most of these reactions are mild and have a self- laxis occurred after infusion of pastered plasma of limited course, however, some may require surgi- human serum albumin and reaction resulted from cal intervention or intensive care treatment, like in nonspecific reaction to protein aggregates and severe cases of ACEI-induced edema or anaphy- in some cases from specific immune response laxis. to caprylate-modifate human serum albumin (109,111). The symptoms of dextran-induced nonallergic References hypersensitivity reactions range from skin reac- 1. Zuberbier T. Pseudoallergy or nonallergic hy- tions to severe circulatory shock severity grades persensitivity. Allergy 1999;54:397-8. I-IV. Dextrans are another example where the 2. Gerth van Wijk R, van Cauwenberge PB, mechanism of a reaction initially classified as Johansson SG. Revised terminology for al- nonallergic anaphylaxis could be clarified. This is lergies and related conditions. Ned Tijdschr called immune complex-mediated anaphylaxis. Tandheelkd 2003;110:328-31. The presence of high IgG-dextran reactive an- tibody, reduction of C1q complement factor and 3. Bircher AJ. Drug-induced urticaria and angi- histopathologic findings in lungs indicate immune oedema caused by non-IgE mediated pat- complex anaphylaxis (112). homechanisms. Eur J Dermatol 1999;9:657- 63. Clinical dextrans such as Dextran 40 and Dex- tran 70 are associated with nonallergic anaphylax- 4. Rieder MJ, Uetrecht JP, Shear NH, Cannon is caused by dextran-reactive IgG antibody (113). M, Miller M, Spielberg SP. Diagnosis of sulfo- Dextran-reactive IgG or IgM antibodies were iden- namide hypersensitivity reactions by in vitro tified (114) and hapten-inhibition by a low molecu- ‘rechallenge’ with hydroxylamine metaboli- lar dextran resulted in a considerable decrease of tes. Ann Intern Med 1989;110:286-9. severe life-threatening events (112,115). Accord- 5. Shear N, Spielberg SP, Cannon M, Miller M. ing to the authors, if Dextran 1 is infused immedi- Anticonvulsant hypersensitivity syndrome. J ately before the clinical dextran, it significantly re- Clin Invest 1988;82:1826-32. duced the incidence of severe reaction (113). Very 6. Szebeni J. Complement activation-rela- rarely, severe reactions occurred despite hapten ted pseudoallergy: a new class of drug-in- inhibition (116). Dextran and gelatins should be duced acute immune toxicity. Toxicology avoided in patients with a known history of drug 2005;216:106-21. allergy (117). 7. Szebeni J. Complement activation-related pseudoallergy caused by liposomes, micellar

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