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Acute symptoms of drug hypersensitivity (urticaria, angioedema, anaphylaxis, anaphylactic shock)MD , Pascal Demoly, MD, PhD Urticaria Angioedema Anaphylaxis Anaphylactic shock Drug hypersensitivity Drug hypersensitivity reactions (HSRs) are the adverse effects of drugs which, whentaken at doses generally tolerated by normal subjects, clinically resemble Although they occur in a small percentage of patients (about one-third of all adversedrug reactions, which affect 10% to 20% of the hospitalized patients and more than7% of the general population), these reactions are often unpredictable and can belife threatening.Only when a definite immunologic mechanism (either drug-specificantibody or T-cell) is demonstrated should these reactions be classified as drugallergy. For general communication, when a drug allergic reaction is suspected,‘‘drug HSR'' is the preferred term, because true drug allergy and nonallergic drugmay be difficult to differentiate from the clinical presentation alone, especiallyin situations of acute severe HSR, such as anaphylaxis. However, for a long-termplan of treatment and prevention, referral to an allergist-immunologist for confirmationof diagnosis is needed to offer specific preventive measurements.
The European Network for Drug Allergy (ENDA), working under the aegis of the European Academy of Allergy and Clinical Immunology (EAACI), has simplified theclinical classification of drug HSRs into 2 types, according to the delay of onset ofthe reaction after the last administration of the drug: (1) immediate reaction, occur-ring less than 1 hour after the last drug intake, usually in the form of urticaria, angioe-dema, rhinitis, conjunctivitis, bronchospasm, and anaphylaxis or anaphylactic shock; Conflict of interest: The authors have nothing to disclose.
a Allergy Immunology and Rheumatology Division, Faculty of Medicine, Ramathibodi Hospital,Mahidol University, 270, Rama 6th Road, Phyathai, Bangkok 10400, Thailandb Allergy Department and INSERM U657, Hoˆpital Arnaud de Villeneuve, University Hospital ofMontpellier, Avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France* Corresponding author.
E-mail address: Med Clin N Am 94 (2010) 691–710doi:10.1016/j.mcna.2010.03.007 0025-7125/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
Limsuwan & Demoly and (2) nonimmediate reaction, with variable cutaneous symptoms occurring aftermore than 1 hour and up to several days after the last drug intake, such as late-occur-ring urticaria, maculopapular eruptions, fixed drug eruptions, vasculitis, toxicepidermal necrolysis, Stevens-Johnson syndrome, or drug reaction with eosinophiliaand systemic symptoms (DRESS). The first category is mostly mediated throughspecific IgE, whereas the latter is specifically T-cell–mediated.
Acute urticarial and angioedema reactions are common clinical problems frequently encountered by internists and general practitioners. Although most are benign and selflimiting, a mucocutaneous swelling of the upper respiratory tract could be life threat-ening by itself or a feature of anaphylaxis.By contrast, urticaria and angioedemaalone are not specific to drug allergic reaction, and can be caused by various patho-genic mechanisms.In this article, the authors review acute symptoms of drug HSRs,especially urticaria, angioedema, anaphylaxis, and anaphylactic shock, and how toapproach these problems in general.
URTICARIA AND ANGIOEDEMA Acute urticaria and angioedema are common clinical problems with an estimatedlifetime incidence of 15% to 25% in the general Acute urticaria ismore common in children, young adults, and people with atopic diseases, whereasthe chronic form is more prevalent in middle-aged women, with peak incidenceduring the third and fourth Isolated angioedema is still a poorly under-stood clinical issue and a difficult subject to approach for both internists andspecialists.
Clinical Features of Urticaria and Angioedema Urticaria (or ‘‘hives'') gives rise to blancheable, raised (edematous), smooth, pink tored papules, although classically it produces pale wheals surrounded by anerythematous flare and is characteristically intensely pruritic. These lesions areusually discrete, round or oval in shape, can vary in size from 1 mm to many centi-meters, and may occur anywhere on the body In the vast majority of casesthe wheals are transient, lasting for only a few hours in any one place, but with newwheals appearing in other places. Most urticarial eruptions therefore ‘‘move''around the body—a useful pointer from clinical history that the eruption is Angioedema, also called Quincke edema, is characterized by an acute, transient, nonpitting, red to skin-colored, well-demarcated, edematous swelling that involvesdeeper layers of skin (deep dermis, or subcutaneous and submucosal layers); it occursin an asymmetric distribution, and has no predilection for dependent areas. Angioe-dema usually affects the face (particularly the lips, tongue, perioral, and periorbitalareas) (), extremities, genitalia, scalp, as well as the upper respiratory airwaysand the intestinal epithelial lining. Pruritus is characteristically absent or minimal, butcan be accompanied by a sense of burning, pressure or tightness, or by a dull achein the affected area. Moreover, whereas most urticarial lesions regress within 24hours, angioedema may last for several Differentiation Between Urticaria and Angioedema Identifying and distinguishing angioedema from urticaria is important. First, along withanaphylaxis, angioedema is the only truly potentially life-threatening aspect of acuteimmediate hypersensitivity reactions, if the airway is affected. Patients should main-tain ready access to epinephrine, because laryngeal edema is a cause of death if
Acute Symptoms of Drug Hypersensitivity Fig. 1. Urticarial lesions with typical raised, edematous, pink, smooth papules and classicallysurrounded by erythematous flare (A), and gyrate pattern of urticaria (B).
unrecognized and/or inadequately treated.Second, patients with urticaria andangioedema tend to have more severe disease, more prolonged disease, and symp-toms that are less responsive to therapy as compared with patients with urticariaFinally, although about half of the patients with urticaria also have angioe-dema, as there is often a continuum spectrum of manifestations ranging from super-ficial wheals in the upper dermis merging with angioedema of the subcutaneous andsubmucosal tissues,40% of the patients have urticaria alone and 10% have isolatedangioedema.Thus for angioedema with urticaria the approach scheme is the same asfor urticaria, whereas isolated angioedema is a separate entity requiring a differentclinical Fig. 2. Angioedema presenting as bilateral eyelid swelling, from nonsteroidal anti-inflam-matory drug–induced angioedema.
Limsuwan & Demoly Differential Diagnosis of Urticaria Although urticaria is generally not difficult to diagnose, classifying patients with drug-induced urticaria is crucial for developing a meaningful differential diagnosis, identi-fying specific triggers, and choosing allergy tests. The following conditions shouldbe ruled out: 1. Dermatographism represents the most common physical urticaria, affecting 2% to 5% of the population. In contrast to the normal urticarial lesions, which are usuallyround or oval in shape, dermatographism consists of linear pruritic wheals appear-ing on areas of skin within 2 to 5 minutes of stroking and resolves after 30 minutesor up to 3 hours. Only a small portion of affected patients are symptomatic andrequire treatment with antihistamines. Systemic symptoms are absent. Commontriggers include scratching the skin and contact with clothing, towels, or sheets.
Dermatographism may follow an acute viral infection or drug reaction, and theduration is variable.
2. Urticarial vasculitis should be suspected when the lesions are painful (more than pruritic), last more than 24 hours, leave permanent pigmentary change, are non-blancheable, form vesicles, or are accompanied by purpura. Questions regardingsystemic (vasculitis) symptoms including fever, arthralgia or arthritis, renaldisease with proteinuria or hematuria, gastrointestinal manifestations of nauseaand abdominal pain, and pulmonary disease with cough, dyspnea, or hemop-tysis should be addressed. Frequently the provoking antigen cannot be found,but diagnostic tests classically reveal elevated acute-phase proteins, includingan erythrocyte sedimentation rate and low complement serum levels (CH50 orC1q, C2, or C4). Skin biopsies help confirmation of diagnosis by revealing theclassic features of leukocytoclastic vasculitis; this can be associated withsystemic lupus erythematosus, rheumatic fever, juvenile rheumatoid arthritis (Stilldisease), or other connective tissue diseases. It is a rule of thumb to performskin biopsies of urticarial lesions if they persist at the same site for more than24 hours.
3. Contact urticaria, in which contact of the skin with an allergen causes immediate hives at the site of contact, can be either allergic, such as allergy to natural rubberlatex, or nonallergic, due to, for example, certain chemicals in foods and cosmetics.
The disease can be complicated by angioedema and even severe anaphylaxis,especially in IgE-mediated allergic contact 4. Erythema multiforme is an acute disorder characterized by persistent targetlike lesions, which are symmetric, round, red or purple, with characteristically darkcyanotic centers that are typically less pruritic than urticaria. Also, these lesionsare usually found on the extremities, including the palms and soles, dorsa of thehands and the feet, forearms, and lower legs. These lesions are self limiting witha recovery phase of approximately 3 weeks.In the absence of severity criteriasuch as the widespread distribution of skin lesion or cutaneous detachment, thereaction is usually associated with herpes simplex or mycoplasma infection, andmostly affects children and young adults.It is not uncommon for these virus-trig-gered reactions to recur.
5. Primary mast cell disorders, although rare, account for a few cases of urticaria; physicians should recognize these disorders. Solitary mastocytomas are morecommon in children, with the classic lesion of hyperpigmented macule or papule,which when mechanically irritated by rubbing the skin develop a wheal and flare(Darier's sign). More than half of childhood mastocytomas resolve duringpuberty. In contrast, urticaria pigmentosa is rarely confused with urticarial Acute Symptoms of Drug Hypersensitivity lesions, given the distinctive pigmented cutaneous lesions for which it is named.
Even less common is systemic mastocytosis, a highly symptomatic but rarelymalignant clonal disorder of the mast cell and its CD341 precursors. This condi-tion is almost always accompanied by other symptoms, including prominentgastrointestinal symptoms, neuropsychiatric symptoms, and recurrent anaphy-laxis, as a result of increased total numbers of mast cells deposited in variousorgans, especially skin, bone marrow, gastrointestinal tract, liver, spleen, orlymph nodes, and elevations of the constitutively expressed a-form of tryptasein the serum. A bone marrow biopsy is needed for the Differential Diagnosis of Angioedema Angioedemas are frequently erroneously labeled when there are clinical manifesta-tions of swollen skin or mucosa around the facial area. Many conditions may mimicangioedema.
1. Edema refers to the swelling of tissue due to excess fluid in an interstitial space.
Edema and angioedema show a predilection for areas where the skin is lax ratherthan taut (especially the eyelids and genitalia), but only edema occurs predomi-nantly in dependent areas such as the buttocks and lower extremities.
2. Facial cellulitis, caused by an infectious process of adjacent organs, is often pain- ful, lasts for several days, is associated with fever and followed by peeling.
3. Superior vena cava syndrome is caused by a progressive obstruction or narrowing of the superior vena cava vein frequently by tumor invasion or mass effect, resultingin the gradual swelling of eyelids, lips, and venous engorgement at the face, neck,and upper part of the thorax.
4. Swelling of the oropharynx should be differentiated from tonsillitis, peritonsillar abscess, and pharyngeal foreign body.
5. Acute (facial) eczema is caused by the direct contact of certain sensitizers with the skin, leading to a pruritic papulovesicular dermatitis characterized early byerythema and edema.
6. Facial swelling as an early manifestation of DRESS ) is accompanied by lymphadenopathy, hypereosinophilia, lymphocytosis, and hepatitis.
7. Dermatomyositis presents with heliotrope (violaceous edema of the eyelids), which is persistent and associated with systemic symptoms and characteristic musculo-cutaneous symptoms such as muscular weakness from myositis and cutaneouseruptions ).
ANAPHYLAXIS AND ANAPHYLACTIC SHOCK Anaphylaxis is the most serious systemic immediate hypersensitivity reaction, oftenbut not always IgE-dependent, is rapid in onset, and can cause death.Althoughthe true prevalence of anaphylaxis is unknown, it is not as rare as generally believed;rather, it seems to be underrecognized and undertreated. In children, adolescents,and young adults, foods are the most common trigger. In middle-aged and olderadults, drugs and stinging insect venoms are important causes, as is idiopathicanaphylaxis.An estimated incidence of anaphylaxis is 50 to 2000 episodes per100,000 person-years with a possible lifetime prevalence of 0.05% to 2%.Althoughdeath from anaphylaxis is considered rare (< about 1%), some drugs have been asso-ciated with these fatalities, such as b-lactams, radiocontrast media (RCM), andmuscle
Limsuwan & Demoly Fig. 3. Face swelling in early manifestation of DRESS syndrome.
Clinical Presentation and Diagnosis of Anaphylaxis and Anaphylactic Shock In the diagnosis of anaphylaxis, the clinical history and physical examination are themost important instruments. Although recently a multidisciplinary group of expertsin the United States has suggested clinical criteria for diagnosing anaphylaxis bythe division into 3 according to the previous history of allergic reactionand known exposure, in order to include atypical presentation, here the authors Fig. 4. Heliotrope sign in dermatomyositis, showing swelling and violaceous discolorationof eyelids.
Acute Symptoms of Drug Hypersensitivity have simplified the procedure by presenting only the first category, in which the diag-nosis is based on a combination of clinical signs and symptoms of at least 2 organinvolvements ). Skin (urticaria and/or angioedema) is involved in almost90% of the episodes. Conjunctivitis is part of an acute mucosal allergic reaction todrugs Other organ involvements include the lower respiratory system(dyspnea, wheezing, hypoxemia) in more than half of the patients, the upper respira-tory airway system (laryngeal or tongue swelling) in up to 20%, gastrointestinal mani-festations (nausea, vomiting, diarrhea, abdominal pain), and cardiovascularmanifestations (dizziness, syncope, hypotension, or collapse) in about one-third ofthe patients.The presence of hypotension and shock are not always necessaryin the diagnosis of However, when there is a drop in blood pressure ofmore than 30% from the patient's baseline or the systolic blood pressure is lower thanthe standard value, the term ‘‘anaphylactic shock'' is used; this can be an isolatedmanifestation in rare patients who experience an acute hypotensive episode afterexposure to a known allergen or in a specific situation such as perioperative anaphy-laxis.In these situations where diagnosis of anaphylaxis poses difficulties, laboratorytests such as plasma histamine or total tryptase may be helpful. However, these testsdo have certain limitations: (1) suboptimal specificity and sensitivity; (2) plasma hista-mine not available worldwide and requiring special handling (eg, centrifuging andfreezing the plasma promptly); (3) limited timing for taking the blood sample (30–60minutes after the onset of the episode). Although plasma or serum total tryptase levelsare more practical (ie, increased from 15 minutes to 3 hours after symptom onset andrequiring no special handling), they are seldom increased except in anaphylactic shocktriggered by an injected agent, such as an injectable antibiotic or anesthetic Symptom onset varies widely but generally occurs within seconds or minutes after exposure. The intravenous route of drug administration is usually associated with Table 1Clinical diagnosis of anaphylaxis Anaphylaxis is highly likely when there is an acute onset of clinical symptoms involving at least 2 organ systems together with skin and mucosal tissue involvement Skin and mucosal tissue Urticaria, angioedema, generalized pruritus or flushing, rhinitis, conjunctivitis Respiratory system Lower airway: dyspnea, wheezing, bronchospasm, reduced peak expiratory flow, hypoxemia Upper airway: stridor or upper airway obstruction from laryngeal edema or tongue swelling, together withhypersialorrhea, dysphonia, or dysphagia Crampy abdominal pain, nausea, vomiting, diarrhea Cardiovascular system Dizziness, syncope, hypotension (collapse) Anaphylactic shock is defined as anaphylaxis accompanied by reduced blood pressure. On rare occasions, patients can present with isolated acute hypotensive episodes Infants and children Low systolic blood pressure (age specific) or >30% decrease in systolic blood pressure Systolic blood pressure <90 mm Hg or >30% decrease from patient's baseline Data from Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definitionand management of anaphylaxis: summary report—Second National Institute of Allergy and Infec-tious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol2006;117(2):391–7; and Kemp SF, Lockey RF, Wolf BL, Lieberman P. Anaphylaxis. A review of 266cases. Arch Intern Med 1995;155(16):1749–54.
Limsuwan & Demoly Fig. 5. Urticaria and angioedema involving eyelids, forehead, and face, associated withconjunctivitis and bronchospam, after positive oral aspirin challenge.
a rapid onset of reaction, whereas symptoms associated with the ingestion of anallergen may be more delayed (within the first 2–3 hours and exceptionally even upto several hours). It should be noted, however, that the onset of symptoms can occurimmediately after ingestion, and such rapidly occurring events can be fatal. There isa direct relationship between the time of onset of the symptoms after antigen admin-istration and their severity: the more rapid the onset, the more severe the Inrare cases, an episode can be protracted, lasting for more than 24 hours, or can recurafter initial resolution (biphasic Differential Diagnosis of Anaphylaxis When the history of exposure to an offending agent is elicited, the diagnosis ofanaphylaxis is often obvious because anaphylaxis is a dynamic continuum, usuallycharacterized by a definable exposure to a potential trigger and by rapid onset, evolu-tion, and resolution of symptoms within minutes to hours after treatment. Skin symp-toms and signs such as itching, flushing, urticaria, and angioedema are extremelyhelpful in the diagnosis of allergic reaction,but might be absent or unrecognizedin 10% or more of all episodes, especially in severe When gastrointes-tinal symptoms or respiratory symptoms predominate, or cardiopulmonary collapsemakes obtaining a history impossible, anaphylaxis may be confused with other enti-ties. Some of these differential diagnoses are listed in Common diagnosticdilemmas involve acute asthma, syncope, and panic These conditions,however, usually lack typical cutaneous signs and symptoms, and vasovagal reactionis associated with nausea, sweating, and bradycardic hypotension whereas anaphy-laxis is almost always associated with tachycardic hypotension.
TRIGGERS OF ACUTE URTICARIA, ANGIOEDEMA, AND ANAPHYLAXISMechanisms Involved Acute urticaria/angioedema or anaphylactic reactions occurring within a few hoursfollowing the last administration of the drug may be due to allergic mechanisms (eitherIgE-dependent or other antibodies such as IgM or IgG) or nonallergic mechanisms(An allergic mechanism involves the cross-linking of IgE and aggregationof the IgE receptors on mast cells and basophils. Nonallergic reactions include Acute Symptoms of Drug Hypersensitivity Table 2Differential diagnosis for anaphylaxis and anaphylactic shock Differential Diagnosis Septic shockVasovagal reactionCardiogenic shock (sudden asystole may be a sign of anaphylactic shock as well) Hypovolemic shock Respiratory distress with Airway foreign body, especially in small children wheezing or stridor Asthma and chronic obstructive pulmonary disease Postprandial syndromes High monosodium glutamate ingestionSulfite ingestionScrombroid fish poisoninga Carcinoid syndromePostmenopausal hot flushesAlcohol-induced flushRed man syndrome (vancomycin injection) Excess endogenous production Systemic mastocytosisa of histamine syndromes Basophil leukemiaaAcute promyelocytic leukemia (tretinoin treatment)a Nonorganic diseases Panic attacksVocal cord dysfunction syndromeMunchausen stridor Cardiovascular (myocardial infarction)aNeurologic events (seizure, cerebrovascular event) a May include hypotension.
Data from Lieberman PL. Anaphylaxis. In: Adkinson NF, Busse WW, Bochner BS, et al, editors.
Middleton's allergy: principles and practice. 7th edition. Elsevier; 2009. p. 1027–50; and TangAW. A practical guide to anaphylaxis. Am Fam Physician 2003;68(7):1325–32.
nonspecific histamine release (eg, opiates, RCM, plasma volume expander, and van-comycin), induction of leukotriene synthesis (nonsteroidal anti-inflammatory drugs[NSAIDs]), or bradykinin accumulation (angiotensin-converting enzyme [ACE] inhibi-Regardless of the initiating trigger and mechanism, cellular events in mastcells and basophils result in the rapid release of granule-associated preformed medi-ators, particularly histamine and tryptase. Moreover, the downstream production ofarachidonic acid metabolites (including prostaglandins, leukotrienes, and synthesisof platelet-activating factor) and array of cytokines and chemokines lead to the devel-opment of immediate anaphylactic symptoms and a late-phase reaction.It is ofinterest that some drugs can trigger acute allergic symptoms via both allergic andnonallergic mechanisms, such as NSAIDs, RCM, opiates, and some chemothera-peutic Urticaria should be regarded as a symptom that can be triggered by a wide range of exogenous factors or endogenous diseases with allergic, inflammatory, or infectiousmechanisms, and not uniquely the allergic reaction in The common causesof acute urticaria/angioedema are acute infections.Acute viral infection, and espe-cially upper respiratory tract infections (URI), appear to be the most common cause ofacute urticaria, which are usually present a few days before the onset of wheal forma-tion. The prevalence of URI in acute urticaria varies between 28% and 62%.Because the drugs commonly prescribed during the treatment of these infectionssuch as antibiotics and NSAIDs can also elicit acute urticaria, they are frequently Limsuwan & Demoly Table 3Common triggers of acute urticaria, angioedema, and anaphylaxis Nonallergic Triggers Allergic Triggers Mostly peanuts, tree nuts, shellfish, fish, milk, and egg Certain food like strawberries Food-dependent exercise induced anaphylaxis (often associated with Chemical substances: RCM,a volume sensitization to omega5-gliadin) expanders, aspirin, NSAIDsa Drug causing direct mast cell –Common: Antibiotics (b-lactams, degranulation: opiates,a vancomycin paclitaxel, docitaxel and doxorubicin, Acute manifestation of autoimmune disease, connective tissue disease, or Platinum compounds –Less common: opiatesa Isolated angioedema Hymenoptera (bee, wasp, hornet, yellow Aspirin, other NSAIDsa jacket, sawfly), fire ant, or other biting C1 INH deficiency (hereditary insects (eg, flies, mosquitoes, kissing angioedema or acquired form) Factor XII mutation and estrogen intake Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; RCM, radiocontrast media.
a Drugs capable of triggering acute HSRs either by nonallergic or allergic (IgE-specific) mecha- nism (see text).
accused wrongly. Unfortunately, there are no clinical predictors to differentiatebetween acute urticaria from infection and that from drug allergy, except the circum-stantial evidence of resolution of infection and hives at the same time.A significantproportion of physical stimuli (such as exposure to sun, water, or temperatureextremes, pressure from, eg, wearing a heavy backpack, vibration), foods, chemicalsubstances, and drugs (such as aspirin, NSAIDs, vancomycin, opiates, RCM, somechemotherapeutic agents, and volume expanders) can cause urticaria and angioe-dema by nonimmune-mediated mechanism (see Aspirin- and NSAID-induced urticaria and angioedema are common. Their prevalence in the general pop-ulation has been reported to be 0.1% to However, in selected populations,such as atopics, young adults, and 21% to 30% of patients with chronic urticaria,the risk of developing wheal and flare after the ingestion of this agent is Pathogenesis is believed to be the inhibition of cyclooxygenase (COX)-1, leading toa shunting of arachidonic acid metabolism toward the 5-lipooxygenase pathway,which results in an increased synthesis and release of cysteinyl leukotrienes.Theintake of aspirin and NSAIDs can also elicit adverse respiratory symptoms, such asasthmatic attacks and nasoocular symptoms (eg, conjunctivitis and rhinosinusitis)through the same pathomechanism, particularly in up to 10% of asthmatic patientsand some atopic Most sensitive persons who experience urticaria,angioedema, or respiratory symptoms may have similar reactions to chemicallydifferent conventional NSAIDs (antigenically unrelated to aspirin), so-called cross-reactivity, and must take low-dose acetaminophen or specific COX-2 inhibitors for Acute Symptoms of Drug Hypersensitivity treatment of fever, pain, or inflammation.Other agents capable of the direct stim-ulation of histamine release from mast cells include opioids (such as codeine andmorphine), vancomycin (red man syndrome), RCM, and certain chemotherapeuticagents (such as paclitaxel, docetaxel, and doxorubicin).Volume expanders,particularly gelatin and dextran, are responsible for a few cases of acute HSR duringoperation.These agents, particularly via intravenous administration, can producesymptoms identical to IgE-mediated immediate type reactions, including urticaria,angioedema, bronchospasm, and anaphylaxis (formerly termed ‘‘anaphylactoid reac-tions''). Other triggers are allergic, such as drug, food, insect sting, and latex (see). Exacerbations of chronic urticaria may be regarded as acute urticaria andallergens may be suspected. These conditions include autoimmune diseases (eg,thyroiditis and autoantibody to IgE receptor) and other systemic diseases (eg, connec-tive tissue diseases, neoplastic conditions, and some chronic infections).
Angioedema is classified as angioedema associated with mast cell degranulation from allergic reaction or nonallergic mechanism, and angioedema mediated by theaccumulation of bradykinin. The first category is usually associated with urticariaand is caused by similar allergic and nonallergic triggers (see ). The latter isusually associated with isolated angioedema and is caused by certain medications(eg, ACE inhibitors), C1 esterase inhibitors (C1 INH), or other deficiencies (hereditaryor acquired angioedema, eg, lymphoma, autoimmune connective diseases).ACEinhibitor–induced angioedema is not dose related, and is a class-specific mediatedangioedema. Apart from the catalysis of the transformation of angiotensin I to angio-tensin II, ACE also inactivates bradykinin. Thus, ACE inhibitors have the potential tokeep bradykinin levels elevated. As bradykinin is a powerful vasoactive substance,excess levels may cause vasodilatation and increased vascular permeability. Theoverall incidence of ACE-induced angioedema is reported to be around 0.1% to0.5%,but it is the most common cause of acute angioedema cases referred toemergency hospital departments (23%–38%), in which up to 20% may be life threat-ening, especially when upper airway involvement occurs.Furthermore, although50% of ACE inhibitor–induced angioedema may occur during the first week of therapy,some patients may have taken the ACE inhibitor without any problem for weeks,months, or even years before the development of The face andoral mucosa, including the larynx and subglottal area, are most often affected, but iso-lated visceral angioedema, causing abdominal pain, has also been reported. Emer-gency treatment as well as hospitalization for observation may be necessary insevere cases. Angiotensin II receptor antagonists do not actually interfere with brady-kinin metabolism; nevertheless, some reports postulate recurrent angioedema afterswitching to these Aspirin and NSAIDs can induce periorbital angioedema either in isolation or as part of an upper respiratory reaction in ‘‘aspirin-sensitive asthma.'' Isolated periorbitalangioedema is a typical manifestation of cutaneous reaction to aspirin and NSAIDsin atopic and young adults (see Most of these patients exhibitcross-reactivity with other NSAIDs, and should receive similar management to thosepresenting with urticaria and angioedema alone or with respiratory Hereditary angioedema (HAE) is a rare, dominantly inherited disease that affects about 1 in 50,000 persons, representing approximately 1% of all cases of angioe-dema. HAE is mediated by bradykinin.It is a result of deficiency (type 1) or dysfunc-tion (type 2) of the plasma inhibitor of the first component of complement C1 INH.
Recently a new, estrogen-dependent form, characterized by a mutation in factor XII,has been This form of HAE affects women, and angioedematous attacksare often triggered by intake of anticonceptive hormones or pregnancy. HAE is Limsuwan & Demoly characterized clinically by recurrent bouts of painless, nonpruritic, nonpitting edemainvolving the face, larynx, gastrointestinal tract, and extremities. Attacks are triggeredby emotional stress, vigorous exercise, alcohol consumption, hormonal changes, andminor trauma such as dental maneuvers, and lasts 1 to 4 days. Facial and extremityedema resolve gradually without harm, whereas untreated laryngeal edema isprogressive and can result in death by Patients with mutationsin factor XII have laryngeal edema less frequently than patients with classic C1 INHdeficiency. Treatment with H1 antihistamines and corticosteroids has little effect, whileCI INH reconstitution or the bradykinin receptor antagonist icatibant reduces Acquired C1 INH deficiency. C1 INH deficiency may also be acquired as a result of immune complex-mediated depletion or antibody directed against C1 INH, associatedwith lymphoproliferative disease, particularly B-cell lymphoma, carcinoma, or connec-tive tissue diseases such as systemic lupus Anaphylaxis' common causes include allergic triggers such as foods, drugs, insect stings, and latex, as well as physical factors/exercise and idiopathic anaphylaxis(where no cause is identified) (see Approximately one-third of anaphylacticepisodes are triggered by foods such as shellfish, peanuts, eggs, milk, fish, andtree nuts. Another common cause of anaphylaxis is a sting from a fire ant or hymenop-tera (bee, wasp, hornet, yellow jacket, and sawfly).The incidence of latex allergyhas stabilized after educational campaigns and the substitution of power-free latexand nonlatex gloves in hospitals. However, latex allergy still incorporates an unpredict-able risk affecting the general population, in both occupational and nonoccupationalsettings exposed to latex (gloves, condoms, and urinary catheters).
The drugs that most often cause anaphylaxis include antibiotics, NSAIDs, RCM, and muscle relaxants.
Antibiotics: In most studies, antibacterial agents were responsible for the highest number of reports of anaphylaxis, including b-lactams (penicillins and cephalo-sporins) and fluoroquinolones. At one time, penicillin was probably the mostcommon cause. Between 1 and 5 per 10,000 patient-courses with penicillinresult in allergic reactions, with 1 in 50,000 to 1 in 100,000 courses having a fatalHowever, it appears that during recent years the incidence ofanaphylaxis to cephalosporins as well as fluoroquinolones is increasing.
Aspirin and NSAIDs: Some NSAIDs can cause anaphylaxis in the outpatient setting.Propyphenazone and pyrazolone were mainly responsible forthis reaction. The mechanism was thought to be allergic in However, other NSAIDs have also been reported to be associated with anaphy-laxis, such as the diclofenac and oxicam groups, and celecoxib, although drug-specific IgE could not be RCM can result in severe adverse reaction at a rate of 0.2% for ionic agents and 0.04% for lower osmolarity, nonionic agents. Although they were previouslythought to induce acute HSR by a nonallergic mechanism, IgE antibody–medi-ated mechanisms have recently been identified in some Muscle relaxants are one of the major causes of anaphylaxis during general anesthesia. IgE antibodies against quarternary ammonium ions have been iden-tified and cross-reactivity to other muscle relaxants have been frequentlyobserved. Patients were successfully treated with test-negative agents.
Chemotherapeutic agents, particularly platinum salts such as carboplatin, cisplatin, and oxaliplatin, are associated with acute HSR after several coursesof treatment and usually with a positive skin test. Cross-reactivity to other platins Acute Symptoms of Drug Hypersensitivity has been reported, and desensitization offers an effective means for continuationof therapy in cancer patients requiring these agents.
Other substances: Opioids have been reported to be a cause of anaphylaxis during general anesthesia in a small fraction of Rare, but importantcauses of anaphylaxis are also chlorhexidin (particularly in urology) and dyessuch as patent blue (used in surgery to trace draining lymph MANAGEMENT OF ACUTE URTICARIA, ANGIOEDEMA, AND ANAPHYLAXISPharmacologic Treatment As with the treatment of any critically ill patient, the treatment of anaphylaxis beginswith a rapid assessment and maintenance of the airway, breathing, and circulation.
When a patient fulfills criteria for anaphylaxis, even with symptoms involving nonvitalorgans, the patient should receive adrenaline/epinephrine immediately intramuscu-larly, in an attempt to prevent more severe anaphylaxis (self-injectable epinephrinepreparations normally contain 0.3 mg epinephrine for adults and 0.15 mg for children;higher doses may be required in adults or overweight persons). Delaying treatmentuntil the development of multiorgan symptoms may be risky because the ultimateseverity of anaphylaxis is difficult or impossible to predict at the time of onset of theSubsequent management strategies are determined on the basis ofthe clinical course and response to adrenaline/epinephrine ().
For urticaria and angioedema however, H1 antihistamines are the mainstay of treat- ment. Both first- and second-generation H1 antihistamines are effective in controllingsymptoms. Second-generation H1 antihistamines are generally considered the firstchoice in treatment, because of the lower sedative The addition of a relativelybrief use of systemic corticosteroids (0.5–1 mg/kg/d) may be considered in patientswith severe symptoms, particularly in the presence of angioedema, to achieve bettersymptomatic control. These medications have serious potential side effects and maybe associated with a significant flare of symptoms after tapering or withdrawal, andthus are not routinely After treatment of an anaphylactic reaction, an observation period should be consid-ered for all patients, given that the reaction might recur as the effect of the adren-aline/epinephrine wears off (intramuscular injection results in increased serum levelsfor an hour or more) and due to the risk of a biphasic reaction (around 1%–20% ofthe A reasonable length of time is 4 to 6 hours for most patients, witha prolonged period or hospital admission for those with severe or refractorysymptoms.
Evaluation and Long-Term Plan of Management of Acute Urticaria,Angioedema, and Anaphylaxis The first step is a thorough history taking to identify the cause of urticaria, angioe-dema, and anaphylaxis, and to determine those at risk for future attacks. In contrastto anaphylaxis, most patients with acute urticaria and angioedema do not requireextensive laboratory evaluation except to confirm a causative agent (eg, skin testingfor a suspected allergen). Moreover, almost all cases of acute urticaria and angioe-dema in adults are self limited within 3 weeks.
A complete history and physical examination are the most important tools in the diagnosis and evaluation of urticaria and angioedema. This process is frequentlytime consuming. Specific questions should address the following: a history of viralinfection; recent insect bites or stings; suspected food; skin contact with foreign Limsuwan & Demoly Box 1Management of acute anaphylaxis Immediate intervention 1. Assessment of airway, breathing, circulation, and consciousness 2. Administer adrenaline/epinephrine 1:1000 dilution (1 mg in 1 mL) intramuscularly, 0.2 to 0.5 mg (0.01 mg/kg in children with maximum dose of 0.3 mg) every 5 to 15 minutes, or ina situation of general anesthesia where intravenous access and cardiac monitoring areavailable, treatment tailored to the severity of symptoms may be used (ie, initial intravenousdose: 10–20 mg in grade II reactions, 100–200 mg in case of grade III reactions, repeated every1–2 minutes as necessary, to control symptoms and blood pressure).
1. Place patient in recumbent position and elevate lower extremities.
2. Establish and maintain airway.
3. Administer oxygen.
4. Establish venous access and administer normal saline intravenously for fluid replacement. If severe hypotension exists, rapid infusion of volume expanders (colloid-containing solution)is necessary.
Specific measures to consider after adrenaline/epinephrine injections, where appropriate 1. H1 antihistamines, such as chlorpheniramine or diphenhydramine 50 mg intravenously.
2. Nebulized b2 agonist (eg, salbutamol) for bronchospasm resistant to epinephrine.
3. Systemic corticosteroid, such as methylprednisolone 1 to 2 mg/kg per day, are not usually helpful acutely, but might prevent prolonged reactions or relapses.
4. Vasopressor (eg, dopamine) for hypotension refractory to volume replacement and 5. Glucagon for patient taking b-blockers.
6. Atropine for symptomatic bradycardia.
7. Consider transportation to an emergency department or an intensive care facility.
8. For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged resuscitation efforts are encouraged.
material, heat, cold, or water; and drugs. It is crucial to identify all medications(including prescription, over-the-counter, oral, topical, conventional including bloodtransfusion, RCM, and herbal) that are taken intermittently or regularly, and whichthe patient is currently using. Questioning about history of latex sensitivity or possibleexposures may reveal a potential occult contact allergen.Despite extensive eval-uation, possible eliciting factors for acute urticaria and angioedema are not alwaysidentified.For patients experiencing anaphylactic reaction, the evaluation andmanagement are more complex, and are detailed in The prescription of self-injectable epinephrine is mandatory until allergy testing, but is of less interest in thecase of a drug allergy. A follow-up evaluation with an allergist should be made in allpatients to confirm the anaphylaxis trigger and to plan for long-term individualizedpreventive measures (see Acute Symptoms of Drug Hypersensitivity Box 2Long-term management and preventive measures for patients with anaphylaxis General measures to be taken before discharging a patient from an emergency department Obtain thorough history to identify potential causes of anaphylaxis and to determine those atrisk of future attacks, and organize: 1. Prescription of self-injectable adrenaline/epinephrine for patients experiencing severe anaphylactic symptoms after exposure to a known allergen in the community (such as foodor insect sting).
2. Patient education, in particular how to avoid the allergen and its cross-reactive substances or how to recognize and treat anaphylactic episodes promptly if they occur; also how togain access to emergency medical services and the closest emergency department.
3. Follow-up with an allergist.
Role of allergist-immunologist specialist Confirmation of allergic triggers Detailed history and physical examination Skin tests: prick and intradermal tests with immediate reading Laboratory tests: specific IgE, in vitro test for drug allergy Controlled administration of suspected allergen: drug provocation test, food challenge Individualized preventive measures and long-term management Desensitization (in confirmed IgE-mediated allergic reaction and no alternative measures) Avoidance of the causative allergen and cross-reactive substance Find safe alternative treatment for the patient (particularly in drug allergy) Premedication may be useful in nonallergic hypersensitivity reaction Diagnostic Workup for Drug Allergy The history of drug allergy alone is in fact often not reliable because different drugs arefrequently taken simultaneously, every one of which is capable of accounting for thesymptoms, and it may be imprecise. Acute urticaria and angioedema are nonspecificprocesses and may be caused by multiple factors as described above, while anaphy-laxis may be confused with other conditions as well. Depending on history only(without proving the relationship between drug intake and symptoms or clarifyingthe underlying pathomechanism of the reaction) leads to overdiagnosis and unneces-sary elimination of useful drugs. Particularly in cases where essential and/or frequentlyprescribed drug classes (eg, b-lactams, paracetamol, NSAIDs, local anesthetics, andmyorelaxants) are involved, a diagnosis procedure should be performed in a specialistcenter, which may include repeated detailed clinical history and physical examination,skin tests, laboratory tests and, ultimately, drug provocation Only a formaldiagnosis of drug HSRs allows one to bring into play the measures required forprevention and treatment. Skin-prick tests and/or intradermal tests with immediatereading (after 20 minutes) are particularly important tools for demonstrating an IgE-dependent mechanism. Unfortunately, reliable skin test procedures and validatedtest concentrations for drug allergy are often missing. However, some agents havesatisfactory high sensitivity and predictive value (eg, penicillins, cephalosporins, Limsuwan & Demoly myorelaxants, iodine RCM), whereas others may be specific with low sensitivity (eg,vaccines, hormones, protamine, opiates, thiopental), and the rest with unknown sensi-tivity and predictive value (local anesthetics, paracetamol, sulfonamides, quinolones,NSAIDs, and most other anti-infectious agents).These procedures should be per-formed at least 4 to 6 weeks after the reaction, in a specialist environment, becausethe tests themselves can reproduce allergic symptoms and, rarely, an anaphylacticreaction.The tests should follow standardized procedures. The laboratory tests(eg, drug-specific IgE) or in vitro tests (eg, stimulation with patient's lymphocytes orbasophils with suspected drug) are few in number and rarely fully validated. However,the development of new and validated laboratory tools may, in the future, replace theneed for drug provocation tests in certain high-risk patients.
Specific Management and Preventive Measures Slow rates of infusion and premedication (antihistamines and glucocorticoids) areadvised in nonallergic HSRs such as RCM, vancomycin, and certain chemotherapydrugs, but they do not prevent allergic reactions. Desensitization is a process thatallows temporary tolerance to allergen, and could be considered when the offendingdrug is essential and no alternatives exist or are unsatisfactory.Finally, a definitivediagnosis of drug allergy requires a declaration to the local Committee on Drug Safety,an ‘‘Allergy Card'' specifying the culprit agent(s), the delivery of lists of drugs to avoidand of possible alternatives. Patient education regarding awareness of one's ownallergies and learning how to read the package insert on all drugs is important.
Clinical manifestations of acute drug HSRs are variable and include urticaria, angioe-dema, anaphylaxis, and anaphylactic shock. Despite the simple clinical recognitionand symptomatic treatment, causative agents of acute urticaria and angioedemaare often difficult to define and, in most cases, may be unknown. For anaphylaxis itis unpredictable, but most useful preventive methods involve finding the culprit agentby collecting a history of previous allergic and anaphylactic episodes, testing, andreplacing the offending agent with another that is not cross-reactive. At the sametime, the proper recognition of anaphylaxis when it occurs, the correct administrationof appropriate dose, and the suitable route of administration of adrenaline/epineph-rine, including other measurements are very important. Referral to an allergist isencouraged to confirm or refuse drug allergy and to define its pathomechanism, whichhelps offer specific treatments and preventive measures.
Acute symptoms of drug hypersensitivity are variable and include urticaria, an- gioedema, bronchospasm, to anaphylaxis or anaphylactic shock.
Urticaria and angioedema are nonspecific reactions, and are most commonly associated with acute viral infection, nonallergic-mediated drug reactions(such as NSAIDs, opioids, and RCM), and physical stimuli.
Isolated angioedema should be viewed as a manifestation of adverse reactions to drugs such as ACE inhibitors and NSAIDs.
Anaphylaxis is an acute severe systemic adverse drug reaction, associated with or without shock, and is mostly associated with allergic reactions, such as anti-biotics, NSAIDs, RCM, and muscle relaxants.
Appropriate dose and route of adrenaline/epinephrine administration is the first treatment and the treatment of choice in anaphylaxis.
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Issue date: December 2004, with amendments April 2007 Quick reference guide (amended) Anxiety: management of anxiety(panic disorder, with or withoutagoraphobia, and generalisedanxiety disorder) in adults inprimary, secondary andcommunity care Amendment of recommendations concerning venlafaxine: April 2007On 31 May 2006 the MHRA issued revised prescribing advice for venlafaxine*. Thisamendment brings the guideline into line with the new advice but does not cover other areas where new evidence may be available. NICE expects to make a decision on a full update later in 2007.
Académie nationale de Pharmacie « MÉDICAMENTS ET ENVIRONNEMENT » de l'Académie nationale de Pharmacie Septembre 2008 MEMBRES DE LA COMMISSION SANTÉ ENVIRONNEMENT HAGUENOER Jean Marie, Président ROUBAN Anne, Secrétaire AUROUSSEAU Michel BOHUON Claude BOURILLET François BOURRINET Patrick CARPENTIER Anne DELAGE Michel DÛCHENE Dominique FESTY Bernard GALLIOT-GUILLEY Martine GUIGNARD Jean-Louis JAMET Jean-Louis JOUANIN Christian LEVI Yves PARIER Jean-Loup RAYNAUD Guy RIBET Jean-Paul SANTINI Claude VELO Giampaolo