acute symptoms of drug hypersensitivity (urticaria, angioedema, anaphylaxis, anaphylactic shock)

8/12/2019 Acute Symptoms of Drug Hypersensitivity (Urticaria, Angioedema, Anaphylaxis, Anaphylactic Shock)

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Acute Symptoms ofDrug Hypersensitivity(Urticaria, Angioedema,

Anaphylaxis,Anaphylactic Shock)Ticha imsu!an, "Da, #ascal Demoly, "D, #hD$,%

&'*+DS

Urticaria Angioedema Anaphylaxis Anaphylactic shock

Drug hypersensitivity


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Drug hypersensitivity reactions (HS+s) are the adverse effects of drugs !hich,!hen taken at doses generally tolerated $y normal su$-ects, clinicallyresem$le allergy./Although they occur in a small percentage of patients (a$outone0third of all adverse drug reactions, !hich affect /12 to 312 of thehospitali4ed patients and more than 52 of the general population), these

reactions are often unpredicta$le and can $e life threatening.3,6

*nly !hen adefinite immunologic mechanism (either drug0specific anti$ody or T0cell) isdemonstrated should these reactions $e classified as drug allergy. 7or generalcommunication, !hen a drug allergic reaction is suspected, 88drug HS+99 is thepreferred term, $ecause true drug allergy and nonallergic drug HS+:may $edifficult to differentiate from the clinical presentation alone, especially insituations of acute severe HS+, such as anaphylaxis. Ho!ever, for a long0term plan of treatment and prevention, referral to an allergist0immunologist forconfirmation of diagnosis is needed to offer specific preventive measurements.

The 'uropean ;et!ork for Drug Allergy (';DA), !orking under the aegis ofthe 'uropean Academy of Allergy and "ontpellier , 7rance %


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6 imsu!an K Demoly

and (3) nonimmediate reaction, !ith varia$le cutaneous symptoms occurring aftermore than / hour and up to several days after the last drug intake, such aslate0occurring urticaria, maculopapular eruptions, fixed drug eruptions,vasculitis, toxic epidermal necrolysis, Stevens0Lohnson syndrome, or drug

reaction !ith eosinophilia and systemic symptoms (D+'SS). The firstcategory is mostly mediated through specific =g', !hereas the latter isspecifically T0cellmediated.Acute urticarial and angioedema reactions are common clinical pro$lems

freMuently encountered $y internists and general practitioners. Although mostare $enign and self limiting, a mucocutaneous s!elling of the upperrespiratory tract could $e life threatening $y itself or a feature of anaphylaxis.5FBy contrast, urticaria and angioedema alone are not specific to drug allergicreaction, and can $e caused $y various pathogenic mechanisms./1 =n thisarticle, the authors revie! acute symptoms of drug HS+s, especially urticaria,angioedema, anaphylaxis, and anaphylactic shock, and ho! to approachthese pro$lems in general.

U+T=

Angioedema, also called Ouincke edema, is characteri4ed $y an acute,transient, nonpitting, red to skin0colored, !ell0demarcated, edematous s!ellingthat involves deeper layers of skin (deep dermis, or su$cutaneous andsu$mucosal layers) it occurs in an asymmetric distri$ution, and has nopredilection for dependent areas. Angioedema usually affects the face(particularly the lips, tongue, perioral, and perior$ital areas) (7ig. 3),extremities, genitalia, scalp, as !ell as the upper respiratory air!ays and theintestinal epithelial lining. #ruritus is characteristically a$sent or minimal, $utcan $e accompanied $y a sense of $urning, pressure or tightness, or $y a dullache in the affected area. "oreover, !hereas most urticarial lesions regress!ithin 3: hours, angioedema may last for several days./1,/6

Differentiation Bet!een Urticaria and Angioedema

=dentifying and distinguishing angioedema from urticaria is important. 7irst, along !ithanaphylaxis, angioedema is the only truly potentially life0threatening aspect of acute


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immediate hypersensitivity reactions, if the air!ay is affected. #atients shouldmaintain ready access to epinephrine, $ecause laryngeal edema is a cause ofdeath if


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7ig. /. Urticarial lesions !ith typical raised, edematous, pink, smooth papules and classicallysurrounded $y erythematous flare (A), and gyrate pattern of urticaria (B).

unrecogni4ed andIor inadeMuately treated./?/PSecond, patients !ith urticaria andangioedema tend to have more severe disease, more prolonged disease, andsymptoms that are less responsive to therapy as compared !ith patients !ithurticaria alone.5,//,/F 7inally, although a$out half of the patients !ith urticaria also haveangioedema, as there is often a continuum spectrum of manifestationsranging from superficial !heals in the upper dermis merging !ith angioedemaof the su$cutaneous and su$mucosal tissues,P :12 of the patients haveurticaria alone and /12 have isolated angioedema.5Thus for angioedema!ith urticaria the approach scheme is the same as for urticaria, !hereasisolated angioedema is a separate entity reMuiring a different clinicalapproach./6

7ig. 3. Angioedema presenting as $ilateral eyelid s!elling, from nonsteroidal anti0inflam0matory druginduced angioedema.


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Differential Diagnosis of Urticaria

Although urticaria is generally not difficult to diagnose, classifying patients !ith drug0induced urticaria is crucial for developing a meaningful differential diagnosis,identifying specific triggers, and choosing allergy tests. The follo!ing

conditions should $e ruled out@

1. Dermatographism represents the most common physical urticaria, affecting 32 to>2 of the population. =n contrast to the normal urticarial lesions, !hich areusually round or oval in shape, dermatographism consists of linear pruritic !healsappearing on areas of skin !ithin 3 to > minutes of stroking and resolvesafter 6Q minutes or up to 6 hours. *nly a small portion of affected patientsare symptomatic and reMuire treatment !ith antihistamines. Systemicsymptoms are a$sent.


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Acute Symptoms of Drug Hypersensi tiv it y 5

pigmentosa is rarely confused !ith urticarial


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P imsu!an K Demoly

lesions, given the distinctive pigmented cutaneous lesions for !hich it is named.'ven less common is systemic mastocytosis, a highly symptomatic $utrarely malignant clonal disorder of the mast cell and its


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Acute Symptoms of Drug Hypersensi ti vi ty F

considered rare ( a$out / 2), some drugs have $een associated !ith thesefatalities, such as L60lactams, radiocontrast media (+


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/1 imsu!an K Demoly

7ig. 6. 7ace s!elling in early manifestation of D+'SS syndrome.


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Acute Symptoms of Drug Hypersensi ti vi ty//

have simplified the procedure $y presenting only the first category, in !hich the diag0nosis is $ased on a com$ination of clinical signs and symptoms of at least 3organ involvements (Ta$le /). Skin (urticaria andIor angioedema) is involved

in almost F12 of the episodes. )./?,3? *ther organ involvements include thelo!er respiratory system (dyspnea, !hee4ing, hypoxemia) in more than half of thepatients, the upper respiratory air!ay system (laryngeal or tongue s!elling) in upto 312, gastrointestinal manifestations (nausea, vomiting, diarrhea,a$dominal pain), and cardiovascular manifestations (di44iness, syncope,hypotension, or collapse) in a$out one0third of the patients./?,3>35 Thepresence of hypotension and shock are not al!ays necessary in thediagnosis of anaphylaxis.33Ho!ever, !hen there is a drop in $lood pressureof more than 612 from the patient9s $aseline or the systolic $lood pressure islo!er than the standard value, the term 88anaphylactic shock99 is used this can$e an isolated manifestation in rare patients !ho experience an acutehypotensive episode after exposure to a kno!n allergen or in a specificsituation such as perioperative anaphylaxis.33 =n these situations !herediagnosis of anaphylaxis poses difficulties, la$oratory tests such as plasmahistamine or total tryptase may $e helpful. Ho!ever, these tests do havecertain limitations@ (/) su$optimal specificity and sensitivity (3) plasma hista0mine not availa$le !orld!ide and reMuiring special handling (eg, centrifugingand free4ing the plasma promptly) (6) limited timing for taking the $lood

sample (61?1 minutes after the onset of the episode). Although plasma or serum totaltryptase levels are more practical (ie, increased from /> minutes to 6 hoursafter symptom onset and reMuiring no special handling), they are seldomincreased except in anaphylactic shock triggered $y an in-ected agent, suchas an in-ecta$le anti$iotic or anesthetic agent.36

Symptom onset varies !idely $ut generally occurs !ithin seconds orminutes after exposure. The intravenous route of drug administration isusually associated !ith

Ta$le /


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definition and management of anaphylaxis@ summary reportNSecond ;ational =nstitute of Allergyand =nfectious DiseaseI7ood Allergy and Anaphylaxis ;et!ork Symposium. L Allergy


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Acute Symptoms of Drug Hypersensi tiv it y/6

7ig. >. Urticaria and angioedema involving eyelids, forehead, and face, associated !ithcon-unctivitis and $ronchospam, after positive oral aspirin challenge.

a rapid onset of reaction, !hereas symptoms associated !ith the ingestion ofan allergen may $e more delayed (!ithin the first 36 hours and exceptionallyeven up to several hours). =t should $e noted, ho!ever, that the onset ofsymptoms can occur immediately after ingestion, and such rapidly occurringevents can $e fatal. There is a direct relationship $et!een the time of onset of

the symptoms after antigen administration and their severity@ the more rapidthe onset, the more severe the episode.3P=n rare cases, an episode can $eprotracted, lasting for more than 3: hours, or can recur after initial resolution($iphasic anaphylaxis).33

Differential Diagnosis of Anaphylaxis

hen the history of exposure to an offending agent is elicited, the diagnosis ofanaphylaxis is often o$vious $ecause anaphylaxis is a dynamic continuum,usually characteri4ed $y a defina$le exposure to a potential trigger and $yrapid onset, evolution, and resolution of symptoms !ithin minutes to hours

after treatment. Skin symptoms and signs such as itching, flushing, urticaria, andangioedema are extremely helpful in the diagnosis of allergic reaction,36 $utmight $e a$sent or unrecogni4ed in /12 or more of all episodes, especially insevere episodes.33,3> hen gastrointestinal symptoms or respiratorysymptoms predominate, or cardiopulmonary collapse makes o$taining ahistory impossi$le, anaphylaxis may $e confused !ith other entities. Some ofthese differential diagnoses are listed in Ta$le 3.


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/: imsu!an K Demoly

nonallergic mechanisms (Ta$le 6).An allergic mechanism involves the cross0linking of =g' and aggregation of the =g' receptors on mast cells and$asophils. ;onallergic reactions include


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Acute Symptoms of Drug Hypersensi tivity/>

Ta$le 3

Differential diagnosis for anaphylaxis and anaphylactic shock

#resentation Differential DiagnosisHypotension Septic shock

asovagal reaction1 and Tang A.A practical guide to anaphylaxis. Am 7am #hysician 3116?P(5)@/63>63.

nonspecific histamine release (eg, opiates, +


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Ta$le 60gliadin)

Drug


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Acute Symp toms of Drug Hypersensi ti vi ty /5

atex

A$$reviations@ ;SA=Ds, nonsteroidal anti0inflammatory drugs +,6?#athogenesis is $elieved to $e the inhi$ition of cyclooxygenase(0lipooxygenase path!ay, !hich results in an increased synthesis and release ofcysteinyl leukotrienes.65 The intake of aspirin and ;SA=Ds can also elicitadverse respiratory symptoms, such as asthmatic attacks and nasoocularsymptoms (eg, con-unctivitis and rhinosinusitis) through the samepathomechanism, particularly in up to /12 of asthmatic patients and someatopic individuals.6P,6F "ost sensitive persons !ho experience urticaria,angioedema, or respiratory symptoms may have similar reactions tochemically different conventional ;SA=Ds (antigenically unrelated to aspirin),


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/P imsu!an K Demoly

so0called cross0reactivity, and must take lo!0dose acetaminophen or specific


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Acute Symptoms of Drug Hypersensi ti vi ty/F

treatment of fever, pain, or inflammation.:1:3*ther agents capa$le of the direct stim0ulation of histamine release from mast cells include opioids (such as codeineand morphine), vancomycin (red man syndrome), +6

Hereditary angioedema (HA') is a rare, dominantly inherited disease thataffects a$out / in >1,111 persons, representing approximately / 2 of allcases of angioedema. HA' is mediated $y $radykinin.>: =t is a result ofdeficiency (type /) or dysfunction (type 3) of the plasma inhi$itor of the first


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component of complement > Thisform of HA' affects !omen, and angioedematous attacks are often triggered$y intake of anticonceptive hormones or pregnancy. HA' is


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Acute Symptoms of Drug Hypersensi tiv it y3/

characteri4ed clinically $y recurrent $outs of painless, nonpruritic, nonpitting edemainvolving the face, larynx, gastrointestinal tract, and extremities. Attacks aretriggered $y emotional stress, vigorous exercise, alcohol consumption,hormonal changes, and minor trauma such as dental maneuvers, and lasts /to : days. 7acial and extremity edema resolve gradually !ithout harm,!hereas untreated laryngeal edema is progressive and can result in death $yasphyxiation./1,/6,>:#atients !ith mutations in factor R== have laryngeal edemaless freMuently than patients !ith classic


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33 imsu!an K Demoly


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Acute Symp toms of Drug Hype rsensi tivity36

has $een reported, and desensiti4ation offers an effective means for continuationof therapy in cancer patients reMuiring these agents.6/

*ther su$stances@ *pioids have $een reported to $e a cause of

anaphylaxis during general anesthesia in a small fraction of patients.?1

+are, $ut important causes of anaphylaxis are also chlorhexidin(particularly in urology) and dyes such as patent $lue (used in surgery totrace draining lymph nodes).5/,53

"A;AE'"';T *7 A


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3: imsu!an K Demoly

freMuently time consuming. Specific Muestions should address the follo!ing@ ahistory of viral infection recent insect $ites or stings suspected food skincontact !ith foreign


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Acute Symptoms of Drug Hypersensi ti vi ty3>

Box /

"anagement of acute anaphylaxis=mmediate intervention

1.Assessment of air!ay, $reathing, circulation, and consciousness

2.Administer adrenalineIepinephrine /@/111 dilution (/ mg in / m) intramuscularly, 1.3 to 1.>mg (1.1/ mgIkg in children !ith maximum dose of 1.6 mg) every > to /> minutes, or in asituation of general anesthesia !here intravenous access and cardiac monitoring areavaila$le, treatment tailored to the severity of symptoms may $e used (ie, initialintravenous dose@ /131 tg in grade == reactions, /11311 tg in case of grade === reactions,repeated every /3 minutes as necessary, to control symptoms and $lood pressure).

Eeneral measures

1. #lace patient in recum$ent position and elevate lo!er extremities.

2. 'sta$lish and maintain air!ay.

3. Administer oxygen.

4. 'sta$lish venous access and administer normal saline intravenously for fluid replacement.=f severe hypotension exists, rapid infusion of volume expanders (colloid0containingsolution) is necessary.

>. Seek help

Specific measures to consider after adrenalineIepinephrine in-ections, !here appropriate

1. H/ antihistamines, such as chlorpheniramine or diphenhydramine >1 mg intravenously.

2. ;e$uli4ed 63agonist (eg, sal$utamol) for $ronchospasm resistant to epinephrine.

3. Systemic corticosteroid, such as methylprednisolone / to 3 mgIkg per day, are not usuallyhelpful acutely, $ut might prevent prolonged reactions or relapses.

4. asopressor (eg, dopamine) for hypotension refractory to volume replacement andepinephrine.

5. Elucagon for patient taking 60$lockers.

6.Atropine for symptomatic $radycardia.

7.

material, heat, cold, or !ater and drugs. =t is crucial to identify allmedications (including prescription, over0the0counter, oral, topical,conventional including $lood transfusion, +


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!ith an allergist should $e made in all patients to confirm the anaphylaxistrigger and to plan for long0term individuali4ed

preventive measures (see Box 3).33,36,56


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Box 3ong0term management and preventive measures for patients !ith anaphylaxis

Eeneral measures to $e taken $efore discharging a patient from an emergency department

*$tain thorough history to identify potential causes of anaphylaxis and to determine those at risk of future

attacks, and organi4e@

1. #rescription of self0in-ecta$le adrenalineIepinephrine for patients experiencing severe anaphylacticsymptoms after exposure to a kno!n allergen in the community (such as food or insect sting).

2. #atient education, in particular ho! to avoid the allergen and its cross0reactive su$stances or ho! torecogni4e and treat anaphylactic episodes promptly if they occur also ho! to gain access toemergency medical services and the closest emergency department.

6. 7ollo!0up !ith an allergist.

+ole of allergist0immunologist specialist


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3P imsu!an K Demoly

myorelaxants, iodine +


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Acute Symptoms of Drug Hypersensi ti vi ty3F

reactions, such as anti$iotics, ;SA=Ds, +


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61 imsu!an K Demoly

+'7'+';5(Suppl 53)@ 65:1.

7. : patients.Br L Dermatol /F?FP/(P)@>PPF5.

8. Erattan P.20.AuMuier0Dunant A, "ockenhaupt ", ;aldi , et al. 6?5, vii.22. Sampson HA, "uno407urlong A,


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Acute Symptoms of Drug Hypersensi tivity6/

3:.ie$erman # , F??13.

3>.Hel$ling A, Hurni T , "ueller U+, et al. =ncidence of anaphylaxis !ith circulatorysymptoms@ a study over a 60year period comprising F:1,111 inha$itants of theS!iss 1.

3F.Bircher AL. Drug0induced urticaria and angioedema caused $y non0=g' medi0ated pathomechanisms. 'ur L Dermatol /FFFF(P)@?>5?6 Mui4@ ?6V. 61.aroche

D, Aimone0Eastin =, Du$ois 7, et al."echanisms of severe, immediate

reactions to iodinated contrast material. +adiology /FFP31F(/ )@/P6F1.6/.imsu!an T , :P.

6?.Sanche40Borges ", :P.

:/. Sanche40Borges ", .


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63 imsu!an K Demoly

43. eone +, FF?1?.46. &ostis LB, &im HL, +usnak L, et al. =ncidence and characteristics of

angioedema associated !ith enalapril. Arch =ntern "ed 311> /?>(/:)@/?65:3.

47. Sa$roe +A, Black A&.Angiotensin0converting en4yme (A3?P.

49. Bluestein H", Hoover TA, Baner-i AS, et al. Angiotensin0convertingen4yme inhi$itor0induced angioedema in a community hospitalemergency department.Ann Allergy Asthma =mmunol 311F /16(?)@>135.

50. 7uchs SA, &oopmans +#, Euchelaar HL, et al. Are angiotensin == receptorantagonists safe in patients !ith previous angiotensin0converting en4ymeinhi$itor0induced angioedemaX Hypertension 311/65(/)@'/.

51. Ho!es E, Tran D. >(:)@:/PF.59. Ei$$s ", &uc4ko!ski &", Benumof L.


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Acute Symptoms of Drug Hypersensi tiv it y66

:.


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?6.arrington +L, "c#hillips S. =ndependent anaphylaxis to cefa4olin !ithout allergy

to other $eta0lactam anti$iotics. L Allergy 5(/)@:>>/.P1.+omano A, Eaeta 7, allu44i +, et al. Diagnosing hypersensitivity reactions to

cephalosporins in children.#ediatrics 311P /33(6)@>3/5.

P/.+omano A, Eueant0+odrigue4 +", iola ", et al. Diagnosing immediate reactionsto cephalosporins.

acute symptoms of drug hypersensitivity (urticaria, angioedema, anaphylaxis, anaphylactic shock)

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