Drug Allergy Book

DRUG ALLERGY
Daniel Vervloet Michel Pradal Michel Castelain
Daniel Vervloet, Michel Pradal, Michel Castelain Department of Pneumology and Allergy Department of Dermatology Hopital Sainte Marguerite Universit de la Mditerranne Marseille FRANCE
DRUG ALLERGY
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Daniel Vervloet/Michel Pradal/Michel Castelain ISBN 91-973440-0-1

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TABLE OF CONTENTS
PREFACE .................................................................................. 5 INTRODUCTION ..................................................................... 6 I. II. III. IV. V. VI. DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE ......................................................... 7 ANALGESICS AND ANTI-INFLAMMATORY DRUGS .......................................................................... 37 ANTIBIOTICS, ANTIVIRAL, ANTIFUNGAL DRUGS .......................................................................... 53 CHEMOTHERAPY DRUGS AND IMMUNOSUPPRESSORS ........................................................... 105 DRUGS USED IN CARDIOLOGY ............................ 151 DYES, PRESERVATIVES, ANTISEPTICS ................ 163
VII. PRODUCTS USED IN DIALYSIS ............................. 185 VIII. DIAGNOSTIC AGENTS............................................. 195 IX. X. XI. ENZYMES ................................................................... 209 HORMONES ............................................................... 217 SERA AND VACCINES ............................................. 239
XII. VITAMINS................................................................... 263 XIII. MISCELLANEOUS .................................................... 273 INDEX................................................................................... 306

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PREFACE
The first version of this work was originally the thesis that Dr Michel Pradal submitted for his Doctorate of Medicine in 1987. Thanks to Pharmacia & Upjohn Diagnostics Division, this first version was published in French in 1990, and received positive reviews among the French allergist community. Two years later, in 1992, we published a second edition, this time in English, in the hope that this work might be a practical help to allergists facing difficulties in making etiologic diagnoses of drug allergies. These difficulties reside in the fact that where drug allergy is concerned, there is but one general rule: there are no general rules. Each drug has its own metabolites and mechanisms, and the diagnostic tools must be adapted to the type of reaction caused by the drug in question and to the mechanisms involved. Seven years after this second edition, we thought it would be useful to publish an updated version enriched with up-to-date knowledge and recent references. To achieve this, I asked dermatologist and allergist Doctor Michel Castelain to join Doctor Pradal and myself and enrich this work particularly in regard to delayed allergic reactions which often show skin reactions. I hope that all the information found here will be useful in the day-to-day practice of allergology, and I thank Pharmacia & Upjohn for its material support. Daniel Vervloet
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INTRODUCTION
Estimations of incidence figures for drug allergy show a variation. In a French study of 2067 adults aged from 20 to 67 visiting a health-care center for check-up examination, 14.7% of the study group reported reliable histories of systemic drug reactions. Others have stated that allergic drug reactions account for 510% of adverse drug reactions. In a Swiss drug monitoring program, about 17% of hospitalized patients showed adverse drug reactions, 5.4 -5.9% appeared to be allergic. Numerous mechanisms have been implicated, but several remain obscure and this lack of knowledge accounts for the difficulties in differentiating allergy from other side effects, assessing the incidence, risk factors, and management strategy for diagnosis and prevention. This book was written as a practical guide to allergy diagnosis management and the main drugs responsible. We have tried to specify the main clinical manifestations and risk factors for each of them, as well as the diagnostic methods (in vivo and, where possible, in vitro), known mechanisms and management.
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I DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE
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DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE
LOCAL ANESTHETICS
These drugs anesthetize the area to which they are applied by blocking nerve conduction and preventing depolarization of cell membranes. There are two main families of local anesthetics: Benzoic acid ester group (group I): benzocaine, chlorprocaine, cocaine, piperocaine, procaine, propoxycaine, tetracaine. Amides (group II): aromatic: articaine, bupivacaine, dibucaine, etidocaine, lidocaine, mepivacaine, prilocaine. thiophenic: alphacaine Amides are by far the most used today.
INCIDENCE
2 to 3% of local anesthesias (faints). True allergic reactions are exceedingly rare (less than than 1% of all reactions).
RISK FACTORS
Long term topical application of anesthetic drugs (contact dermatitis).
CLINICAL MANIFESTATIONS Reactions unrelated to drugs:

psychomotor: hyperventilation, vaso-vagal, adrenergic sympathetic stimulation operative trauma Toxic responses in normal subjects: central nervous system effects cardiovascular effects
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Reactions due to either adjuvants or injection, but not to the local anesthetic itself: associated drugs: epinephrine, sulfites, parabens, antibiotics, analgesics; traumatic subcutaneous emphysema. Type I allergic reactions: anaphylactic shock, urticaria, angioedema are exceptional. Fixed drug eruptions: extremely rare (lidocaine, mepivacaine). Delayed-type hypersensitivity (contact allergy) is more frequent due to the increasing use of topical preparations containing local anaesthetics of the amide group. Several of these cases have been reported in chronically treated patients with topical applications of Emla cream (lidocaine + prilocaine). Cases of contact allergy to lidocane have been also reported (antihemorroidal cream, phlebectasias treatment). Historically, delayed-type hypersensitivity was reported mainly with esters which are much less commonly used nowadays. Cross-reactivity among amides is not always encountered.
DIAGNOSTIC METHODS
Cutaneous testing Prick-tests are mostly negative. Intradermal skin-tests: false positive at 1/10 and pure concentration. Few case reports with type I clinical manifestations and positive intradermal skin-tests with 1/10 000 to 1/100 concentrations. Patch-tests are useful in the diagnosis of type IV manifestations (contact dermatitis) to esters and amides. No specific IgE found
MECHANISMS
No absolute demonstration of IgE-mediated reactions. The role of preservatives (parabens, sulfites) remains controversial. Type IV reactions: contact dermatitis (esters and amides).
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MANAGEMENT
Challenge test remains the gold standard in local anesthetic reactions. Many suggested dosing protocols exist: for example (at 15 minute intervals). 1 prick 2 S.C 3 S.C 4 S.C 5 S.C 0.1 ml 0.5 ml 1 ml 2 ml undiluted undiluted undiluted undiluted undiluted
Alternative therapies: preservative-free preparations be aware of cross-reactivity between esters (frequent) and amides (less frequent) antihistamines (diphenhydramine) may be used as anesthetics general analgesia (N2O) hypnosis
REFERENCES
Fisher M.M, Bowey C.J, Alleged allergy to local anaesthetics, Anaesth. Intensive. Care., 1997 ; 25 (6): 611-4 Cuesta-Herranz J, de las Heras M, Fernandez M, Lluch M, Figueredo E, Umpierrez A, Lahoz C, Allergic reaction caused by local anesthetic agents belonging to the amide group, J.Allergy. Clin. Immunol., 1997 ; 99 (3): 427-8 Eggleston S.T, Lush L.W, Understanding allergic reactions to local anesthetics, Ann. Pharmacother, 1996 ; 30 (7.8): 851-7 Gall H, Kaufmann R, Kalveram C.M, Adverse reactions to local anesthetics: analysis of 197 cases, J.Allergy. Clin. Immunol, 1996 ; 97 (4): 933-7 Wasserfallen J.B, Frey P.C, Long-term evaluation of usefulness of skin and incremental challenge tests in patients with history of adverse reaction to local anesthetics, Allergy, 1995 ; 50: 162-5 Sindel L.J, de Shazo R.D, Accidents resulting from local anesthetics. True or false allergy ?, Clin. Rev. Allergy, 1991 ; 9 (3.4): 379-95.
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HYPNOTICS
BARBITURATES
METHOHEXITAL
Methohexital is a barbiturate derivative used for brief surgical procedures.
INCIDENCE
Reported incidence ranges from 1/7000 to 0/23000.
0.2% in dentistry. No deaths have been reported. CLINICAL MANIFESTATIONS

Essentially cutaneous, mucosal (pruritus, urticaria, rash, edema) and cardiovascular. Respiratory (bronchospasm) and digestive symptoms are unusual. Symptoms are usually delayed (a few minutes after injection).
DIAGNOSTIC METHODS
None.
MECHANISMS
Non specific histamine-release.
MANAGEMENT
Avoidance.
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REFERENCES
Liu L.M, Liu P.L, Moss J, Severe histamine-mediated reaction to rectally administered methohexital, Anesthesiology, 1984 ; 61 (1): 95-7 McDonald D, Methohexitone in dentistry. Scientific results of 4379 administrations. 5: complications, Dent. Anaesth. Sedat., 1982 ; 11 (2): 51-7 Harrison G.R, Thompson I.D, Adverse reaction to methohexitone and gallamine, Anaesthesia, 1981 ; 36 (1): 40-4 Driggs R.L, ODay R.A, Acute allergic reaction associated with methohexital anesthesia: report of six cases J. Oral. Surg., 1972 ; 30: 906-9.
THIOPENTAL
Frequently used hypnotic, barbiturate anesthetic.
INCIDENCE
1/23000 to 1/29000 administrations. Deaths rarely reported.
RISK FACTORS
Previous exposure (94%). Female gender (gender ratio 3/1)
CLINICAL MANIFESTATIONS
General: anaphylactic shock Respiratory: bronchospasm. Cutaneous: flush, generalized erythema, angioedema, fixed drug eruption. Possible delayed reactions. Haematological: haemolytic anemia.
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DIAGNOSTIC METHODS
Cutaneous testing Prick-tests or intradermal tests. Dilution 1/1000 to 1/10 of 2.5% thiopental. Detection of thiopentone-reactive IgE antibodies by the RAST method ; which specificity is confirmed by hapten inhibition studies.
MECHANISMS
Immediate hypersensitivity: Usually IgE-mediated. Allergenic determinants: pentyl and ethyl groups attached to position 5 on the pyrimidine ring nucleus and the secondary region of the ring, encompassing and including the attached hetero atom. Possible involvement of non-specific histamine release.
MANAGEMENT
Avoidance.
REFERENCES
Bremang J.A, Halasi S, Fixed drug eruption associated with anaesthesia, Can.J.Anaesth., 1995 ; 42 (7): 628-30 Baldo B.A, Fisher M.M, Diagnostic de lallergie IgE dpendante aux curares, au thiopental et aux opiacs, Ann.Fr.Anesth.Reanim., 1993 ; 12 (2): 173-81 Baldo B.A, Fisher M.M, Harle D.G, Allergy to thiopentone Clin. Rev. Allergy, 1991 ; 9 (3-4): 295-308. Baldo B.A, Harle D.G, Drug allergenic determinants (pp 11-51), In: Molecular approaches to the study of allergens. Monographs in allergy, Vol.28. BA Baldo ed. Karger, Basel, 1990. Harle D.G, Baldo B.A, Smal M.A, Wajon P, Fisher M.M, Detection of thiopentone reactive IgE antibodies following anaphylactoid reactions during anaesthesia, Clin. Allergy, 1986 ; 16: 493-8.
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NON-BARBITURATES
ETOMIDATE
Short-acting general anesthetic.
INCIDENCE
Exceedingly rare.
Essentially cutaneous and gastrointestinal. Few cardiovascular and respiratory effects.
DIAGNOSTIC METHODS
No in vivo or in vitro diagnostic method currently available.
MECHANISMS
Etomidate is a poor histamine releaser.
MANAGEMENT
Avoidance.
REFERENCES
Fazackerley E.J, Martin A.J, Tolhurst-Cleaver C.L, Watkins J, Anaphylactoid reaction following the use of etomidate , Anaesthesia, 1988 ; 43 (1): 953-4. Bricker S.R, Angioneurotic edema following etomidate/lignocaine, Anaesthesia, 1987 ; 42 (3): 323-4. Watkins J, Etomidate, an immunologically safe anaesthetic agent, Anaesthesia., 1983 ; 38 (S): 34-8
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KETAMINE
INCIDENCE
Exceedingly rare.
General: anaphylactic shock. Cutaneous: rash, urticaria. Respiratory: laryngospasm.
DIAGNOSTIC METHODS
Cutaneous testing Intradermal skin-tests: 0.05 ml of Ketalar 5% or ketamine base 1/ 100 and 1/10 positive in one patient.
MECHANISMS
Probable IgE-mediated hypersensitivity.
MANAGEMENT
Avoidance.
REFERENCES
Karayan J, Lacoste L, Breuil K, Allergie la ktamine , Ann.Fr.Anesth.Reanim., 1990 ; 9 (4): 396-7 Mathieu A, Goudsouzian N, Swider M.T, Reaction to ketamine: anaphylactoid or anaphylactic ? Br. J. Anaesth., 1975 ; 47: 624-7
PROPANIDID
Short-acting general anesthetic used especially for tooth extractions.
INCIDENCE
Very high: 1 out of 500 to 1 out of 700 anesthesias.
Severe reactions: 0.007% to 0.13%.

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General: anaphylactic shock. Respiratory: bronchospasm. Dermatological: various delayed reactions. Digestive: nausea, vomiting, diarrhea.
DIAGNOSTIC METHODS
Complement assay at the time of the accident (difficult). Blood histamine measurement at the time of the accident.
MECHANISMS
Responsibility of solvent: cremophor E.L., which activates the classical or alternative complement pathway, releasing C3a anaphylatoxin and leukocyte migration. Non-specific histamine release.
MANAGEMENT
Prohibited in many countries since 1983. Avoidance.
REFERENCES
Guerrero J, Trevilla J.M, de las Mulas M, Herrera J.C, Malagon F, Reaccion anafilactica a la propanidida, Rev. Esp. Anesthesiol Reanim., 1985 ; 32 (5): 252-3. Christmas J.P, Immune reaction to propanidid, Anaesthesia, 1984 ; 39: 470-3.
PROPOFOL
Propofol (2-6 diisopropylphenol) is an alkyl phenol in a lipid vehicle (soybean oil, egg lecithin, glycerol) used in anesthesia.
INCIDENCE
1/60 000 1.2% of peroperative anaphylactic shocks in France.
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RISK FACTORS
Previous drug allergy. Allergy to muscle relaxants. Association with atracurium.
General: anaphylactic shock. Cutaneous: urticaria, angioedema, facial edema, erythema. Respiratory: bronchospasm. Ocular: conjunctival chemosis.
DIAGNOSTIC METHODS
Cutaneous testing Skin prick-tests. Intradermal skin-tests from 1 g/ml to 100 g/ml (1/1000 to 1/ 10). Positive in most patients with anaphylactic reactions. Specific IgE (RIA): positive in 10/14 propofol allergic patients. Leukocyte-specific histamine release: positive in 3/5 propofol allergic patients.
MECHANISMS
IgE-mediated hypersensitivity in most cases. Propofol contains 2 isopropyl group that may act as the epitopes.
MANAGEMENT
Do not use propofol in muscle relaxant-allergic patients. Do not use atracurium with propofol (high frequency of anaphylactoid reactions). Avoidance.
REFERENCES
Laxenaire M.C, Utilisation du Diprivan* chez le patient allergique , Ann.Fr.Anesth.Reanim., 1994 ; 13 (4): 498-502 Mc Hale S.P, Konieczko K, Anaphylactoid reaction to propofol, Anaesthesia., 1992 ; 47 (10): 864-5 de Leon-Casasola O.A, Weiss A, Lema M.J, Anaphylaxis due to propofol, Anesthesiology, 1992 ; 77 (2): 384-6
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Laxenaire M.C, Mata-Bermejo E, Moneret-Vautrin D.A, Gueant J.L, Lifethreatening anaphylactoid reactions to propofol (Diprivan*) , Anesthesiology, 1992 ; 77 (2): 275-80 Mc Leskey C.H, Anaphylactoid reactions following propofol-atracurium sequence (letter ; comment), Can.J.Anaesth., 1990 ; 37 (8): 946-7
MORPHINOMIMETICS
CODEINE
Codeine (methylmorphine, morphine monomethyl ether) belongs to the opiod group. The main indication of codeine is as a cough suppressant.
INCIDENCE
Very low.
RISK FACTORS
Intravenous use in children.
General: arterial hypotension (intravenous route), pseudoscarlet fever. Cutaneous: pruritus, urticaria, macular and maculopapular eruptions, angioedema, erythema multiforme, erythema nodosum, scarlatiniform rashes, fixed drug eruption (occupational dermatitis from codeine has been reported). Respiratory: bronchospasm.
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DIAGNOSTIC METHODS
Cutaneous testing Skin patch-tests: codeine phosphate 0.1% aq. (fixed drug erup tion). codeine phosphate 0.001% to 0.033% aq. (urticarial rash). Oral challenge tests (fixed drug eruption).
MECHANISMS
Non immunological histamine release (pruritus, urticaria). Delayed-type hypersensitivity (urticaria, rash). Vasomotor depression, ganglionar blockade and histamine release could explain hypotension.
MANAGEMENT
Avoid intravenous use in children. The risk of cross-sensitivity is higher with morphine congeners than with phenylpiperidine or methadone-type agents.
REFERENCES
Gonzalo-Garijo M.A, Revenga-Arranz F, Fixed drug eruption due to codeine (letter), Br.J.Dermatol., 1996 ; 135 (3): 498-9 Rodriguez F, Fernandez L, Garcia-Abujeta J.L, Maquiera E, Llaca H.F, Jerez J, Generalized dermatitis due to codeine, Contact. Dermatitis. , 1995 ; 32 (2): 120 de Groot A.C, Conemans J, Allergic urticarial rash from oral codeine, Contact. Dermatitis., 1986 ; 14 (4): 209-14. Shanahan E.C, Marshall A.G, Garrett C.P.O, Adverse reactions to intravenous codeine phosphate in children. A report of 3 cases, Anaesthesia, 1983 ; 38 (1): 40-3.
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FENTANYL
Major morphinomimetic analgesic, used exclusively in anesthesia.
INCIDENCE
Extremely rare.
RISK FACTORS
Previous sensitization to another phenylpiperidine drug.
General: anaphylactic shock. Cutaneous: urticaria, angioedema, diffuse rash (transdermal fentanyl). Respiratory: bronchospasm.
DIAGNOSTIC METHODS
Cutaneous testing Intradermal skin-tests positive from 0.5 ng/ml to 5 ng/ml (2 cases reported).
MECHANISMS
Fentanyl does not induce non-specific histamine-release. IgE-mediated hypersensitivity (positive skin-tests).
MANAGEMENT
Avoidance.
REFERENCES
Stoukides C.A, Stegman M, Diffuse rash associated with transdermal fentanyl, Clin.Pharm., 1992 ; 11 (3): 222 Bennett M.J, Anderson L.K, Mc Millan J.C, Ebertz J.M, Hanifin J.M, Hirshman C.A, Anaphylactic reaction during anaesthesia associated with positive intradermal skin test to fentanyl, Can. Anaesth. Soc. J., 1986 ; 33 (1): 75-8.
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Pevny I, Danhauser I, Anaphylaktisher schock wahrend der narkose mit positivem hauttest auf fentanyl und alloferin, Anaesthesist., 1981 ; 30: 400-4
MEPERIDINE - PETHIDINE
Narcotic analgesic frequently used for analgesia and general anesthesia (induction).
INCIDENCE
Very low.
General: anaphylactic shock. Cutaneous: flush, urticaria. Respiratory: cough, wheezing.
DIAGNOSTIC METHODS
Specific IgE (RAST): positive in a few cases of anaphylaxis. Immediate skin-tests may be positive (do not exceed a concentration of 1/100000).
MECHANISMS
IgE-mediated hypersensitivity. Non-specific histamine release (meperidine is one of the strongest histamine-releasers of all anaesthetic agents).
MANAGEMENT
Avoidance.
REFERENCES
Flacke J.W, Flacke W.E, Bloom B.C, Van Etton A.P, Kripke B.J, Histamine release by 4 narcotics: a double blind study in humans, Anesth. Analg., 1987 ; 66: 723-30. Levy J.H, Rockoff M.A, Anaphylaxis to meperidine, Anesth. Analg., 1982 ; 61 (3): 301-3 Waisbren B.A, Hypersensitivity to meperidine, JAMA, 1978 ; 239 (14): 1395
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MORPHINE
Morphine, historically chief among the opioids , is widely used as an analgesic in various clinical situations (postoperative period, cancer).
INCIDENCE
Extremely rare.
General: anaphylactic shock. Cutaneous: urticaria. Respiratory: bronchospasm.
DIAGNOSTIC METHODS
Cutaneous testing Intradermal skin-tests: positive 1/100 000 (solution of 10 mg/ ml) Specific IgE (RIA morphine-sepharose) positive in a patient.
MECHANISMS
Nonspecific histamine release . IgE-mediated hypersensitivity: the morphine allergenic determinant comprises the cyclohexenyl ring, with a hydroxyl group at C6 and a methyl substituent attached to the N-atom.
MANAGEMENT
Avoidance. Cross-reactivity with codeine and other opioids may occur.
REFERENCES
Harle D.G, Baldo B.A, Coroneos N.J, Fisher M.M, Anaphylaxis following administration of papaveretum. Case report: implication of IgE antibodies that react with morphine and codeine and identification of an allergic determinant. Anesthesiology., 1989 ; 71 (4): 489-94 Rossi R, Dick W, Anaphylactoide reaktion nach intravenser injektion von morphinum hydrochloricum, Anesthesist. , 1982 ; 31: 463-5
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Fahmy N.R, Hemodynamics, plasma histamine and catecholamine concentrations during an anaphylactoid reaction to morphine , Anesthesiology, 1981 ; 55: 329-31
MUSCLE RELAXANTS
Family of agents widely used in general anesthesia to achieve muscle relaxation. Suxamethonium, Vecuronium, Pancuronium, Atracurium, Mivacurium, Rocuronium, Cisatracurium
INCIDENCE
One anaphylactic shock out of every 10000 general anesthesias. 10% of these reactions are fatal. Muscle relaxants account for 60 to 70% of all allergic reactions occurring during general anesthesia.
RISK FACTORS
Use of muscle relaxants with a flexible chain. Female gender (80% of cases). No involvement of atopy. Previous allergic reactions to muscle relaxants.
General: collapse, tachycardia, arrhythmia, cardiac arrest. Respiratory: bronchospasm. Dermatological and mucosal: flush, diffuse erythema, diffuse urticaria, angioedema. Digestive: diarrhea. Haematological: disseminated intravascular coagulation.
DIAGNOSTIC METHODS
Intradermal skin tests or prick tests (using undiluted muscle relaxants). High diagnostic performance if conducted with proper concentrations, i.e. for intradermal skin testing:
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100 g/ml for suxamethonium. 200 g/ml for pancuronium. 100 g/ml for rocuronium 2 g/ml for mivacurium 400 g/ml for vecuronium. 10 g/ml for atracurium. 200 g/ml for cisatracurium Subjects remain positive for several years (up to 30 years). Detection of anticurare and antisuxamethonium IgE antibodies by RAST methods. Specific histamine release.
MECHANISMS
Immediate IgE-mediated hypersensitivity: detection of IgE specific to muscle relaxants (quaternary ammonium ion determinants) accounting for cross reactions between different curarizing anesthetics and reactions upon first contact with a muscle relaxant (antihypertensors, antiseptics, antibiotics, cosmetics, and soaps with a quaternary ammonium ion structure). Mediator release from target cells. Leukocytes from subjects with a history of anaphylactic accidentsbrought into contact with increasing concentrations of muscle relaxants in vitro, release histamine which can be measured (dose-dependent response). Histamine release from basophils involves IgE antibodies. Role of quaternary ammonium ion determinants. The rigidity of the chain linking quaternary ammoniums plays a triggering role in allergic reactions. Flexible molecules with simple carbon chains (Suxamethonium) can stimulate sensitized cells more strongly than rigid molecules (Pancuronium). Some reactions are not based on an IgE mechanism, but on a nonspecific histamine release effect.
MANAGEMENT
Use safer muscle relaxants such as Pancuronium rather than Suxamethonium.
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Systematic screening-tests in a general population are not advisable due to the poor positive predictive value of the tests. Patients with a history of anaphylactic reactions: Conduct preoperative skin-tests with all muscle relaxants. (Frequent cross-reactivity between 2 or more muscle relaxants) If skin-tests are positive, do not use the offending muscle relaxants. If skin-tests are negative, the agents may be administered . (good negative precitive value). No preventive treatment can avoid anaphylactic reactions
REFERENCES
Porri F, Lemiere C, Birnbaum J, Guilloux L, Lanteaume A, Didelot R, Charpin D, Vervloet D, Prevalence of muscle relaxants sensitivity in a general population: implications for a preoperative screening, Clin. Exp. Allergy, 1998 ; in press Nicklas R.A, Anaphylaxis during general anesthesia, the intraoperative period and postoperative period, J. Allergy. Clin. Immunol., 1998 ; 101: S512-6 Laxenaire M.C et le groupe dtude des ractions anaphylactodes peranesthesiques, Substances responsables des chocs anaphylactiques peranesthesiques, Ann. Fr. Anesth., 1996 ; 15: 1211-8 Porri F, Pradal M, Rud C, Charpin D, Alazia M, Gouin F, Vervloet D, Is systematic preoperative screening for muscle relaxants and latex allergy advisable ?, Allergy, 1995 ; 50: 374-7 Birnbaum J, Vervloet D, Allergy to muscle relaxants, Clin. Rev. Allergy., 1991 ; 9 (3-4): 281-93 Marone G, Stellato C, Mastronardi P, Mazzarella B, Nonspecific histaminereleasing properties of general anesthetic drugs, Clin. Rev. Allergy, 1991 ; 9 (3-4): 269-80 Leynadier F, Sansarricq M, Didier J.M, Dry J, Prick-tests in the diagnosis of anaphylaxis to general anaesthetics, Br. J. Anaesth., 1987 ; 59: 683-9
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BENZODIAZEPINES
DIAZEPAM
Leading benzodiazepine, widely used against seizures and as a muscle relaxant.
INCIDENCE
Low in France but one injection out of 1000 when cremophor E.L. was used as the solvent (not in France). The most common offending molecules are diazepam and flunitrazepam.
General: anaphylactic shock, collapse. Cutaneous: urticaria, angioedema, hives, flush, polymorphous erythema, purpura. Respiratory: dyspnea, bronchospasm. Renal: allergic interstitial nephropathy.
DIAGNOSTIC METHODS
Cutaneous testing Usually negative. In one case prick-test positive with solvent. In one case patch-test positive. Positive reintroduction test (with caution) if necessary.
MECHANISMS
Unknown. Major role of solvents (chromophor E.L., propylene glycol, sodium benzoate).
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Other hypothesis: Immediate IgE-mediated hypersensitivity: Prausnitz-Kustner test positive in one case. The active metabolite common to all benzodiazepines is desmethyldiazepam, which appears to be an antigenic molecule and accounts for cross reactivity among different benzodiazepines. Complement activation. Non-specific histamine release.
MANAGEMENT
Manifestations are usually observed when cremophor E.L. is used as a solvent (not used in France).
REFERENCES
Daumal M, Gillon J.C, Guilbert J.M, Line B, Manoury B, Pila Y, Syndrome de detresse respiratoire aigue aprs choc anaphylactique, (rle du diazpam et de la succinylcholine), Cahiers dAnesthsiologie, 1984 ; 32 (4): 313-5. Huttel M.S, Schou Olesen A, Stoffersen E, Complement-mediated reactions to diazepam with cremophor as solvent (Stesolid M.R.) . Br. J. Anaesth., 1980 ; 52: 77-9
MIDAZOLAM
Midazolam hydrochloride is a short-acting imidazobenzodiazepine used in anesthesiology.
INCIDENCE
Extremely rare.
General: anaphylactic shock. Cutaneous: angioedema, rash. Respiratory: bronchospasm.
DIAGNOSTIC METHODS
None.
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MECHANISMS
Unknown.
MANAGEMENT
Avoidance.
REFERENCES
Fujita Y, Ishikawa H, Yokota K, Anaphylactoid reaction to midazolam , Anesth. Analgesia., 1994 ; 79 (4): 811-2 Yakel D.L Jr, Whittaker S.E, Elstad M.R, Midazolam-induced angioedema and bronchoconstriction, Crit. Care. Res., 1992 ; 20 (2): 307-8
NEUROLEPTICS
DROPERIDOL
Droperidol is a neuroleptic drug (butyrophenone class) frequently used postoperatively as an antiemetic and a sedative.
INCIDENCE
Exceptional.
RISK FACTORS
Phenothiazine hypersensitivity.
General: anaphylactic shock. Cutaneous: angioedema (swollen tongue), erythema of face and torso. Respiratory: bronchospasm.
Diagnostic methods
Cutaneous testing Intradermal skin-tests (1/1000) positive in 2 patients.
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MECHANISMS
IgE-mediated hypersensitivity (positive cutaneous tests, one case with positive Prausnitz-Kustner test). Increase in serum histamine due to inhibition of histamine-Nmethyltransferase.
MANAGEMENT
Avoidance.
REFERENCES
Palombaro J.F, Klingelberger C.E, Angioedema associated with droperidol administration, Ann. Emerg. Med., 1996 ; 27 (3): 379-81 Corke P.J, Murray G, Angio-oedema with droperidol, Anaesth. Intensive. Care., 1993 ; 21 (3): 375 Clark R.J, Tongue-swelling with droperidol, Anaesth. Intesive. Care., 1993 ; 21 (6): 898 Moss J, Verburg K.M, Henry D.P, Droperidol inhibits histamine N-methyl transferase, Anesthesiology, 1985 ; 63: A303. Occelli G, Saban Y, Pruneta R.M, Pourcher N, Michel A.M, Maestracci P, Deux cas danaphylaxie au droperidol , Ann. Fr. Anesth. Reanim, 1984 ; 3 (6): 440-2
PLASMA SUBSTITUTES
DEXTRANS
Dextrans, glucose polymers, are used as plasma expanders, thromboembolic prevention and as distention and irrigating fluids for various endoscopic procedures. They are produced by Leuconostoc mesenteroides.
INCIDENCE
1/2000 grade III /IV without hapten inhibition ; 1/70000 grade III/ IV with hapten inhibition. Deaths reported.
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RISK FACTORS
Atopy (grade I and II reactions). High levels of dextran-reactive antibodies (grade III and IV reactions). Clinical manifestations
GENERAL: ANAPHYLACTIC SHOCK, FEVER.

Cutaneous: general itching, macular rash, urticaria, flushing, angioedema. Respiratory: dyspnea, tightness of chest, wheezing, coughing, pulmonary edema. Other: nausea, vomiting, joint pains, oliguria, convulsions, increased clotting time. Classification of dextran-induced adverse reactions. Grade I: skin manifestations (urticaria, flush, erythema), back pain, mild fever. Grade II: mild to moderate hypotension, gastrointestinal disturbances. Grade III: severe hypotension, shock, bronchospasm. Grade IV: cardiac and/or respiratory arrest. Grade V: death.
DIAGNOSTIC METHODS
Cutaneous testing (usually negative). Dextran reactive antibodies (passive hemagglutination). Dextran specific IgG and IgM (ELISA): the presence of a high level of specific IgG antibodies is a major risk factor.
MECHANISMS
The majority of adverse reactions are mild anaphylactoid, nonimmunogenic reactions. The severe reactions are immunogenic (immune-complex mediated) anaphylactic reactions, caused by naturally occurring IgG class dextran-reactive antibodies . When dextran is infused into a patient with high titer of dextran-reactive antibodies, immunecomplexes are generated and lead to the release of mediators.
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MANAGEMENT
Hapten inhibition. 20 ml of Promit (dextran 1 (15%)) must be injected prior to infusion of clinical dextrans. If more than 15 minutes have passed following the injection before starting the infusion, another dose of dextran 1 should be given. This leads to a 35-fold reduction of severe (grade III/IV/V) reactions to clinical dextran. Concerning preloading in pregnant women prior to epidural analgesia, dextrans should be avoided and replaced by gelatins or crystalloid solutions due to the risk to the fetus of anaphylactic shock in the mother (antidextran IgG cross the placental membrane). 18 neonatal deaths and 7 cases of neurological impairment have been reported in France.
REFERENCES
Hedin H, Ljungstrom K.G, Prevention of dextran anaphylaxis. Ten years experience with hapten dextran, Int. Arch. Allergy. Immunol., 1997 ; 113 (1-3): 358-9 Bircher A.J, Hedin H, Berglund A, Probable grade IV dextran-induced anaphylactic reaction despite hapten inhibition, J. Allergy. Clin. Immunol., 1995 ; 95 (2): 633-4 Huhn A.M, Anaphylactic reactions to high molecular weight dextran during hysteroscopic surgery, C.R.N.A, 1995 ; 6 (4): 167-71 Ljungstrom K.G, Safety of dextran in relation to other colloids-ten years experience with hapten inhibition, Infusionsther. Transfusionsmed., 1993 ; 20: 206-10 Barbier P, Jonville A.P, Autret E, Coureau C, Fetal risks with dextrans during delivery, Drug. Saf., 1992 ; 7 (1): 71-3 Ring J, Anaphylactoid reactions to intravenous solutions used for volume substitution, Clin. Rev. Allergy, 1991 ; 9 (3-4): 397-414
GELATINS
Gelatins are used as plasma expanders in emergency situations. Fluid gelatins are produced by hydrolysis of collagen and chemical modification:
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succinylation (modified fluid gelatin); cross-linking with glyoxal and subsequent degradation by oxidation and heating (oxypolygelatin); cross-linking with hexamethylene diisocyanate (urea linked gelatin).
INCIDENCE
Gelatins linked to urea: 0.146% to 0.852% administrations (0.048% of serious manifestations). Oxypolygelatins: 0.617% of administrations. Modified fluid gelatins: 0.066% to 0.338 % of administrations (0.016% of serious manifestations).
RISK FACTORS
Gelatin allergy (gummy bears, sweets/foods such as liquorice, marshmallows, corned beef, brawn, fruit yogurt, instant whipped cream, instant pudding, juices). Drug allergy. Male gender.
General: anaphylactic shock Cutaneous: urticaria +++. Respiratory: bronchospasm. ENT: sneezing. Classification of allergic reactions: I urticaria, flush. II same + nausea +dyspnea + tachycardia, arterial hypotension. III same + vomiting, diarrhea + bronchospasm + cyanosis + shock IV same + respiratory arrest + cardiac arrest. V death.
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DIAGNOSTIC METHODS
Cutaneous testing Intradermal skin-tests: positive from 1/1000 to 1/10 in a few patients with anaphylactic shock Specific IgE (UniCAP /Pharmacia CAP System). Histamine-release by blood basophils.
MECHANISMS
Direct histamine-release (urea linked gelatins by excess of diisocyanate) IgE-mediated hypersensitivity.
MANAGEMENT
Antihistamines H1 and H2 are useful in prevention of minor cutaneous reactions. Avoidance of gelatins.
REFERENCES
Laxenaire M.C, Charpentier C, Feldman L, Ractions anaphylactodes aux substituts colloidaux du plasma: incidence, facteur de risque, mcanismes. Enqute prospective multicentrique franaise, Ann.Fr.Anesth.Reanim., 1994 ; 13 (3): 301-10 Duffy B.L, Harding J.N, Fuller W.R, Peake S.L, Cardiac arrest following Haemaccel, Anaesth. Intensive. Care., 1994 ; 22 (1): 90-2 Ring J, Anaphylactoid reactions to intravenous solutions used for volume substitution, Clin. Rev. Allergy, 1991 ; 9(3-4): 397-414. Wahl R, Kleinhans D, IgE-mediated allergic reactions to fruit gums and investigation of cross-reactivity between gelatin and modified gelatincontaining products, Clin. Exp. Allergy., 1989 ; 19 (1): 77-80 Vervloet D, Senft M, Dugue P, Arnaud A, Charpin J, Anaphylactic reactions to modified fluid gelatins, J. Allergy. Clin. Immunol, 1983 ; 71: 535-40
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HYDROXYETHYLSTARCH (HES)
Hydroxyethylstarch or hetastarch is a synthetic colloid derived from amylopectin used as plasma substitute. pentastarch (250 000 D) hetastarch (480 000 D)
INCIDENCE
0.058% to 0.085% (grade I to IV) 0.006% (grade III/IV) Pruritus: 10 to 40%
General: anaphylactic shock. Cutaneous: rash, urticaria, pruritus: beginning 1 to 3 weeks after HES infusion ; lasted 6 weeks to 6 months ; related to the type (concentration and molecular weight of HES ) and total infusion dose .
DIAGNOSTIC METHODS
Cutaneous testing Skin prick-tests. Intradermal skin-tests 0.05 ml Hetastarch 1/10 and pure: seldom positive. Anti-HES IgM, IgG, IgA (ELISA) IgM are found 1/1004 in patients following administration of starch with no clinical significance. One patient with high titers of IgG, IgM, IgA, 6 months after anaphylactic shock.
MECHANISMS
Poor histamine-releaser. Complement activation. Non IgE-HES specific antibodies. Pruritus: direct stimulation of cutaneous nerves by HES deposits in macrophages and endothelial cells.
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MANAGEMENT
Avoidance.
REFERENCES
Dieterich H.J, Kraft D, Sirtl C, Laubenthal H, Schimetta W, Polz W, Gerlach E, Peter K, Hydroxyethylstarch antibodies in humans: incidence and clinical relevance, Anesth. Analg., 1998 ; 86 (5): 1123-6 Gall H, Schultz K.D, Boehncke W.H, Kaufmann R, Clinical and pathophysiological aspects of hydroxyethylstarch-induced pruritus: evaluation of 96 cases, Dermatology., 1996 ; 192 (3): 222-6 Cox N.H, Popple A.W, Persistent erythema and pruritus, with a confluent histiocytic skin infiltrate, following the use of a hydroxyethylstarch plasma expander, Br.J.Dermatol., 1996 ; 134 (2): 353-7 Kreimeier U, Christ F, Kraft B, Lauterjung L, Niklas M, Peter K, Messmer K, Anaphylaxis due to hydroxyethylstarch reactive antibodies, Lancet, 1995 ; 346 (8966): 49-50 Laxenaire M.C, Charpentier C, Feldman L, Reactions anaphylactodes aux substituts colloidaux du plasma: incidence, facteurs de risque, mecanismes. Enqute prospective multicentrique franaise, Ann.Fr.Anesth.Reanim., 1994 ; 13 (3): 301-310 Cullen M.J, Singer M, Severe anaphylactoid reaction to hydroxyethylstarch, Anaesthesia, 1990 ; 45 (12): 1041-42
MANNITOL
Mannitol is a hexahydric alcohol closely related to the hexose sugars ; which has been used in a variety of clinical situations for its osmotic diuretic qualities (chemotherapy, cerebral edema).
INCIDENCE
Very low. Fewer than 10 cases reported.
RISK FACTORS
Atopy.
General: anaphylactic shock.
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Cutaneous: urticaria, rash, pruritus, periorbital edema. Respiratory: sneezing, bronchospasm, chest tight-ness.
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests positive at 1/100. No specific IgE. Specific histamine-release (RIA method) positive in a patient with anaphylactic shock.
MECHANISMS
Hyperosmolar solutes are capable of inducing non-cytotoxic basophil histamine release. IgE-mediated hypersensitivity: positive cutaneous tests, specific histamine-release.
MANAGEMENT
Avoidance.
REFERENCES
Schmid P, Wuthrich B, Peranaesthetic anaphylactoid shock due to mannitol, Allergy, 1992 ; 47 (1): 61-2 Ackland S.P, Hillcoat B.L, Immediate hypersensitivity to mannitol: a potential cause of apparent hypersensitivity to cisplatin, Cancer. Treat. Rep., 1985 ; 69 (5): 562-3 Mc Neill I.Y, Hypersensitivity reaction to mannitol, Drug. Intell. Clin. Pharm., 1985 ; 19 (7-8): 552-3 Findlay S.R, Kagey-Sobotka A, Lichtenstein L.M, In vitro basophil histamine-release induced by mannitol in a patient with mannitol-induced anaphylactoid reaction , J. Allergy. Clin. Immunol., 1984 ; 73 (5.1): 578-83 Lamb J.D, Keogh J.A, Anaphylactoid reaction to mannitol, Can. Anaesth. Soc. J., 1979 ; 26 (5): 435-6
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ANALGESICS AND ANTI-INFLAMMATORY DRUGS
II ANALGESICS AND ANTIINFLAMMATORY DRUGS
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ACETAMINOPHEN
Acetaminophen is a widely used analgesic and antipyretic.
INCIDENCE
Uncommon in non-aspirin sensitive patients. Specific acetaminophen allergy is probably exceptional.
Urticaria (61% of reactions), angioedema, maculopapular exanthemas, fixed drug eruption, pigmentary purpura, exfoliative dermatitis, pruritus, acute generalized exanthematous pustulosis. Anaphylactic shock Bronchospasm. Rhinoconjunctivitis.
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests: one positive case reported following generalized urticaria. Patch-tests: paracetamol syrup in pet. (30%) ; paracetamol suppository in pet. (30%), pure paracetamol powder in pet. (30%): positive in 3 patients with delayed manifestations. Specific IgE: one case reported following generalized urticaria. Oral challenge (50 mg, 100 mg, 250 mg, 500 mg, 750 mg) at 30 minute intervals.
MECHANISMS
Acetaminophen possesses a weak cycloxygenase inhibitor action. Aspirin-sensitive patients may react to high doses (> 650 mg) of acetaminophen, which suggests cycloxygenase inhibition. Type I hypersensitivity to paracetamol is rare, but does exist.
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MANAGEMENT
Cross reactivity between acetaminophen and other NSAIDs is conflictual (0 to 34%). Low frequency has been reported when acetaminophen challenge doses of 650 mg or less are administered (0 to 6 %). Avoid high doses of acetaminophen (>1000 mg) in aspirin-sensitive asthmatic patients. Use oral provocation challenge to ascertain that analgesic substitutes are safe . One case of aseptic pustular eruption due to paracetamol with worsening of lesions, (appearance of toxic epidermal necrolysis) and severe hemodynamic disturbances following intravenous use of propacetamol hydrochloride.
REFERENCES
Mendizabal S.L, Diez Gomez M.L, Paracetamol sensitivity without aspirin intolerance, Allergy, 1998 ; 53 (4): 457-8 de Almeida M.A, Gaspar A.P, Carvalho F.S, Nogueira J.M, Pinto J.E, Adverse reactions to acetaminophen, ASA and NSAIDs in children: what alternatives?; Allergy. Asthma. Proc., 1997 ; 18 (5): 313-8 Ownby D.R, Acetaminophen-induced urticaria and tolerance of ibuprofen in an eight year-old child, J. Allergy. Clin. Immunol., 1997 ; 99: 151-2 de Coninck A.L, van Strubarq A.S, Pipeleers-Marichal M.A, Huyghens L.P, Suys E.T, Roseeuw D.I, Acute generalized exanthematous pustulosis induced by paracetamol. A case with severe hemodynamic disturbances , Dermatology., 1996 ; 193 (4): 338-41 Ibanez M.D, Alonso E, Munoz M.C, Martinez E, Laso M.T, Delayed hypersensitivity reaction to paracetamol (acetaminophen), Allergy, 1996 ; 51 (2): 121-3 Schwarz N, Ham Pong A, Acetaminophen anaphylaxis with aspirin and sodium salicylate sensitivity: a case report, Ann. Allergy. Asthma. Immunol., 1996 ; 77: 473-4 Settipane R.A, Schrank P.J, Simon R.A, Mathison D.A, Christiansen S.C, Stevenson D.D, Prevalence of cross sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects, J. Allergy. Clin. Immunol., 1995 ; 96: 480-5 Leung R, Plomley R, Czarny D,Paracetamol anaphylaxis , Clin. Exp. Allergy., 1992 ; 22 (9): 831-3
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ANTHRALINIC ACID DERIVATIVES

Group of NSAIDs including glafenine, antrafenine, floctafenine, and the fenamates (mefenamic acid, flufenamic, etofenamic and meclofenamic acids).
INCIDENCE (CONFLICTUAL)
Glafenine: 1/2000 to 3,4/100 000 courses. 14 cases of allergy requiring hospital admission in the Netherlands in 1981. Antrafenine: 1.3/100 000 treatments. Floctafenine: 0.6/100 000 treatments.
RISK FACTORS
Intolerance to other NSAIDs.
Anaphylactic shock. Urticaria, angioedema. Bronchospasm. Renal failure, hepatitis, blood dyscrasias.
DIAGNOSTIC METHODS
Cutaneous testing. One case of positive intradermal skin test with glafenine 0.1 to 1 mg/ ml and meclofenamate 0.1 to 1 mg/ ml. Leukocyte migration test: positive in 50% of patients with glafenine intolerance. Basophil histamine release: positive in 16% of patients with glafenine intolerance. Double blind placebo-controlled challenge.
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MECHANISMS (UNCERTAIN)
IgE-mediated hypersensitivity: one case reported with positive skin tests in a patient specifically allergic to anthralinic derivatives but tolerating aspirin and other NSAIDs. Intolerance: similar mechanisms to other NSAIDs.
MANAGEMENT
Avoidance of glafenine and related molecules (withdrawn in numerous countries). Ascertain other NSAID tolerance.
REFERENCES
Fernandez-Rivas M, de la Hoz B, Cuevas M, Davila I, Quirce S, Losada E, Hypersensitivity reactions to anthralinic acid derivatives, Ann. Allergy., 1993 ; 71 (6): 515-8 Stricker B.H, de Groot R.R, Wilson J.H, Glafenine-associated anaphylaxi as a cause of hospital admission in the Netherlands, Eur. J. Clin. Pharmacol., 1991 ; 40 (4): 367-71 Stricker B.H, de Groot R.R, Wilson J.H, Anaphylaxis to glafenine (letter), Lancet. 1990 ; 336 (8720): 943-4 Cheymol G, Biour M, Bruneel M, Albengres E, Hamel J.D, Bilan dune enqute nationale prospective sur les effets indsirables de la glafenine, de lantrafenine, et de la floctafenine, Therapie. 1985 ; 40: 45-50
ASPIRIN AND NON STEROID ANTI-INFLAMMATORY DRUGS (NSAIDs)

Aspirin and NSAIDs are widely used drugs in the field of pain and inflammatory disorders.
INCIDENCE
Aspirin induced asthma asthmatic adults: 10%
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Aspirin induced urticaria chronic urticaria: 21 to 30% (mean 23%) rhinitis and asthma: 1.5% normal individuals: 0.3%.
RISK FACTORS
Female gender (urticaria). HLA DQW2 (controversial), decrease of incidence of DPB1 0401 in both aspirin-tolerant and aspirin-sensitive asthmatics. Atopy (localized periorbital edema).
General: anaphylactoid reaction, (zomepirac, tolmetine, diclofenac). Rhinoconjunctivitis/asthma: chronic eosinophilic rhinosinusitis with or without nasal polyps and secondary purulent infection of the paranasal sinuses ; then asthma, usually severe and corticodependant. Classic triad: rhinitis with nasal polyps, asthma and ASA sensitivity. Cutaneous: chronic urticaria (in free patients and in patients with chronic urticaria), angioedema, isolated periorbital edema (younger subjects; atopy, intolerance to multiple NSAIDs not structurally related), Lyells syndrome (fenbrufen, indomethacin, piroxicam), purpura (phenylbutazone, salicylate, derivatives), photodermatitis (naproxen, piroxicam, tiaprofenic acid, benoxaprofen). Haematological: eosinophilia, cytopenia. Respiratory: hypersensitivity, pneumonitis (fever, cough, pulmonary infiltrates): most reactions occur in patients with inflammatory arthritis. Drugs involved: naproxen, sulindac, ibuprofen, azapropazone, indomethacin, piroxicam, phenylbutazone, oxyphenylbutazone, diclofenac. New triad: atopy, NSAIDs sensitivity and oral anaphylaxis from aeroallergens (mites).
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DIAGNOSTIC METHODS
Cutaneous testing. Usually ineffective and negative ; one case of positive cutaneous test with aspirin polylysine 2 mg/ ml in a patient with urticaria. Specific IgE (controversial). IgE antibodies against platelet antigens. Specific antibodies to salicyloyl and O-methylsalicyloyl (RASTRAST inhibition). Controlled oral challenges: gold standard in the diagnostic of NSAID hypersensitivity. Urticaria (aspirin). Day 1: placebo. Day 2: 100 mg , 200 mg. Day 3: 325 mg , 650 mg Urticarial responses are measured by skin scores recorded every 2 hours. Rhinosinusitis/asthma. Oral challenge (single blind or double blind) Day 1 Day 2 Day 3 8 H00 AM 11H00 AM 2H00 PM placebo placebo placebo ASA 3 or 30 mg ASA 60 mg ASA 100 mg 150 mg 325 mg 650 mg
Classical response (86%): FEV1 decrease > 20% + naso-ocular reaction. Asthma only: FEV1 decrease > or = 20% Rhinitis: naso-ocular reaction only. Mild asthma: FEV1 decrease 15 to 20% combined with naso-ocular reaction. No reaction. Bronchial inhalation challenge with Lysine-ASA. Lysine-acetylsalicylate conjugate, available as a powder, soluble in water (ASA-Lysine: 11.25 mg, 22.5 mg, 45 mg , 90 mg, 180 mg, 360 mg). No severe bronchoconstriction. Easier to perform .
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Other drugs (single-blind, placebo-controlled drug challenge). Paracetamol 100 mg, 250 mg, 500 mg, at 60 minute intervals. Isonixin 100 mg, 400 mg, at 60 minute intervals. Salsalate 500 mg, 1000 m at 60 minute intervals. Diflunisal 100 mg, 500 mg, at 60 minute intervals. Mefenamic acid 50 mg, 125 mg, 250 mg at 60 minute intervals. Clonixin 50 mg, 125 mg at 60 minute intervals. Diclofenac 25 mg, 50 mg at 120 minute intervals. Piroxicam 10 mg, 20 mg at 120 minute intervals. Ketoprofen 10 mg, 25 mg, 50 mg at 120 minute intervals.
MECHANISMS
Leukotriene C4, histamine and tryptase are released from cells in ASA-sensitive asthmatics following ASA challenge. Leukotriene over-production is related to marked eosinophilic infiltration of the mucosa. Administration of aspirin shifts the metabolism of arachidonic acid towards the 5-lipooxygenase pathway with synthesis of leukotriene sulfidopeptides (LTC4, LTD4, LTE4) which are potent bronchoconstrictors. Metabolites of arachidonic acid (LTC4, LTD4, LTE4) may be detected in urine and bronchial and nasal fluid following aspirin challenge. Platelets have been implicated in the pathogenesis of asthma intolerance, since they release free radicals of O2 and cytocidal mediators in response to NSAIDs. Platelets from ASA-sensitive patients become cytotoxic in the presence of ASA. Studies performed in patients suffering from asthma due to aspirin intolerance have demonstrated higher levels of IL5, an elevated count of eosinophils, and higher levels of ECP compared to aspirintolerant asthmatic patients. Sensitivity to aspirin-like drugs in ASA-sensitive patients. prostaglandin synthetase inhibitors: indomethacin 100%, fenoprofen 100%, naproxen 100%, zomepirac 80 to 100%, ibuprofen 97%, mefenamic acid 60%, phenylbutazone 42%
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no prostaglandin synthetase inhibitors: sodium salicylate < 1%, choline salicylate < 1%, salicylate < 1%, propoxyphene < 1%
MANAGEMENT
URTICARIA. Avoidance of ASA/NSAIDs. Long-term desensitization does not appear feasible for patients with ASA/NSAIDs-induced urticaria. Hypersensitivity pneumonitis. Avoidance. Use of systemic corticosteroids. RHINOSINUSITIS/ASTHMA. Avoidance of all NSAIDs. Asthmatics with normal sinus X-rays or CT scans of the sinuses. and asthmatics with clear evidence of IgE-mediated allergy are at low risk of ASA sensitivity. Desensitization. ASA desensitization may be considered in patients with: uncontrolled respiratory inflammation despite appropriate treatment (local and systemic corticosteroids). patients requiring frequent sinus surgery. patients with arthritis or recurrent arterial thromboembolic diseases. Aspirin desensitization is accompanied by a reduced aspirininduced production of sulfido peptide leukotrienes (LTE4). Do not administer topical ophtalmic ketorolac, flurbiprofen, suprofen, and diclofenac in asthmatic patients with ASA sensitivity due to the risk of bronchospasm. Nimesulide (4 nitro-2 phenoxymethane-sulfon-anilide) is an NSAID-inhibiting cox2 and is well-tolerated in 90 to 100% of asthmatics and 92.8 to 98% of NSAID-intolerant patients. Imidazole salicylate, a new NSAID, which inhibits Tx A2 synthesis without interfering with cyclooxygenase pathway, is safe in ASA-intolerant patients.
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REFERENCES
Szczeklik A, Dworski R, Mastalerz L, Prokop A, Sheller J.R, Nizankowska E, Cmiel A, Oates J.A, Salmeterol prevents aspirin-induced attacks of asthma and interferes with eicosanod metabolism, Am. J. Respir. Crit. Care. Med, 1998 ; 158: 1168-72 Zhu D.X, Zhao J.L, Mo L, Li H.T, Drug allergy: identification and characterization of IgE-reactivities to aspirin and related compounds, J. Invest. Allergol. Clin. Immunol., 1997 ; 7 (3): 160-8 Quiralte J, Blanco C, Castillo R, Delgado J, Carrillo T, Intolerance to non steroidal inflammatory drugs: results of controlled drug challenges in 98 patients, J. Allergy. Clin. Immunol., 1996 ; 98 (3): 678-85 Nasser S.M, Pfister R, Christie P.E, Sousa A.R, Barker J, Schmitz-Schumann M, Lee P.H, Inflammatory cell populations in bronchial biopsies from aspirin-sensitive asthmatic subjects, Am. J. Respir. Crit. Care. Med, 1996 ; 153 (1): 90-6 Bochenek G, Nizankowska E, Szczeklik A, The atopy trait in hypersensitivity to non steroidal anti-inflammatory drugs, Allergy, 1996 ; 51: 16-23 Nasser S.M, Patel M, Bell G.S, Lee T.H, The effect of aspirin desensitization on urinary leukotriene E4 concentrations in aspirin-sensitive asthma, Am. J. Respir. Crit. Care. Med, 1995 ; 151 (5): 1326-30 Lee T.H, Mechanism of aspirin sensitivity, Am. Rev. Respir. Dis., 1992 ; 145 (2.2): S34-6 Stevenson D.D, Simon R.A, Sensitivity to aspirin and non steroidal antiinflammatory drugs, In. Allergy. (Middleton E.R, Reed C.E, eds) page 174765. St Louis CV Mosby 1992
PROPACETAMOL
Propacetamol (N,N-diethyl glycidyl ester of acetaminophen) is a soluble bioprecursor of acetaminophen. It is composed of an acetaminophen molecule coupled to a vector: diethylglycine. A very effective and well tolerated analgesic, it is a prodrug widely used for its analgesic and antipyretic properties. Following intravenous injection, propacetamol is readily hydrolized into acetaminophen 2 and N,N-diethylglycine 3).
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INCIDENCE
Several cases of occupational contact dermatitis have been reported in nurses handling propacetamol .
RISK FACTORS
Nurses frequently handling propacetamol (surgery, intensive care units, oncology).
Chronic eczema with vesiculous flares on the back of the hands sometimes extending to wrists, forearms, and occasionally on the face.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests with propacetamol are positive ; but negative with solvent, acetaminophen and diethylglycine.
MECHANISMS
Patch-tests with N,N-diethylglycine phenyl ester (activated form of N,N- diethylglycine) in 10% pet. are positive in patients with contact dermatitis to propacetamol. This strongly suggests that propacetamol acts as an activated form of N,N-diethylglycine, transferring this part of the molecule to nucleophilic residues of proteins. So acetaminophen allergy has never been observed in propacetamol-allergic patients.
MANAGEMENT
The wearing of gloves for preparing propacetamol is mandatory, especially in cases where allergic history enhances the risk of occupational sensitization.
REFERENCES
Berl V, Barbaud A, Lepoitevin J.P, Mechanism of allergic contact dermatitis from propacetamol: sensitization to activated N,N-diethylglycine , Contact Dermatitis, 1998 ; 38: 185-8 Barbaud A, Trechot P, Bertrand O, Schmutz J.L, Occupational allergy to propacetamol, Lancet; 1995 ; 346: 902
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PYRAZOLINE DRUGS OR PYRAZOLONES

Clinical use of this family of analgesics was sharply curtailed due to its potentially fatal bone marrow toxicity (agranulocytosis). Metamizol. Propylphenazone. Amidophenazone. Phenazone.
INCIDENCE
Metamizol: from 0.13% to 2.4% of cutaneous reactions.
Anaphylactic shock. Urticaria, angioedema (allergy). Allergic vasculitis . Fixed drug eruption. Erythema multiforme. Toxic epidermal necrolysis . Maculopapular eruption. Allergy contact dermatitis. Bronchospasm (intolerance).
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests: positive at 0.001 to 0.01% in most patients with allergic symptoms (anaphylactic shock, urticaria). Specific IgE (RAST) for 1 - phenyl - 2.3 - dimethyl - 3 - pyrazoline - 5 - one found in 17/19 pyrazolone sensitive patients. Oral challenge. Contraindicated if anaphylactic shock. Sometimes useful in patients with asthma or urticaria.
MECHANISMS
IgE-mediated hypersensitivity: positive skin tests + specific IgE ; especially in patients with anaphylactic shock or urticaria. Intolerance: similar mechanisms to other NSAIDs.
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MANAGEMENT
In patients with specific pyrazolone allergy, ascertain safe other NSAIDs. Avoid all NSAIDs in cases of intolerance.
REFERENCES
Zhu D, Becker W.M, Schulz K.H, Schubeler K, Schlaak M, Detection of IgE antibodies specific for 1 - phenyl - 2,3 - dimethyl - 3 - pyrazoline - 5 - one by RAST*: a serological diagnostic method for sensitivity to pyrazoline drugs, Asian. Pac. J. Allergy. Immunol., 1992 ; 10 (2): 95-101 Voigtlander V, Adverse dermatological reaction to pyrazolones , Agents. Actions. Suppl., 1986 ; 19: 303-11 Szczeklik A, Analgesics, allergy and asthma , Drugs. 1986 ; 32 (s4): 14863
TOPICAL NON STEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDs)

Widely used in the treatment of various eczemas.
INCIDENCE
Difficult to evaluate. French contact dermatitis group (GERDA) recently reported 62 observations. The first national pharmacovigilance inquiry (1993-95) in France reported 260 cases of local intolerance to topical NSAIDs among 11 million units sold.
RISK FACTORS
Sun exposure. Summertime. Arylpropionic derivatives (ketoprofen).
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Contact dermatitis, photocontact dermatitis, contact erythema multiforme. The mean duration of application is 13 days ; eruption may be prolonged (mean duration 25 days) with frequent regional or generalized extension. Oral administration of NSAIDs following cutaneous sensitization may lead to severe generalized eruption.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests and photopatch-tests (UVA, UVB and total light). Oral challenge may be dangerous and should be avoided.
MECHANISMS
Delayed contact hypersensitivity and virtual photocontact sensitivity (preponderance of UVA). Cross-sensitivity exists between NSAIDs of the same family. Photo allergy is due to the benzophenone moiety of ketoprofen, or thiophene-phenylketone moiety of tiaprofenic acid but not to the arylpropionic function.
MANAGEMENT
Avoidance of causative family Use of NSAIDs of other families if mandatory. If there is photosensitivity to ketoprofen or tiaprofenic acid, avoid fenofibrate and benzophenones. Alminoprofen, fenoprofen, flurbiprofen, ibuprofen or naproxen may be tolerated in such cases.
REFERENCES
le Coz C.J, Bottlaender A, Scrivener J.N, Santinelli F, Cribier B.J, Heid E, Grosshans E, Photocontact dermatitis from ketoprofen and tiaprofenic acid: cross-reactivity study in 12 consecutive patients, Contact Dermatitis, 1998 ; 38: 245-52
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Bastien M, Milpied-Homsi B, Baudot S, Dutartre H, Litoux P, Photosensibilisation de contact au ketoprofene. 5 observations. , Ann. Derm. Venereol., 1997 ; 124: 523-6 Milpied B, Rseau Revidal et AINS topiques: un an dexprience, La lettre du GERDA, 1997 ; 14: 50-4
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ANTIBIOTICS, ANTIVIRAL, ANTIFUNGAL DRUGS
III ANTIBIOTICS, ANTIVIRAL, ANTIFUNGAL DRUGS
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ACYCLOVIR
Acyclovir is a structural analogue of guanosine which inhibits viral DNA-polymerase and is widely used as an antiviral drug in herpes and herpes-zoster infections.
INCIDENCE
Rare.
RISK FACTORS
AIDS. Repeated topical use .
Topical use: contact dermatitis. Systemic administration: generalized eczema, vesicular eruption, phlebitis, urticaria.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests with acyclovir 5% in water or pet. must be read at 30 min, 48 and 72 or 96 hours. Some cases of sensitization are due to vehicle constituents (propylene glycol).
MECHANISMS
Delayed contact dermatitis.
MANAGEMENT
Avoidance of acyclovir (topical and systemic) and valacyclovir.
REFERENCES
Montoro J, Basomba A, Fixed drug eruption due to acyclovir, Contact Dermatitis, 1997 ; 36: 225-31 Goday J, Aguirre A, Gil-Ibarra N, Ezaguirre X, Allergic contact dermatitis from acyclovir, Contact Dermatitis, 1991 ; 24: 380-1
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ALLYLAMINES
New class of antifungal agents (terbinafine).
INCIDENCE
Severe cutaneous side-effects: 1/100000.
Rashes, urticaria, erythema multiforme (2 to 5 weeks after starting treatment), Stevens-Johnsons syndrome and toxic epidermal necrolysis (5 to 8 days after the first intake). All cases were regressive within 4 to 18 days after stopping terbinafine.
DIAGNOSTIC METHODS
Patch-tests with 1% terbinafine are negative in Lyells syndrome.
MECHANISMS
Unknown.
MANAGEMENT
Avoidance.
REFERENCES
Mc Gregor J.M, Rustin M.H.A, Terbinafine and erythema multiforme, Br.J.Dermatol., 1994 ; 131: 587-8 Carstens J, Wendelboe P, Sogaard H, Thestrup-Pedersen K, Toxic epidermal necrolysis and erythema multiforme following therapy with terbinafine, Acta. Derm. Venereol., 1994 ; 74: 391-2
AMINOGLYCOSIDES
Aminoglycosides are broad-based heterosides with a broadspectrum antibiotic action.
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Streptidine group. Streptomycin, dihydrostreptomycin, hydroxystreptomycin, manosidostreptomycin. Desoxystreptamine group. 1,3 substitution (trisaccharide): kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin. 1,2 substitution (tetrasaccharide): paramomycin, neomycin.
INCIDENCE
High for neomycin and streptomycin: >2% of treatments. Occasional for gentamicin and amikacin: 0.1 to 2% of treatments. Uncommon for kanamycin: 0.1 to 0.5% of treatments.
General: anaphylactic shock uncommon, fever (11% with longterm streptomycin), serum sickness. Cutaneous: urticaria, rash (11% with streptomycin; 0.8% with gentamicin; 0.6% with tobramycin), contact dermatitis (3 to 10% with streptomycin), exfoliative dermatitis. Haematological: eosinophilia, immunological blood dyscrasia.
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests: one case positive with systemic reaction in a patient with anaphylactic shock following topical use of framycetin (framycetin sulfate 10 mg/ ml). Patch-tests: * positive in 12% of patients treated with streptomycin. * positive in patients presenting contact dermatitis, rash, fever. * positive with neomycin in 10 to 35% of patients with leg ulcers. The presence of antibodies against specific aminosides has rarely been demonstrated. antistreptomycin IgG antibodies in association with hemolytic anemia (direct and indirect Coombs); antierythrocyte antibodies (neomycin, gentamicin, kanamycin).
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MECHANISMS
IgE-mediated hypersensitivity (rare). Cell-mediated delayed hypersensitivity for contact dermatitis (neomycin) ; neomycin is the antibiotic with the highest contact sensitizing power. Sensitization tends to occur on altered skin (leg ulcers) and with long-term application.
MANAGEMENT
Avoid use of offending antibiotics for leg ulcers. The use of neomycin should be avoided in dermatology. Cross sensitivity between aminosides has been documented (neomycin-framycetin: 93% ; neomycin-ribostamycin 73% ; neomycin-kanamycin 60% ; neomycin-gentamycin 46% ; neomycin-tobramycin 40%).
REFERENCES
Assier-Bonnet H, Revuz J, La nomycine topique, risques et bnfices. Plaidoyer pour un retrait , Ann. Dermatol. Venereol., 1997 ; 124: 721-5 Proebstle T.M, Jugert F.K, Merk H.F, Gall N, Severe anaphylactic reaction to topical administration of framycetin, J. Allergy. Clin. Immunol., 1995 ; 96 (3): 429-30 Samsoen M, Metz R, Melchior E, Foussereau J, Allergie croise entre les antibiotiques aminosides, Ann. Dermatol. Venereol., 1979 ; 106 (8-9): 683-9 Chung C.W, Carson T.R, Cross sensitivity of common aminoglycoside antibiotics, Arch. Dermatol., 1976 ; 112: 1101-7. Rippen R.P, Anaphylactic reaction after Chymacort ointment. Br. Med. J., 1966 ; 1: 1172.
STREPTOMYCIN
Streptomycin is a chemical complex substance, being composed of a central hexose (streptidine) linked to an amine-substituted disaccharide. Widely used in the past (tuberculosis), its use has declined drastically but is now routinely added to cell culture media (PHA-LAK) and to Hams F-10 medium, which is used for in vitro fertilization.
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INCIDENCE
High in the past (> 2% of treatments).
General: anaphylactic shock, fever, serum sickness. Cutaneous: urticaria, rash, contact dermatitis, exfoliative dermatitis. Haematological: eosinophilia, haemolytic anemia.
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests (1 to 10 mg/ ml). Intradermal skin-tests (1 mg/ ml). Patch-tests with streptomycin in 2% pet. positive in patients with contact dermatitis. Specific IgE (RAST, ELISA) few cases with positive results Histamine-release test: one case with dose-dependent release following stimulation with streptomycin (1 ; 0.1 ; 0.01 g/ml). Drug re-challenge.
MECHANISMS
High molecular mass impurities (streptomycin polymers) related to some reactions aminogroups of streptomycin are the allergens involved in immediate-type allergies.
MANAGEMENT
Desensitization (3 hours) beginning with 1 mg intravenously.
REFERENCES
Perez R, Garces M, Marcos M, Alonso L, Carretero P, Juste S, Blanco J, Navarro J, Anaphylaxis induced by streptomycin in cell media, Allergy, 1996 ; 51 (2): 135-6 Gauchia R, Rodriguez-Serna M, Silvestre J.F, Linana J.J, Ahaga A, Allergic contact dermatitis from streptomycin in a cattle breed, Contact. Dermatitis, 1996 ; 35 (6): 374-5
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Abeck D, Kuwert C, Segnini-Torres M, Przybilla B, Ring J, Streptomycininduced anaphylactic reaction during in vitro fertilization (IVF), Allergy., 1994 ; 49 (5): 388-9 Tinkelman D.G, Bock S.A, Anaphylaxis presumed to be caused by beef containing streptomycin, Ann. Allergy., 1984 ; 53 (3): 243-4
AMPHOTERICIN B
Liposomal preparations of amphotericin B have the advantage of lower toxicity compared with conventional preparations. Ambisome has proved effective in the treatment of fungal infections including candida, aspergillus and cryptococcus.
INCIDENCE
3/187 in transplant recipients. One case of fatal cardiac arrest.
RISK FACTORS
AIDS.
Anaphylactic shock, fever. Bronchospasm. Rash, erythema, edema.
DIAGNOSTIC METHODS
None.
MECHANISMS
Unknown. The lipid content of the drug is suspected to be the culprit.
MANAGEMENT
Anaphylaxis to ambisome does not preclude subsequent use of amphotericin B, which is well tolerated.
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REFERENCES
Torre I, Lopez-Herce J, Vazquez P, Anaphylactic reaction to liposomal amphotericin B in children (letter), Ann. Pharmacother., 1996 ; 30 (9): 10367 Ringden O, Andstrm E, Remberger M, Svahn B.M, Tollemar J, Allergic reactions and other rare side effects of liposomal amphotericin, Lancet, 1994 ; 344 (8930): 1156-7 Laing R.D.S, Milne L.J.R, Leen C.L.S, Malcolm G.P, Steers A.J.W, Anaphylactic reactions to liposomal amphotericin, Lancet. , 1994 ; 344 (8923): 682 Tollemar J, Ringden O, Andersson S, Sundberg B, Ljungman P, Tyden G, A randomized double-blind study of AmBisome (liposomal amphotericin B) in prophylaxis of invasive fungal infections in bone marrow transplant recipients, Bone Marrow Transplant., 1993 ; 12: 577-81
AZOLE DERIVATIVES
FLUCONAZOLE
Fluconazole is a triazole antifungal agent used in the treatment of infections of the nails, skin, oral and vaginal mucosa ; systemic candidiasis, cryptococcal meningitis and as prophylaxis for cryptococcal infections in HIV patients.
INCIDENCE
Probably very low.
Anaphylactic shock. Rashes, maculopapular eruptions, fixed drug eruptions, angioedema, toxic epidermal necrolysis, Stevens-Johnsons syndrome.
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DIAGNOSTIC METHODS
Cutaneous testing . One case with positive skin-prick tests 1/10.
MECHANISMS
Unknown.
MANAGEMENT
Cross-reactivity with other azole derivatives is likely. Desensitization (orally): 0.2 mg to 400 mg in 15 days.
REFERENCES
Craig T.J, Peralta F, Boggavarapu J, Desensitization for fluconazole hypersensitivity, J. Allergy. Clin. Immunol, 1996 ; 98 (4): 845-6 Neuhaus G, Pavic N, Pletscher M, Anaphylactic reaction after oral fluconazole, B.M.J, 1991 ; 302 (6788): 1341
ITRACONAZOLE
Triazole antifungal agent used for treatment of histoplasmosis, coccidiodomycosis, paracoccidiodomycosis, sporotrichosis, candidosis and aspergillosis.
INCIDENCE
Probably low.
Erythematous rash. Maculopapular rash.
DIAGNOSTIC METHODS
Skin-prick tests: negative. Drug re-challenge.
MECHANISMS
Unknown.
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MANAGEMENT
Desensitization. 1 mg to 200 mg over 4 hours.
REFERENCES
Douglas R, Spelman D, Czarny D, OHehir R, Desensitization to itraconazole (letter, comment), J. Allergy. Clin. Immunol., 1997 ; 99 (2): 269 Bittleman D.B, Stapleton J, Casale T.B, Report of successful desensitization to itraconazole (see comments), J. Allergy. Clin. Immunol, 1994 ; 94 (2.1): 270-1
KETOCONAZOLE
Ketoconazole is a synthetic imidazole-derivative antifungal agent used in the treatment of systemic and subcutaneous mycosis; also effective in the treatment of dermatophytosis and superficial mycosis.
INCIDENCE
Very low (4 cases published).
Anaphylactic shock. Pruritus, rash, urticaria, facial angioedema.
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests with 1, 10, 20, 40 mg/ ml positive with a concentration of 10 mg/ ml in a patient with allergic reaction to ketoconazole. No specific IgE found. Histamine release test was positive in the same patient. Oral challenge: 25 mg, 50 mg, 100 mg, 200 mg positive in the same patient following a cumulative dose of 75 mg.
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MECHANISMS
IgE-mediated hypersensitivity is likely. Cross-reactivity with other azole derivatives is possible, but not demonstrated .
MANAGEMENT
Avoidance.
REFERENCES
Beal M, Bernard C, Zenut M, Simmonnet F, Lavarenne J, Boch C, Reaction anaphylactique au ketoconazole, Therapie., 1996 ; 51 (5): 604-5 Gonzalez-Delgado P, Florido-Lopez F, Saenz de San Pedro B, Cuevas-Agusti M, Marin-Pozo J.F,Hypersensitivity to ketoconazole, Ann. Allergy., 1994 ; 73 (4): 326-8
METRONIDAZOLE
Nitroimidazole derivative used for the treatment of anaerobic infections and trichomonas infections.
INCIDENCE
Uncommon.
Fever, serum sickness. Bronchospasm. Urticaria, maculopapular rash, fixed drug eruption, pustulosis.
DIAGNOSTIC METHODS
1.5 mg of 0.75% metronidazole vaginal gel applied to the vaginal mucosa induced wheals of 6 x 6 mm in one patient and 2.5 x 5 mm in another with severe allergic reactions to metronidazole.
MECHANISMS
IgE-mediated hypersensitivity is likely in some cases.
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MANAGEMENT
Cross-reactivity between metronidazole and tinidazole (fixed drug eruption). Desensitization. Two different protocols have been published: 0.0025 mg to 1 000 mg in 8 steps (orally) 5 g to 125 mg intravenously (3h40), then 250 mg, 500 mg, 2 g orally (3 h).
REFERENCES
Pearlman M.D, Yashar C, Ernst S, Solomon W, An incremental dosing protocol for women with severe vaginal trichomoniasis and adverse reactions to metronidazole, Am. J. Obstet. Gynecol., 1996 ; 174 (3): 934-6 Knowles S, Chhoudhury T, Shear N.H, Medronidazole hypersensitivity, Ann. Pharmacother., 1994 ; 28 (3): 325-6 Kurohara M.L, Kwong F.K, Lebherz T.B, Klaustermeyer W.B, Metronidazole hypersensitivity and oral desensitization, J. Allergy Clin. Immunol., 1991 ; 88 (2): 279-80
BACITRACIN
Antibiotic polypeptide complex produced by Bacillus subtilis widely used as topical antibacterial medication.
INCIDENCE
Immediate allergy is infrequent (10 cases reported) Contact dermatitis is common.
RISK FACTORS
Compromised skin barrier (leg ulcers, excoriated dermatitis, burns). Clinical manifestations Usually severe: anaphylactic shock with hypotension (80%) pruritus, flush, swelling of the tongue and face urticaria Contact dermatitis.
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DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests positive in a few cases of anaphylaxis (intradermal skin-tests may be dangerous). Positive patch-tests in contact dermatitis.
MECHANISMS
Strong evidence of IgE-mediated hypersensitivity including positive immediate skin tests, positive Prausnitz-Kstner tests, although IgE antibodies have not been disclosed by other methods.
MANAGEMENT
Avoidance.
REFERENCES
Lin F.L, Woodmansee D, Patterson R, Near-fatal anaphylaxis to topical bacitracin ointment, J. Allergy. Clin. Immunol, 1998 ; 101 (1.1): 136-7 Dyck E.D, Vadas P, Anaphylaxis to topical bacitracin, Allergy., 1997 ; 52: 870-1 Knowles S.R, Shear N.H, Anaphylaxis from bacitracin and polymyxin B (polysporin) ointment, Int. J. Dermatol., 1995 ; 34 (8): 572-3 Eedy D.J, Mc Millan J.C, Bingham E.A, Anaphylactic reactions to topical antibiotic combinations, Postgrad. Med. J., 1990 ; 66 (780): 858-9 Sprung J, Schedewie H.K, Campine J.P, Intraoperative anaphylactic shock after bacitracin irrigation, Anesth. Analg., 1990 ; 71 (4): 430-3
CHLORAMPHENICOL
Antibiotic produced by Streptomyces venezuelae. It comprises a nitrobenzene ring linked to propanol, with an amide group binding to a derivative of dichloroacetamide acid.
INCIDENCE
Uncommon.
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RISK FACTORS
Allergy to penicillin. Severe infection. Previous exposure to phenicols.
Topical use of chloramphenicol may lead to: contact dermatitis, anaphylactic shock, aplastic anemia. General: anaphylactic shock, fever. Respiratory: bronchospasm. Cutaneous: urticaria, maculopapular rash, angioedema, contact dermatitis. Haematological: aplastic anemia.
DIAGNOSTIC METHODS
Cutaneous testing. Positive scratch and patch test reported in some cases involving cutaneous manifestations (patch-tests with chloramphenicol 1% in pet). Antibodies against chloramphenicol have been found, with no obvious clinical manifestation.
MECHANISMS
Unknown. The dichloroacetamide ring is probably the major antigenic determinant.
MANAGEMENT
Avoidance. Cross-sensitivity between chloramphenicol and synthetic derivatives is likely.
REFERENCES
Le Coz C.J, Santinelli F, Facial contact dermatitis from chloramphenicol with cross-sensitivity to thiamphenicol, Contact. Dermatitis., 1998 ; 38: 108-9
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Moyano J.C, Alvarez M, Fonseca J.L, Bellido J, Munoz-Bellido F.J, Allergic contact dermatitis to chloramphenicol, Allergy., 1996 ; 51 (1): 67-9 Mc Ghee C.N.J, Anastas C.M, Widespread ocular use of topical chloramphenicol: is there justifiable concern regarding idiosyncratic aplastic anaemia?, Br. J. Ophtalmol., 1996 ; 80 (2): 182-4 Liphshitz I, Loewenstein A, Anaphylactic reaction following application of chloramphenicol eye ointment, Br. J. Ophtalmol., 1991 ; 75 (1): 64 Schewach-Millet M, Shapiro D, Urticaria and angioedema due to topically applied chloramphenicol ointment, Arch. Dermatol., 1985 ; 121: 587. Palchick B.A, Funk E.A, Mc Entire J.E, Hamory B.H, Anaphylaxis due to chloramphenicol, Am. J. Med. Sci., 1984 ; 288 (1): 435.
CLINDAMYCIN
Clindamycin is a semi-synthetic derivative of lincomycin active against most gram-positive and anaerobic bacteria. Clindamycin together with pyrimethamine has been used as alternative treatment for toxoplasmic encephalitis in AIDS patients.
INCIDENCE
Up to 10% of patients treated develop rashes at the end of the first week, or during the second week of therapy. 58% of patients treated with pyrimethamine/clindamycin have cutaneous reactions after an averageof 13 days.
General: anaphylactic shock. Respiratory: bronchospasm. Cutaneous: contact dermatitis (very rare), pruritus, maculopapular eruptions, lip or palpebral edema, Stevens-Johnson syndrome, leukocytoclastic angeitis.
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests (150 mg/ ml): negative.
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Intradermal skin-tests: negative. Patch-tests (clindamycin phosphate 1% pet. or aq.): positive in patients with contact dermatitis. No specific IgE found. Detection of hemagglutinating antibodies which specificity has been confirmed by inhibition of hemagglutination.
MECHANISMS
Residual impurities from the manufacturing process.
MANAGEMENT
Desensitization (orally, in AIDS patients with toxoplasmic encephalitis). Day 1: 20 mg, 20 mg, 20 mg Day 2: 40 mg, 40 mg, 40 mg Day 3: 80 mg, 80 mg; 80 mg Day 4: 150 mg, 150 mg, 150 mg Day 5: 300 mg, 300 mg, 300 mg Day 6: 600 mg, 600 mg, 600 mg Day 7: 600 mg, 600 mg, 600 mg, 600 mg Discontinuation of the treatment 9% to 14% due to adverse effects.
REFERENCES
Garcia R, Galindo P.A, Feo F, Gomez E, Fernandez F, Delayed allergic reactions to amoxycillin and clindamycin, Contact. Dermatitis, 1996 ; 35 (2): 116-7 Caumes E, Bocquet H, Guermonprez G, Rogeaux O, Bricaire F, Katlama C, Gentilini M, Adverse cutaneous reactions to pyrimethamine/sulfadiazine and pyrimethamine/clindamycin in patients with AIDS and toxoplasmic encephalitis, Clin. Infect. Dis., 1995 ; 21 (3): 656-8 Marcos C, Sopena B, Luna I, Gonzalez R, de la Fuente J, Martinez-Vazquez C, Clindamycin desensitization in an AIDS patient, AIDS, 1995 ; 9 (10): 1201-2 Vidal C, Iglesias A, Saez A, Rodriguez M, Hypersensitivity to clindamycin, D. I. C. P, 1991 ; 25 (3): 317
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DAPSONE
Diaminodiphenylsulfone is traditionally used in the treatment of leprosy and dermatitis herpetiformis; it is also part of the treatment for Pneumocystis carinii pneumonitis in HIV patients.
INCIDENCE
Unknown, probably low (0.3%). Mortality: 11%. 1949: 2% of patients treated with dapsone for leprosy. 21 cases of sulfone syndrome due to dapsone reported up to 1994.
RISK FACTORS
HIV patients. High doses.
Dapsone hypersensitivity syndrome (occurring 2 - 8 weeks of starting therapy): fever, arthralgias, rash (erythema, maculopapular eruption, exfoliative dermatitis), haemolytic anemia, lymphocytosis, hepatitis, lymphadenopathy, hepatosplenomegaly, eosinophilia. Usual dose 50 to 300 mg/day: 85% rash, 40% haemolytic anemia.
DIAGNOSTIC METHODS
Low complement levels.
MECHANISMS
Hypersensitivity to dapsone may be caused by metabolites of dapsone-forming haptens, with formation of antidapsone antibodies. Dapsone is metabolized primarily via two pathways: N-acetylation and N-hydroxylation (oxidation). N-acetylation is mediated by Nacetyltranferase type 2 showing a bimodal pattern of activity; slow and fast acetylation. Dapsone N-hydroxylation is mediated by human lever microsomal enzymes P4503A4, 2C6 and 2C11. This
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pathway is thought to be the initial step in the formation of toxic intermediate metabolites (nitrosamines) that can induce haemolytic anemia.
MANAGEMENT
Use 50 mg/day in adults, 25 mg/day in children. Corticosteroids (no controlled study). On withdrawing dapsone, patients usually recover within 2-8 weeks. For the treatment of leprosy, replace with clofazimine (50 mg/day). For the treatment of dermatitis herpetiformis, replace with another sulfonamide (sulfapyridine).
REFERENCES
Mc Kenna K.E, Robinson J, The dapsone hypersensitivity syndrome occurring in a patient with dermatitis herpetiformis , Br.J.Dermatol., 1997 ; 137 (4): 657-8 Prussick R, Shear N.H, Dapsone hypersensitivity syndrome, J. Am. Acad. Dermatol., 1996 ; 35 (2.2): 346-9 Bocquet H, Bourgault-Villada I, Delfau-Larue M.H, Wechsler J, Revuz J, Roujeau J.C, Syndrome dhypersensibilit la dapsone. Clone T circulant transitoire, Ann. Dermatol. Venereol., 1995 ; 122 (8): 514-6 Chalasani P, Baffoe-Bonnie H, Jurado R.L, Dapsone therapy causing sulfone syndrome and lethal hepatic failure in an HIV-infected patient , South. Med. J., 1994 ; 87 (11): 1145-6 de Soldenhoff R, Are dapsone hypersensitivity reactions dose-related?, Lepr. Rev., 1990 ; 61 (4): 391-2
ETHAMBUTOL
Ethambutol was widely used in the treatment of tuberculosis. Side effects other than ocular toxicity are rare.
INCIDENCE
Cutaneous reactions: 0.5%. Drug fever: 0.3%.
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General: fever. Cutaneous: pruritus, maculoerythematous rash, toxic epidermal necrolysis, purpura. Respiratory: dyspnea, pulmonary infiltrates. Haematological: eosinophilia, neutropenia, thrombocytopenia.
DIAGNOSTIC METHODS
Drug re-challenge is usually positive in the cases of fever or maculopapular rash.
MECHANISMS
Unknown.
MANAGEMENT
Desensitization if absolutely necessary: 0.1 mg ; 0.5 mg; 1 mg; 2 mg; 4 mg; 8 mg ; 16 mg; 32 mg; 50 mg; 100 mg; 200 mg at 45 minutes intervals; then 400 mg 3H30 later; then 400 mg x 3 the next day.
REFERENCES
Wong P.C, Yew W.W, Wong C.F, Choi H.Y, Ethambutol-induced pulmonary infiltrates with eosinophilia and skin involvement, Eur. Respir. J., 1995 ; 8 (5): 866-8 Matz J, Borish L.C, Routes J.M, Rosenwasser L.J, Oral desensitization to rifampin and ethambutol in mycobacterial disease, Am. J. Respir. Crit. Care Med., 1994 ; 149 (3.1): 815-7 Wong C.F, Yew W.W, Ethambutol-induced neutropenia and eosinophilia, Chest, 1994 ; 106: 1638-9 Pegram P.S Jr, Mountz J.D, OBar P.R, Ethambutol-induced toxic epidermal necrolysis, Arch. Intern. Med., 1981 ; 141 (12): 1677-8 Kerremans A, Majoor C.L, Gribnau F.W, Hypersensitivity to ethambutol, Tubercle., 1981 ; 62 (3): 215-7
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ISONIAZID
Isoniazid is a major antituberculosis drug.
INCIDENCE
5% of patients.
General: fever, flu-like syndrome. Cutaneous: morbilliform, maculopapular or urticarial rash, contact dermatitis (occupational in nurses and manufactories). Respiratory: lung infiltrates, interstitial pneumonia.
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests: 0.06 to 6 mg/ ml. Patch-tests: isoniazid 2% in dis. water (contact dermatitis). Specific IgE .
MECHANISMS
IgE-mediated hypersensitivity in a few cases. Delayed hypersensitivity (contact dermatitis).
MANAGEMENT
Desensitization is possible and effective. Start with 0.1 mg and go to 150 mg in 17 hours.
REFERENCES
Meseguer J, Sastre A, Malek T, Salvador M.D, Systemic contact dermatitis from isoniazid, Contact Dermatitis, 1993 ; 28 (2): 110-1 Holland C.L, Malasky C, Ogunkoya A, Bielory L, Rapid oral desensitization to isoniazid and rifampin, Chest, 1990 ; 98: 1518-9 Asai S, Shimoda T, Hara K, Fujiwara K, Occupational asthma caused by isonicotinic acid hydrazide (INH) inhalation, J. Allergy Clin. Immunol., 1987 ; 80 (4): 578-82.
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Fujiwara K, Saita T, Shimoda T, Asai S, Hara K, Isonicotinic acid hydrazide as an antigen, J. Allergy. Clin. Immunol., 1987 ; 80 (4): 582-5 Gabrail N, Severe febrile reaction to isoniazid, Chest, 1987 ; 91: 620-1.
MACROLIDES
Widely used class of antibodies which act by inhibiting bacterial protein synthesis.
INCIDENCE
Uncommon (0.5 to 2.3% of treatments) for skin reactions. Exceptional for anaphylaxis and acute respiratory failure.
RISK FACTORS
Penicillin allergy. Lupus erythematosus.
Anaphylaxis. Asthma (spiramycin ++). Fixed drug eruption (erythromycin), urticaria, maculopapular rash, vasculitis (rare), contact dermatitis. Urticaria, vasculitis, fixed drug eruption and thrombocytopenic purpura recently described with clarithromycin.
DIAGNOSTIC METHODS
Cutaneous testing: usually negative with erythromycin. One case with positive skin prick-tests (erythromycin lactobionate 10 mg/ ml) Positive patch-tests in fixed drug eruption (skin lesions). Specific IgE: usually negative. One case with erythromycin specific IgE (sepharose radioimmunoassay).
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Leukocyte histamine release. Drug re-challenge.
MECHANISMS
IgE-mediated hypersensitivity in few patients.
MANAGEMENT
Avoidance. Cross-reactivity among macrolides has not been demonstrated.
REFERENCES
Rosina P, Chieregato C, Schena D, Fixed drug eruption from clarithromycin , Contact. Dermatitis., 1998 ; 38: 105-22 Jorro G, Morales C, Braso J.V, Pelaez A, Anaphylaxis to erythromycin , Ann. Allergy. Asthma. Immunol., 1996 ; 77: 456-8 Pascual C, Crespo J.F, Quiralte J, Lopez C, Wheeler G, Martin-Esteban M, In vitro detection of specific IgE antibodies to erythromycin, J. Allergy. Clin. Immunol., 1995 ; 95 (3): 668-71 Igea J.M, Quirce S, De la Hoz B, Fraj J, Pola J, Diez-Gomez M.L, Adverse cutaneous reactions due to macrolides, Ann. Allergy., 1991 ; 66: 2168.
PENICILLIN AND OTHER BETA-LACTAMS

-lactams: bactericidal antibiotics that act on bacteria during their growth phase by inhibiting the formation of specific peptide bonds on the bacterial wall. Penicillins: natural or semi-synthetic antibiotics with a core structure consisting of a -lactam fused to a thiazolidine (6 amino penicillanic acid) differing simply in regard to their lateral fixed chain on the 6 amino function. Cephalosporins: antibiotics with a core structure consisting of a -lactam fused to a 1.3-thiazine ring system.
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Some anaphylactic reactions to cephalosporins are due to antibodies directed against specific side chains in these molecules rather than the -lactam ring.
INCIDENCE
Penicillins: 1/1 000 administrations, i.e. 0.7 to 10% of treatments. Responsible for 75% of anaphylactic deaths in the USA. Urticaria: 4.5% of treatments. Systemic reactions: 2% of treatments. Anaphylactic shock: 0.2% of treatments. Mortality: 0.02% of treatments. Cephalosporins: 1.1 to 3% cutaneous reactions.
RISK FACTORS
Atopy not implicated. Sensitivity to moulds not implicated. Intravenous administration. Mean age, 20 to 49 years. Prior history of penicillin reaction (risk x 6).
Immediate (< 1 h): anaphylactic shock, urticaria, angioedema, laryngospasm, bronchospasm (especially with benzylpenicillin). Accelerated (1 to 72 h): mainly urticaria. cutaneous: maculopapular rash, pruritis, erythema multiforme, bullous erythema, erythrodermia (especially with amino penicillin) serum sickness hematological: hemolytic anemia, neutropenia, thrombocytopenia renal: acute interstitial nephropathy. Late (> 72 h): maculopapular rash, contact dermatitis
DIAGNOSTIC METHODS
Cutaneous testing.
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Scratch, prick or intradermal skin tests with: Polylysine penicilloyl (main component): P. P. L. 6 10-5 M. Variable amounts of minor components (M. D. M.): benzylpenicillin, benzylpenicilloic acid, benzylpenilloate, benzylpenicilloylamine or benzylpenicilloate salt (now standardized on lyophilized form). Begin with the polylysine penicilloyl prick-test. If negative do the intradermal test with polylysine penicilloyl. If negative do the prick test with minor component mixture, and if this is negative do the intradermal test with minor component mixture. Results: wheal: 03 mm: 35 mm: 510 mm: > 10 mm: negative test undetermined test positive test strongly positive test
In case of anaphylactic shock, begin the test with M. D. M. at diluted concentrations (1/100 and 1/10). The reported incidence of positive skin-tests for detection of IgE sensitization in patients with suspected previous history of allergy to penicillin is less than 20%. Risk of anaphylactic reactions to penicillin is < 3% if skin tests for major and minor determinants are negative. For drugs other than penicillin G, conduct empirical skin tests using 0.25 mg/ ml; 2.5 mg/ ml; 25 mg/ ml for prick tests, and if negative 2.5 mg/ ml and 25 mg/ ml for intradermal injection. N.B.: A patch test may be positive in patients with contact dermatitis to aminopenicillin. Specific IgE: RAST and ELISA for the major determinant of the most common penicillins are available. However, there are no tests for IgE antibodies to minor determinants.
MECHANISMS
The metabolites of benzyl penicillin are haptens and can lead to the formation of antibodies by conjugating with a carrier to form a complete antigen (serum or tissue protein).
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Reactions to penicillin may be caused by consuming milk or meat from cows treated with penicillin. Pregnant or nursing mothers treated with penicillin may induce reactions in fetuses or babies. Also occupational exposure, skin tests (theoretical). IMMEDIATE IGE HYPERSENSITIVITY Detection of IgE antibodies against major components (especially in accelerate reactions). Detection of IgE antibodies against minor components (especially in immediate reactions). Detection of IgE antibodies against side chains in some patients allergic to cephalosporins. IgE-mediated reactions are responsible for anaphylactic shock, angioedema as well as some forms of urticaria. CYTOTOXIC MECHANISMS Detection of IgG antibodies against erythrocytes and neutrophils. This mechanism is responsible for hemolytic anemia and leukoneutropenia. HYPERSENSITIVITY DUE TO IMMUNE COMPLEXES Implicated in serum sickness as well as in some forms of urticaria and maculopapular rash. DELAYED CELL-MEDIATED HYPERSENSITIVITY Responsible for contact dermatitis and some form of maculopapular rash. Two particular problems: Ampicillin rash (5 to 8% of patients treated). Nonimmunological mechanism: the amine function of aminopenicillins causes changes in leukocyte function (especially lymphocytes), particularly if there is a concurrent disease (viral infection, chronic lymphoid leukemia). Cross sensitivity between penicillin and cephalosporins: 8 to 10% risk of allergy to cephalosporins in patients allergic to penicillin.
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MANAGEMENT
Patients with a positive history of penicillin allergy and negative skin-tests for major and minor determinants have a risk of < 3%. Patients with a positive history and a positive skin-test response to penicillin have a 50% or greater risk of repeat reaction after administration of penicillin. Patients with a positive history of penicillin allergy but with negative skin-tests to major and minor determinants may receive a cephalosporin at no greater risk than the general population. Patients with a positive history of penicillin allergy and positive skin-tests to penicillin determinants have a 5-10% risk of clinical reactions to cephalosporins. An alternative antibiotic class should be proposed or provocation-desensitization with the cephalosporin if needed. The negative predictive value of skin-tests with cephalosporins is unknown. Example of penicillin desensitization: 0 min: 100 U orally (penicillin V) 15 min: 200 U orally 30 min: 400 U orally 45 min: 800 U orally 1 h: 1 600 U orally 1 h 15: 3 200 U orally 1 h 30: 6400 U orally 1 h 45: 12800 U orally 2 h: 25000 U orally 2 h 15: 50000 U orally 2 h 30: 100000 U orally 2 h 45: 200000 U orally 3 h: 400000 U orally 3 h 15: 200000 U subcutaneous (penicillin G) 3 h 30: 400000 U subcutaneous 3 h 45: 800000 U subcutaneous 4 h: 1 000000 U intramuscular
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REFERENCES
Nicklas R.A, Bta-lactam antibiotics, J. Allergy. Clin. Immunol., 1998 ; 101: S498-501 Birnbaum J, Vervloet D, Allergie aux penicillines, Rev. fr. Allergol., 1997 ; 37: 29-35 Bernstein I.L, Storms W.W, Practice parameters for allergy diagnostic testing, Ann. Allergy. Asthma. Immunol, 1995 ; 75 (6.2): 543-625 Adkinson N.F Jr, Tests for immunological drug reactions, In: Rose NR, de Marco EC ed. Manual of clinical laboratory immunology. 4th ed. Washington: American society of microbiology, 1992: 717-22 Blanca M, Vega J.M, Garcia J, Carmona M.J, Terado S, Avila M.J, Miranda A, Juarez C, Allergy to penicillin with good tolerance to other penicillins. Study of the incidence in patients allergic to betalactams, Clin. Exp. Allergy, 1990 ; 20: 475-81 Redelmeier D.A, Sox H.C Jr, The role of skin testing for penicillin allergy, Arch. Intern. Med., 1990 ; 150: 1939-45. Saxon J, Immediate hypersensitivity reactions to b-lactam antibiotics , Ann. Int. Med., 1987 ;107: 204-15. Stark B.J, Earl H.S, Gross G.N, Lumry W.R, Goodman E.L, Sullivan T.J, Acute and chronic desensitization of penicillin allergic patients using oral penicillin, J. Allergy Clin. Immunol., 1987 ; 79 (3): 523-32.
PENTAMIDINE
Aerosolized pentamidine is widely used for pneumocystis carinii pneumonitis in AIDS patients. Conversely, theintravenous form of the drug is seldom used, for reasons of efficacy and toxicity.
INCIDENCE
Bronchospasm: 10 to 29%. Cutaneous reactions: morbilliform eruptions 15%.
Cutaneous: morbilliform eruptions, erythroderma; generalized urticaria, contact urticaria ( nurses), facial rash.
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Respiratory: bronchospasm (aerosolized pentamidine), laryngeal edema, tongue swelling, hypersensitivity pneumonitis. Other: conjunctivitis.
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests positive with 3 mg/ ml pentamidine isethionate in contact urticaria and some cases of bronchospasm. Intradermal skin-tests: false positive with 0.015 and 0.15 mg/ ml pentamidine. Intravenous test dose is dangerous (2 deaths reported).
MECHANISMS
Non specific histamine release (documented with intravenous pentamidine). IgE-mediated hypersensitivity (contact urticaria, some cases of bronchospasm). Irritative effect (bronchospasm).
MANAGEMENT
Use premedication with nebulized albuterol and/ or cromolyn sodium prior to aerosolized pentamidine. Slow intravenous administration (decreases non specific histamine release). In patients with hypersensitivity to systemic pentamidine; cautious administration of aerosolized pentamidine is safe when the following protocol is applied: Dilution of 300 mg of pentamidine isethionate in 20 ml of sterile water (15 mg/ ml). Dilution 1/10 000 1/1 000 1/100 1/10 Full strength Volume inhaled 4 4 4 4 20
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Pentamidine (mg) 0.006 0.06 0.6 6 300
REFERENCES
Carr A, Cooper D.A, Pathogenesis and management of HIV-associated drug hypersensitivity, AIDS. Clin. Rev., 1995 - 96: 65-97 Belsito D.V, Contact urticaria from pentamidine isethionate , Contact. Dermatitis., 1993 ; 29 (3): 158-9 Pradalier A, Vincent D, Boue S, Girard P.M, Bronchospasme de mcanisme allergique a lisethionate de pentamidine en arosol, Presse. Med., 1993 ; 22 (11): 554 Baum C.G, Sonnabend J.A, OSullivan M, Prophylaxis of AIDS-related Pneumocystis carinii pneumonia with aerosolized pentamidine in a patient with hypersensitivity to systemic pentamidine, J. Allergy. Clin. Immunol, 1992 ; 90 (2): 268-9 Gordin F.M, Simon G.L, Wofsy C.B, Mills J, Adverse reactions to trimethoprim-sulphamethoxazole in patients with the acquired immunodefiency syndrome, Ann. Intern. Med., 1984 ; 100: 495-9
PRAZIQUANTEL
Praziquantel is an isoquinolin drug widely used as trematodicide.
INCIDENCE
Exceptional (one case published).
RISK FACTORS
Unknown.
Urticaria. Difficulty swallowing. Tightness of the chest.
DIAGNOSTIC METHODS
None.
MECHANISMS
Unknown.
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MANAGEMENT
Desensitization. Premedication with hydroxyzine, dexamethasone and prednisone 6 hours prior to administration of praziquantel: 18 mg x 6 then 180 mg x 3, then 360 mg x 3 (at 15 minute intervals).
REFERENCES
Huang S.W, A clinical approach to a patient with praziquantel hypersensitivity, J. Allergy. Clin. Immunol., 1992 ; 90: 5-867
PYRAZINAMIDE
Synthetic pyrazine analogue of nicotinamide used in the treatment of tuberculosis.
INCIDENCE
Uncommon.
Mainly cutaneous: flushing, rash, urticaria.
DIAGNOSTIC METHODS
Cutaneous testing Patch-tests: pyrazinamide 1% eth. and 10% eth. positive in one patient with a pruriginous rash.
MECHANISMS.
Undetermined.
MANAGEMENT
Desensitization if absolutely necessary: starting dose 5 mg. Increasing by 50 to 100% every 30 minutes up to the total dose.
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REFERENCES
Shorr A.F, Trotta R.F, Pyrazinamide hypersensitivity, Chest , 1996 ; 109 (3): 855-6 Goday J, Aguirre A, Diaz-Perez J.L, A positive patch test in a pyrazinamide drug eruption, Contact Dermatitis, 1990 ; 22 (3): 181-2 Soyez F, Surpas P, Vestri R, Philip-Joet F, Arnaud A, Raction inhabituelle au pirilne, Rev. fr. Allergol., 1988 ; 28: 1.
QUININE
Quinine is the main alkaloid derived from cinchona bark. It is used in medicine mainly as an antimalarial drug but also as an antipyretic and analgesic easily available in many over-the-counter preparations (treatment of leg cramps).
INCIDENCE
Anaphylaxis is uncommon. Thrombocytopenia is more frequent (1/1000 to 1/3500).
Anaphylactic shock, fever. Eczematous eruption (photoallergic), lichenoid photosensitivity, contact dermatitis (hair lotions), fixed drug eruption, allergic vasculitis, rash. Agranulocytosis, thrombocytopenia, hemolytic uremic syndrome, disseminated intravascular coagulation.
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests: positive 1/1000 in one case of anaphylaxis. Patch-tests (quinine 1% pet). Photo-patch tests.
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Serologic methods Quinine dependent neutrophil antibodies IgG, IgM (immunofluorescence, agglutination). Quinine dependent platelet antibodies IgG, IgM (immunofluorescence). Quinine dependent erythrocyte antibodies (antiglobulin test). Specific IgE Positive RAST and RAST-inhibition in one case of anaphylaxis. Oral provocation test: positive in one case of anaphylaxis.
MECHANISMS
IgE-mediated hypersensitivity: few cases with positive cutaneous tests and specific IgE. Cytotoxicity: thrombocytopenia, anemia, leukopenia. Delayed cell-mediated hypersensitivity: contact dermatitis.
MANAGEMENT
Cross-sensitivity between quinine and quinidine (photoallergy) Quinine should be available one prescription only. Warning of quinine potential harmful effects should be printed on all over the counter preparations and on bottles of tonic-water.
REFERENCES
Maguire R.B, Stronsek D.F, Campbell A.C, Recurrent pancytopenia, coagulopathy and renal failure associated with multiple quinine-dependent antibodies, Ann. Intern. Med., 1993 ; 119: 215-7 Aster R.H, Quinine sensitivity: a new cause of the hemolytic uremic syndrome, Ann. Intern. Med, 1993 ; 119: 243-4 Ljunggren B, Hindsen M, Isaksson M, Systemic quinine photosensitivity with photoepicutaneous cross-reactivity to quinidine , Contact. Dermatitis., 1992 ; 26: 1-4 Pin I, Dor P.H, Vervloet D, Senft M, Charpin J, Hypersensibilit immdiate la quinine, Presse Med., 1985 ; 14 (17): 967-9.
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QUINOLONES
Synthetic antibiotics first generation quinolones were used for treatment of urinary tract infections because of their rapid excretion by kidney. New quinolones are used in various systemic infections. First generation: Nalidixic acid, Oxolinic acid, Pipemidic acid, Flumequin Second generation: Pefloxacin, Norfloxacin, Ofloxacin, Ciprofloxacin, Enoxacin, Lomefloxacin Third generation: Sparfloxacin.
INCIDENCE
18 to 23/10 million days of treatment. In France 43 cases of anaphylaxis to quinolones were transmitted to pharmacovigilance in 1992 (first generation quinolones were almost always involved).
RISK FACTORS
AIDS. Female gender. Sun exposure (photosensitivity). Past exposure to quinolones or related compounds (Chloroquine, Glafenine, Tiliquinol, Nitroxolin).
General: anaphylactic shock, fever, arthralgias. Cutaneous: maculopapular or bullous exanthema, pruritus, angioedema, fixed drug eruption and rarely Stevens-Johnson or Lyells disease (enoxacin, sparfoxacin and lomefloxacin are wellknown to cause photosensitivity). Differentiate from other side effects: gastrointestinal disturbance, neuropsychiatric manifestations.
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DIAGNOSTIC METHODS
Cutaneous testing. Skin- prick tests and intradermal tests give false positive results. Photo-patch tests with lomefloxacin are usually negative and crosssensitivity with other quinolones is rarely reported. Specific IgE: none. Challenge test: 11 cases published. Cross-reactivity between first and second generation quinolones +++.
MECHANISMS
Unknown.
MANAGEMENT
Eviction (all quinolones). If absolutely necessary: desensitization. Ciprofloxacin 0,05 mg to 150 mg (3H).
REFERENCES
Kimura M, Kawada A, Photosensitivity induced by lomefloxacin with crosssensitivity to ciprofloxacin and fleroxacin, Contact. Dermatitis., 1998 ; 38: 180 Bircher A.J, Rutishauser M, Oral desensitization of maculopapular exanthema from ciprofloxacin, Allergy. , 1997 ; 52: 1246-8 Arboit F, Bessot J.C, Deblay F, Dietemann A, Charpentier C, Pauli G, Lallergie aux quinolones. A propos de huit observations, Rev. Fr. Allergol., 1997 ; 37 (1): 15-9 Lantner RR, Ciprofloxacin desensitization in a patient with cystic fibrosis, J. Allergy.Clin. Immunol., 1995 ; 96: 1001-2 Davila I, Diez M.L, Quirce S, Fraj J, de La Hoz B, Lazaro M, Cross reactivity between quinolones. Report of three cases, Allergy 1993 ; 48: 388-90
RIFAMPICIN
Rifampicin is a semi-synthetic broad-spectrum antibiotic very effective against mycobacteria, Brucella, and Staphylococci.
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INCIDENCE
Anaphylactic shock is rare (6/30 000 reports of possible allergic reactions to rifampicin). Flu-like syndrome: rare when administered in daily regimens (0.1 to 4%) ; frequent in intermittent or discontinuous regimens (20%).
RISK FACTORS AIDS.

Intermittent treatment (flu-like syndrome, acute haemolytic anemia, renal failure, thrombocytopenic purpura).
General: anaphylactic shock, serum sickness. Cutaneous: pruritus, erythema, facial swelling, maculopapular rash, urticaria, vasculitis, Stevens-Johnsons syndrome, red man syndrome. Respiratory: shortness of breath, bronchospasm. Haematological: thrombocytopenia, haemolytic anemia. Renal: renal failure.
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests: 1/1000 to 1/10 (intravenous rifampicin 60 mg/ ml): positive in a few cases of anaphylactic shock. Specific IgE (RAST) Circulating rifampicin dependent antibodies, especially when intermittent therapy is used (Coombs test, complement binding test, antiglobulin test) Circulating immune complexes. Haemolytic complement titers
MECHANISMS
Possible IgE-mediated hypersensitivity: anaphylactic shock with immediate positive skin-tests.
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Type II hypersensitivity: blood dyscrasias. Type III hypersensitivity: serum sickness.
MANAGEMENT
Desensitization (contra-indicated if severe manifestations: renal failure, thrombocytopenia). 2 protocols: 0.1 mg ; 0.5 mg ; 1 mg ; 2 mg ; 4 mg ; 8 mg ; 16 mg ; 32 mg ; 50 mg: 100 mg ; 150 mg at 45 minutes intervals, then 300 mg 3H30 later, then 300 mg x 2 next day. 0.1 mg to 300 mg within 17 hours.
REFERENCES
Matz J, Borish .C, Routes J.M, Rosenwasser L.J, Oral desensitization to rifampin and ethambutol in mycobacterial disease, Am. J. Respir. Crit. Care. Med, 1994 ; 149 (3.1): 815-7 Parra F.M, Perez-Elias M.J, Cuevas M, Ferreira A, Serum sickness-like illness associated with rifampicin, Ann. Allergy., 1994 ; 73 (2): 123-5 Cnudde F, Leynadier F, The diagnosis of allergy to rifampicin confirmed by skin-test: letter ; comment, Am. J. Med., 1994 ; 97 (4): 403-4 Holland C.L, Malasky C, Ogunkoya A, Bielory L, Rapid oral desensitization to isoniazid and rifampin, Chest, 1990 ; 98: 1518-9. Nessi R, Domenichini E, Fowst G, Allergic reactions during rifampicin treatment: a review of published cases, Scand. J. Respir. Dis. Suppl., 1973 ; 84: 15-19
RIFAMYCIN SV
Semi-synthetic antibiotic derived from Rifamycin B. Widely used by surgeons for local application.
INCIDENCE
Uncommon.
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Contact dermatitis. Contact urticaria. Anaphylactic reactions.
DIAGNOSTIC METHODS
Cutaneous testing. Prick-tests 50g/ml. Intradermal tests 50 g/ml to 5000 g/ml (positive in 4/4 patients with anaphylaxis). Specific IgE: detected in at least one case. Histamine release (positive in 2/3 patients with anaphylaxis). Antiparasite cytotoxicity by platelets (positive in 4/4 patients with anaphylaxis).
MECHANISMS
IgE-mediated allergy.
MANAGEMENT
Avoidance. Possible cross-reactivity with Rifampicine and Rifabutine.
REFERENCES
Magnan A, Venemalm L, Porri F, Vervloet D, Anaphylactic reaction to rifamycin SV: presence of specific IgE antibodies, J. Allergy. Clin. Immunol., 1999 in press Cardot E, Tille-Leblond I, Jeannin P, Facon A, Breuil K, Patte F, Tonnel A.B, Anaphylactic reaction to local administration of Rifamycin SV, J. Allergy. Clin. Immunol. 1995 ; 95: 1-7 Piazza I, Anaphylactic reaction to local administration of Rifamycin (abstract), Allergologie. 1989 ; 12 (s): 96 Grob J.J, Pommier G, Robaglia A, Collet-Vilette A.M, Bonerandi J.J, Contact urticaria from Rifamycin, Contact. Dermatitis. 1987 ; 16: 284-5
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SODIUM FUSIDATE
Sodium fusidate is a sodium salt of fusidic acid widely used for the treatment of cutaneous infections with Staphylococcus aureus.
INCIDENCE
25 cases of contact dermatitis have been reported.
RISK FACTORS
Atopic dermatitis. Venous stasis Leg ulcers.
Contact eczema.
DIAGNOSTIC METHODS
Patch-tests with sodium fusidate in 1 to 2% in pet. or in 0.1% propylene glycol.
MECHANISMS
Type IV delayed hypersensitivity.
MANAGEMENT
Avoidance.
REFERENCES
Giordano-Labadie F, Pelletier N, Bazex J, Contact dermatitis from sodium fusidate, Contact Dermatitis, 1996 ; 34: 159
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SULFAMETHOXAZOLETRIMETHOPRIM (SMX-TMP)
Both components of cotrimoxazole act as antifolate drugs by inhibiting the biosynthesis of tetrahydrofolic acid. Cotrimoxazole is widely used in AIDS patients with Pneumocystis carinii pneumonia.
INCIDENCE
General population: 3 to 5%. AIDS patients treated with high-dose cotrimoxazole: 44 to 83%. Severe, life threatening idiosyncratic toxicity: 1/10000.
RISK FACTORS (uncertain)

Degree of immunodeficiency (CD4+<200/mm3). Duration and dose of therapy. Coexisting viral infection. Slow acetylator phenotype. Atopic diathesis.
Differentiate: Pharmacologic toxicity: blood dyscrasias associated with folate deficiency, renal tubular acidosis, nausea and vomiting, headache and neurological disturbances, hypoglycemia, goitrogenic effects. Intrinsic toxicity: renal toxicity, methaemoglobinaemia, keratoconjunctivitis sicca. Idiosyncratic or hypersensitivity toxicity: 1 Sulfonamide allergy (rare). Anaphylactic shock. Bronchospasm. Urticaria, rash. 2 Sulfonamide hypersensitivity reactions (AIDS). Occurring 7-12 days after starting treatment.
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Cutaneous rash: erythematous, maculopapular, pruritis, most prominent on the body and upper limbs. Fever. Anicteric hepatitis. Acute interstitial pneumonitis. Aseptic meningitis, myocarditis, serum sickness, uveitis, eosinophilia, leukocytosis. Other cutaneous manifestations: erythema nodosum, erythema multiforme, lupus erythematosus, toxic epidermal necrolysis.
DIAGNOSTIC METHODS (in immediate type I reactions)

Cutaneous testing. Skin-prick tests with SMX-poly-L-tyrosine up to 1 mg/ ml. Intradermal skin-tests with SMX-poly-L-tyrosine 0.03 mg/ ml. 27% positive in 44 patients with histories of allergic reaction to sulfamethoxazole. Inhibition of skin-test reactivity with a monovalent inhibitor. Specific IgE anti -SMX (RAST and RAST inhibition).
MECHANISMS
1 IgE-mediated hypersensitivity (rare). positive skin-tests, specific IgE. The major determinant is N4-sulfonamidyl group 2 Sulfonamide hypersensitivity reactions in AIDS patients. SMX is either acetylated or hydroxylated at the N4 position to form: N4 acetyl SMX (45-70%) and N4 hydroxyl SMX (2-5%): SMX-HA. The SMX-HA metabolic is believed to be critical in the pathogenesis of many of the SMX adverse effects. SMX is oxidized to SMX-HA by the cytochrome P450 and by myeloperoxidase-dependent oxidation in neutrophils and macrophages/ monocytes. SMX-HA auto-oxidizes to the more reactive nitroso metabolites with production of superoxide anion radicals.
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Nitroso-SMX reacts with glutathione to form an unstable semimercaptal which is reduced back to SMX-HA in the presence of excess glutathione. Slow acetylator phenotype is associated with a susceptibility to sulfonamide hypersensitivity reactions. Glutathione protects against the toxicity of SMX-HA to isolated peripheral blood mononuclear cells by preventing its oxidation to nitroso SMX. The nitroso SMX which covalently binds to proteins is the ultimate toxic metabolite. This binding is inhibited by acetylation, reaction with glutathione or reduction back to SMX-HA and SMX. In summary, high incidence of hypersensitivity reactions to sulfonamides in AIDS patients is probably multifactorial: highdose regimens, altered immunological responses, altered pathways of drug metabolism. There is no correlation between presence of anti-SMX-antibodies (IgG) and occurrence of adverse reaction, except thrombocytopenia.
MANAGEMENT
Cross-sensitivity between SMX-TMP and sulfadiazine is frequent. There is no evident cross-reactivity between sulfonamide antimicrobials and sulfamide diuretics (furosemide, chlorothiazide, acetazolamide) ; hypoglycemics (tolbutanol, chlorpropanol) or antihypertensives (diazoxide). Faced with hypersensitivity reaction to cotrimoxazole in AIDS patients, there are 3 possibilities: 1 Treatment throughout the duration of hypersensitivity. The rash (general exanthema, pruritic or non-pruritic, fever) may be treatedsymptomatically with antihistamines and may resolve. 2 Re-challenge A history of cutaneous rash is not a contra-indication to retreatment, since only 20 to 66% cutaneous reactions occur on re-challenge. 3 Desensitization.
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Numerous studies, involving no more than 45 patients differed greatly with regard to the inclusion criteria, duration of the protocol, dose progression and success rate (33 to 96%). For example: Hours D1 9 AM 11 AM 1 PM 5 PM 9 AM 3 PM 9 PM 9 AM Dose of SMX-TMP (mg) 4-0.8 8-1.6 20-4 40-8 80-16 160-32 200-40 400-80
D2
D3
Risk factor of desensitization failure: female sex. Life-threatening reactions may occur during desensitization.
REFERENCES
Caumes E, Guermonprez G, Lecomte C, Katlama C, Bricaire F, Efficacy and safety of desensitization with sulfamethoxazole and trimethoprim in 48 previously hypersensitive patients infected with human immunodeficiency virus, Arch. Dermatol., 1997 ; 133 (4): 465-9 Cribb A.E, Lee B.L, Trepanier L.A, Spielberg S.P, Adverse reactions to sulfonamide and sulfonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis, Adverse Drug. React. Toxicol. Rev., 1996 ; 15 (1): 9-50 Carr A, Cooper D.A, Pathogenesis and management of HIV-associated drug hypersensitivity, AIDS. Clin. Rev., 1995 - 96: 65-97 Meekins C.V, Sullivan T.J, Gruchalla R.S, Immunochemical analysis of sulfonamide drug allergy: identification of sulfamethoxazole-substituted human serum proteins , J. Allergy. Clin. Immunol, 1994 ; 94 (6.1): 1017-24 Gruchalla R.S, Sullivan T.J, Detection of human IgE to sulfamethoxazole by skin-testing with sulfamethoxazoyl-poly-L-tyrosine, J. Allergy. Clin. Immunol., 1991 ; 88 (5): 784-92
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SULPHADIAZINE
Sulphadiazine combined with pyrimethamine is the most effective first-line treatment of cerebral toxoplasmosis in AIDS patients (sulphadiazine 1-1.5 g q 6 hours p.o. x 6 weeks + pyrimethamine 100-200 mg loading dose, then 50-75 mg / day p.o. x 6 weeks + leucovorin 10-20 mg / day p.o.).
INCIDENCE
High, but no accurate findings.
RISK FACTORS
AIDS.
General: fever (10%), conjunctivitis. Cutaneous: rash (19%): maculoerythematous or morbilliform ; itching, facial angioedema, Stevens-Johnsons syndrome. Haematological: leukopenia (40%), thrombocytopenia (12%).
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests (1 mg/ ml, 2 mg/ ml, 5 mg/ ml) are negative. No specific histamine release.
MECHANISMS
See sulfamethoxazole-trimethoprim.
MANAGEMENT
Alternative therapy Replace sulphadiazine with clindamycin, azithromycin, clarithromycin or atovaquone Desensitization: 2 different protocols have been published: 1- Oral route in 5 days +/- corticosteroids
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Day 1: 10 g to 200 g Day 2: 300 g to 8 mg Day 3: 15 mg to 500 mg Day 4: 500 mg: 1 x 4 / day Day 5: 500 mg: 2 x 4 / day Success rate: 62% 2- Oral route in 10 days without corticosteroids Day 1: 5 mg and 10 mg Day 6: 1 g and 1 g Day 2: 20 mg and 40 mg Day 7: 1 g/8 hours Day 3: 80 mg and 160 mg Day 8: 1g/6 hours Day 4: 250 mg and 500 mg Day 9: 1.5 g/6 hours Day 5: 750 mg and 750 mg Day 10: 2 g/6 hours Success rate: 100%
REFERENCES
Behbahani R, Moshfeghi M, Baxter J.D, Therapeutic approaches for AIDSrelated toxoplasmosis, Ann. Pharmacother., 1995 ; 29 (7-8): 760-8 Peters B.S, Carlin E, Weston R.J, Loveless S.J, Sweeney J, Weber J, Main J, Adverse effects of drugs used in the management of opportunistic infections associated with HIV infection, Drug. Saf., 1994 ; 10 (6): 439-54 Tenant-Flowers M, Boyle M.J, Carey D, Marriott D.J, Harkness J.L, Penny R, Cooper D.A, Sulphadiazine desensitization in patients with AIDS and cerebral toxoplasmosis, AIDS., 1991 ; 5 (3): 311-5 de la Hoz Caballer B, Fernandez-Rivas M, Fraj Lazaro J, Quirce Gancedo S, Davila Ruiz I, Puyana Ruiz J, Cuesta Herranz J, Alvarez Cuesta E, Cuevas M, Perez Elias M, Management of sulfadiazine allergy in patients with acquired immunodeficiency syndrome, J. Allergy. Clin. Immunol., 1991 ; 88 (1): 137-8
TETRACYCLINE GROUP
The tetracycline antibiotics are a group of broad spectrum protein synthesis inhibiting compounds used in the treatment of Gram+ and Gram - infections. In dermatological practice, they are commonly used in the treatment of acne and rosacea. Natural tetracyclines: basic tetracycline, chlortetracycline, oxytetracycline
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Semi-synthetic tetracyclines: doxycycline, minocycline
INCIDENCE
Uncommon. Deaths reported.
General: anaphylactic shock, serum sickness, fever, arthralgia, arthritis. Respiratory: pneumonitis, bronchospasm. Cutaneous: pruritus, urticaria, erythema multiforme, Lyells syndrome, Stevens-Johnsons syndrome, fixed drug eruption, angioedema, contact dermatitis, photosensitivity. Hepatic: hepatitis. Renal: acute interstitial nephritis. Haematological: autoimmune hemolytic anemia, thrombocytopenia, leukopenia. 3 distinct syndromes have been reported: hypersensitivity syndrome reaction (HSR): fever, rash, internal organ involvement, occurring 2 to 4 weeks after the start of therapy serum sickness like reaction (SSLR): fever, rash, arthralgia and/or lymphadenopathy, urticaria, exanthema drug induced lupus (DIL) .
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests: positive in one patient with anaphylaxis. Patch-tests (chlortetracycline hydrochloride 0.5% in pet). Hemagglutinating antibodies positive in patients with Lyells syndrome . Migration inhibitory factor (MIF) + mast cell degranulation test positive in 4/15 patients. Re-challenge with minocycline or tetracycline is not recommended in patients with severe reactions.
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MECHANISMS
The potential reactive metabolites generated by minocycline may bind to tissue macromolecules, thereby causing direct cell damage, or they may act as haptens.
MANAGEMENT
Cross-sensitivity between tetracycline/doxycycline and minocycline concerning fixed drug eruptions is not constant. Patients who experienced a serious adverse event while receiving one of the tetracycline antibiotics must avoid all tetracyclines until more information is available. Patients receiving long-term minocycline therapy should have an antinuclear antibody test and assessment of hepatic transaminase levels only if symptoms develop during their course of treatment.
REFERENCES
Shapiro L.E, Knowles S.R, Shear N.H, Comparative safety of tetracycline, minocycline and doxycycline, Arch. Dermatol., 1997 ; 133 (10): 1224-30 Knowles S.R, Shapiro L.E, Shear N.H, Serious adverse reactions induced by minocycline and review of the literature, Arch. Dermatol., 1996 ; 132 (8): 934-9 Harel L, Amir J, Livni E, Straussberg R, Varsano I, Serum-sickness-like reaction associated with minocycline therapy in adolescents, Ann. Pharmacother., 1996 ; 30: 481-3 Bargman H, Lack of cross-sensitivity between tetracycline, doxycycline and minocycline with regard to fixed drug sensitivity to tetracycline, J. Am. Acad. Dermatol., 1984 ; 11 (5.1): 900-2 Menon M.P.S, Das A.K, Tetracycline asthma: a case report, Clin. Allergy., 1977 ; 7: 285-90
TRIMETHOPRIM
Trimethoprim (2.4-diamino-5-(3',4',5'-trimethoxybenzyl) pyrimidine) is a synthetic folate antagonist anti-infective agent used for the treatment of urinary tract infections and for Pneumocystis pneumonia in AIDS patients.
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INCIDENCE
High.
Anaphylactic shock. Bronchospasm, hypersensitivity pneumonitis. Rash, pruritus, general urticaria, facial angioedema, fixed drug eruption.
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests with trimethoprim 10 mg/ ml in glycerol. Specific IgE RAST TMP-HSA + RAST inhibition (TMP-HSA coupled to bisoxirane-activated sepharose or nitrocellulose paper disks).
MECHANISMS
IgE-mediated hypersensitivity (positive cutaneous tests, specific IgE) 3 different IgE antibody binding determinants: 3-4 dimethoxybenzyl group. 2-4 diamino-5-(3',4'-dimethoxy-benzyl) pyrimidine group. entire TMP molecule.
MANAGEMENT
Avoidance.
REFERENCES
Pham N.H, Baldo B.A, Manfredi M, Zerboni R, Fine structural specificity differences of trimethoprim allergenic determinants, Clin. Exp. Allergy, 1996 ; 26: 1155-60 Cabanas R, Caballero M.T, Vega A, Martin-Esteban M, Pascual C, Anaphylaxis to trimethoprim, J. Allergy. Clin. Immunol, 1996 ; 97 (1.1): 137-8 Harle D.G, Baldo B.A, Smal M.A, Van Nunen S.A, An immunoassay for the detection of IgE antibodies to trimethoprim in the sera of allergic patients, Clin. Allergy., 1987 ; 17: 209-16
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VANCOMYCIN
Preferred antimicrobial agent for the treatment of methicillineresistant Staphylococcus aureus . Vancomycin is a complex tricyclic glycopeptide obtained from the nocardia species Amycolatopsis orientalis.
INCIDENCE
Adults: 5 to 14%. Children: 1.6 to 35%.
RISK FACTORS
Association with narcotics. Age < 40 years: risk factor for infusion-related and delayed reactions. Duration > 7 days: risk factor for delayed reactions.
Red man syndrome: flushing, pruritus, hypotension (occurs in 50% to 90% of normal volunteers infused with 1 g of vancomycin over one hour). Delayed cutaneous eruptions: maculopapular rashes, exfoliative dermatitis, erythema multiforme, Stevens-Johnsons syndrome, toxic epidermal necrolysis. Occurring 8 to 55 days after the start of treatment. Often associated with eosinophilia, fever, interstitial nephritis. Linear IgA bullous dermatosis. One case with dyspnea, fever, hypoxia and eosinophilia (inhaled vancomycin used in decontamination of the respiratory tract for allogenic bone marrow transplantation).
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests are usually negative. Intradermal skin-tests: few cases published positive with 0.02 ml at 0.1 g/ml.
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Basophil histamine release test. One case published of specific histamine release and crossreactivity between vancomycin and teicoplanin.
MECHANISMS
Red man syndrome is due to histamine release into the blood by vancomycin with no antibody or complement involvement. Hypotension is linked to peripheral vasodilatation following histamine release. Myocardial dysfunction is secondary to endogenous myocardial histamine release, or direct inotropic myocardial depression. IgE-mediated hypersensitivity reactions do exist in a few cases.
MANAGEMENT
PREVENTION OF THE RED MAN SYNDROME: Decreasing vancomycin doses. Slowing infusion rate (no faster than 10 mg/ min). Pretreatment with an antihistamine (hydroxyzine 50 mg 2 hours before a vancomycin dose). DESENSITIZATION Rush: 0.5 mg/500 ml// 4 hours to 1 000 mg/250 ml// 4 hours in 13 days. Fast: 0.0001 mg/ ml infusion to 10 mg/ ml infusion in 100 minutes with pretreatment (antihistamines). Cross-reactivity between vancomycin and teicoplanin remains controversial.
REFERENCES
Marik P.E, Ferris N, Delayed hypersensitivity reaction to vancomycin, Pharmacotherapy., 1997 ; 17 (6): 1341-44 Korman P.M, Turnidge J.D, Grayson M.L, Risk factors for adverse cutaneous reactions associated with intravenous vancomycin , J. Antimicrob. Chemother., 1997 ; 39 (3): 371-81 Anne S, Middleton E Jr, Reisman R.E, Vancomycin anaphylaxis and successful desensitization, Ann. Allergy., 1994 ; 73 (5): 402-4
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Wong J.T, Ripple R.E, Mc Lean J.A, Marks D.R, Bloch K.J, vancomycin hypersensitivity: synergism with narcotics and desensitization by a rapid continuous intravenous protocol, J. Allergy. Clin. Immunol., 1994 ; 94 (2.1): 189-94
ZIDOVUDINE
Dideoxynucleoside analog of thymidine, acting as a virostatic drug against HIV by interfering with viral reverse transcriptase.
INCIDENCE
Few cases of zidovudine allergy have been published.
RISK FACTORS
Unknown.
Erythroderma. Maculopapular rash. Urticaria. Fever. Leukocytoclastic vasculitis. Bronchospasm.
DIAGNOSTIC METHODS
No in vitro or in vivo tests are available.
MECHANISMS
Unknown. Possible production of toxic metabolites (like sulfonamides).
MANAGEMENT
Desensitization. 2 protocols have been published. 0.008 mg to 1 200 mg (37 days) 10 mg to 500 mg (10 days) The protective effect of corticosteroids is controversial.
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REFERENCES
Duque D, de la Puente J, Rodriguez F, Pellon L.F, Maquiera E, Jerez J, Zidovudine-related erythroderma and successful desensitization: a case report, J. Allergy. Clin. Immunol., 1996 ; 98: 234-5 Carr A, Penny R, Cooper D.A, Allergy and desensitization to zidovudine in patients with acquired immunodeficiency syndrome (AIDS), J. Allergy. Clin. Immunol., 1993 ; 91 (2): 683-85 Mc Kinley G.F, Mazza D.S, Grieco M.H, Urticarial reaction to zidovudine, Lancet., 1990 ; 336: 384
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CHEMOTHERAPY DRUGS AND IMMUNOSUPPRESSORS
IV CHEMOTHERAPY DRUGS AND IMMUNOSUPPRESSORS
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ALKYLATING AGENTS
CHLORAMBUCIL
Chlorambucil is an alkylating agent widely used in the treatment of lymphoproliferative diseases.
INCIDENCE
Uncommon.
General: fever, stomatitis, pharyngitis, conjunctivitis. Cutaneous: toxic epidermal necrolysis, maculopapular erythema, urticaria. Pulmonary: interstitial pneumonitis (14 cases up to 1994). Hematological: immune hemolytic anemia (antibody able to bind complement to erythrocytes only in the presence of chlorambucil).
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests: chlorambucil mixed in vaseline 5% and 10% positive in 2 cases of toxic epidermal necrolysis. Cutaneous biopsy (toxic epidermal necrolysis). Re-challenge test is often positive but harmful.
MECHANISMS
Unproven, but type III allergic reaction is likely (immune complex deposition).
MANAGEMENT Avoidance. Cross-reactivity between alkylating agents is exceptional.
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REFERENCES
Aydogdu I, Ozcan C, Harputluoglu M, Karincaoglu Y, Turhan O, Ozcanu A, Severe adverse skin reaction to chlorambucil in a patient with chronic lymphocytic leukemia, Anticancer. Drugs., 1997; 8 (5): 468-9 Crestani B, Jaccard A, Israel-Biet D, Couderc L.J, Frija J, Clauvel J.P, Chlorambucil - associated pneumonitis, Chest., 1994; 105 (2): 634-6 Pietrantonio F, Moriconi L, Torino F, Romano A, Gargovich A, Unusual reaction to chlorambucil: a case report, Cancer. Lett., 1990; 54 (3): 109-11 Thompson-Moya L, Martin T, Heuft H.G, Neubauer A, Herrmann R, Allergic reaction with immune hemolytic anemia resulting from chlorambucil, Am. J. Hematol., 1989; 32 (3): 230-1 Hitchins R.N, Hocker G.A, Thomson D.B, Chlorambucil allergy- a series of three cases, Aust. N.Z. J. Med., 1987; 17 (6): 600-2
CYCLOPHOSPHAMIDE
Nitrogen mustard derivative widely used in the treatment of various malignancies and auto-immune disorders.
INCIDENCE
Low. Fewer than 25 cases reported.
CLINICAL MANIFESTATIONS (higher with intravenous than oral route)

Urticaria (+++) immediate or delayed. Anaphylactic shock +/- bronchospasm (+++). Angioedema. Vasculitis.
DIAGNOSTIC METHODS
Cutaneous testing with cyclophosphamide, ifosfamide, and cyclophosphamide metabolites: 4 hydroperoxycyclophosphamide and phosphoramide mustard. Prick-tests and intradermal tests: cyclophosphamide and ifosfamide 1 mg/ ml and 10 mg/ ml; cyclophosphamide metabolites 1 g/ml to 10 mg/ ml.
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A few cases with positive skin-tests to cyclophosphamide, ifosfamide, or metabolites. No specific IgE.
MECHANISMS
Possible IgE-mediated allergy. Cyclophosphamide is a low molecular weight compound able to form an immunogenic complex with a carrier protein. Phosphoramide mustard contains the bischlorethylamine group common to the nitrogen mustards leading to potential crossreactivity with other nitrogen mustards (melphalan, chlorambucil, ifosfamide).
MANAGEMENT
Avoidance. Use of an other nitrogen mustard (ifosfamide) is sometimes possible under strict medical supervision.
REFERENCES
Popescu N.A, Sheehan M.G, Kouides P.A, Loughner J.E, Condemi J.J, Looney R.J, Leddy J.P, Allergic reactions to cyclophosphamide: delayed clinical expression associated with positive immediate skin-tests to drug metabolites in five patients, J. Allergy. Clin. Immunol., 1996; 97: 26-33 Knysak D.J, Mc Lean J.A, Solomon W.R, Fox D.A, Mc Cune W.J, Immediate hypersensitivity reaction to cyclophosphamide , Arthritis. Rheum., 1994; 37 (7): 1101-4 Cromar B.W, Colvin M, Casale T.B, Validity of skin tests to cyclophosphamide and metabolites, J. Allergy Clin. Immunol., 1991; 88: 965-7 Kim H.C, Kesarwala H.H, Colvin M, Saidi P, Hypersensitivity reaction to a metabolite of cyclophosphamide, J. Allergy Clin. Immunol., 1985; 76 (4): 5914.
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MECHLORETHAMINE
Antimitotic alkylating agent known as nitrogen mustard administered intravenously in the treatment of hematological disorders and applied topically in the treatment of mycosis fungoids and severe psoriasis.
INCIDENCE
Frequent when applied topically. Uncommon when administered intravenously.
General: anaphylactic shock. Respiratory: dyspnea. Cutaneous: pruritus, urticaria, angioedema, bullous reactions, contact dermatitis (topical use), erythema multiforme.
DIAGNOSTIC METHODS
Cutaneous testing: prick-tests and patch-tests positive in patients with reactions to topical mechlorethamine.
MECHANISMS
Unknown for immediate reactions. Cell-mediated hypersensitivity for contact dermatitis.
MANAGEMENT
Desensitization in patients with mycosis fungoids. topical desensitization: from 0.01 mg/100 ml to 20 mg/ 100 ml intravenous desensitization.
Not always successful. REFERENCES

Pariser D.M, Childers R.C, Kechijian P, Halprin K.M, Taylor J.R, Intravenous desensitization to mechlorethamine in patients with psoriasis, Arch. Dermatol., 1976; 112 (8): 1113-4
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Constantine V.S, Fuks Z.Y, Farber E.M, Mechlorethamine desensitization in therapy for mycosis fungoids. Topical desensitization to mechlorethamine (nitrogen mustard) contact hypersensitivity, Arch. Dermatol., 1975; 111 (4): 484-8
MELPHALAN
Nitrogen mustard class cytostatic alkylating agent, used as a first line drug in the treatment of multiple myeloma.
INCIDENCE
2.4% (intravenous route). Uncommon when administered orally (0.3%). No deaths reported.
RISK FACTORS
IgA multiple myeloma (55% of cases). Intravenous route.
CLINICAL MANIFESTATIONS (at least 2 prior doses, up to 28 previous doses) General: anaphylactic shock. Cutaneous: urticaria, angioedema, rash, pruritus. Respiratory: interstitial pneumonitis. DIAGNOSTIC METHODS
Leukocyte migration inhibition test: one positive test in a case of interstitial pneumonitis.
MECHANISMS
Alkylation reaction may occur in vivo, and altered proteins may serve as new antigens capable of stimulating antibodies to the hapten-protein complex.
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MANAGEMENT
Avoidance of the intravenous route. Some reactive patients may be switched to oral melphalan with no further reaction.
Cross reactivity with other alkylating agents is exceptional (cyclophosphamide). REFERENCES

Weiss R.B, Hypersensitivity reactions , Semin.Oncol., 1992; 19 (5): 458-77 Liote H, Gauthier J.F, Prier A, Gauthier-Rahman S, Kaplan G, Akoun G, Pneumopathie interstitielle, aige, rversible, induite par le melphalan, Rev. Mal. Respir., 1989; 6 (5): 461-4 Lawrence B.V, Anaphylaxis due to oral melphalan , Cancer, Treat. Rep., 1980; 64 (4-5): 731-2 Cornwell G.G. III, Pajak T.F, Mc Intyre O.R, Hypersensitivity reactions to IV melphalan during treatment of multiple myeloma: Cancer and Leukemia Group B experience, Cancer. Treat. Rep., 1979; 63 (3): 399-403
AMINOGLUTETHIMIDE
Estrogen biosynthesis inhibitor, producing a medical adrenalectomy in patients with breast cancer.
INCIDENCE
Common (>20%).
RISK FACTORS
Associated radiotherapy.
General: anaphylactic shock, fever. Cutaneous: maculopapular rash, oral ulcerations, capillaritis.
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DIAGNOSTIC METHODS
No in vivo or in vitro method is currently available for diagnosis, other than challenge by reintroduction.
MECHANISMS
Undetermined.
MANAGEMENT
Avoidance. Corticosteroid therapy may be useful.
REFERENCES
Vanek N, Hortobagyi G.N, Buzdar A.U, Radiotherapy enhances the toxicity of aminoglutethimide, Med. Pediatr. Oncol., 1990; 18 (2): 162-4 Zambetti M, Brambilla C, Tancini G, Bonadonna G, Aminoglutethimide in postmenopausal breast cancer refractory to multiple hormonal and cytostatic treatments, Tumori., 1987; 73 (4): 369-73 Leloire O, Forzy G, Derreumaux L.L, Cordonnier D, Vincent G, Reaction anaphylactique svre laminoglutthimide (lettre), Presse. Med., 1986; 15 (1): 34
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ANTHRACYCLINE ANTIBIOTICS
DAUNORUBICIN
Antimitotic antibiotic used to treat hematological disorders.
INCIDENCE
Uncommon (1 to 2%). No deaths reported.
General: fever; anaphylactic shock. Cutaneous: rash; urticaria, angioedema.
DIAGNOSTIC METHODS
No in vivo or in vitro method is currently available for diagnosis.
MECHANISMS
Unknown.
MANAGEMENT
Avoidance. Possible cross reactivity with doxorubicin.
REFERENCES
Ma D, Isbister J.P, Cytotoxic-induced fulminant hyperpyrexia, Cancer, 1980; 45: 224951. Crowther D, Powles R.L, Bateman C.J.T, Beard M.E.J, Gauchi C.L, Wrigley P.F.M, Malpas J.S, Hamilton-Fairley G, Bodley-Scott R., Management of adult acute myelogenous leukaemia, Br. Med. J., 1973; 1: 1317. Freeman A.I, Clinical note: allergic reaction to daunomycin (NSC-82151), Cancer. Chemother. Rep., 1970; 54: 475-6
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DOXORUBICIN
Doxorubicin is an anthracycline antibiotic isolated from cultures of Streptomyces peucetius It is used in the treatment of hematological malignancies and solid and soft tissue tumors. Pegylated liposomal doxorubicin may be less cardiotoxic than free doxorubicin but mucositis is increased.
INCIDENCE
Uncommon: urticaria 1/160 to 3%. One death reported.
RISK FACTORS
Clindamycin allergy? Intravenous route.
General: anaphylactic shock. Cutaneous: pruritus, urticaria, rash, flush, flare reaction: erythema, pruritus, urticaria localized or adjacent to the site of infusion, handfoot syndrome (palmar-plantar dysesthesia). E.N.T.: nasal congestion. Respiratory: bronchospasm.
DIAGNOSTIC METHODS
Drug re-challenge.
MECHANISMS
Direct degranulation of mast cells or circulating basophils without antibody mediation. Activation of alternate complement-activity pathway.
MANAGEMENT
The use of pegylated liposomal doxorubicin (PLD) increases the frequency (7 to 9%) of hypersensitivity reactions in the first cycles of treatment (flushing, shortness of breath, facial swelling,
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headache, chills, back pain, tightness in the chest and throat, hypotension). Concerning use of intravesical doxorubicin: if the reaction is severe; give an other effective intravesical agent if the reaction is mild and self-limiting; prophylactic administration of antihistamines may be useful.
REFERENCES
Alberts D.S, Garcia D.J, Safety aspects of pegylated liposomal doxorubicin in patients with cancer, Drugs, 1997; 54 (S4): 30-5 Arena F.P, Sherlock S, Doxorubicin hypersensitivity and clindamycin (letter), Ann. Intern. Med., 1990; 112 (2): 150 Lee M, Sharifi R, Generalized hypersensitivity reaction to intravesical thiotepa and doxorubicin , J. Urol., 1987; 138 (1): 143-4 Solimando D.A Jr, Wilson J.P, Doxorubicin-induced hypersensitivity reactions, Drug. Intell. Clin. Pharm., 1984; 18 (10): 808-11 Collins J.A, Hypersensitivity reaction to doxorubicin , Drug. Intell. Clin. Pharm., 1984; 18 (5): 402-3
L-ASPARAGINASE
Polypeptide of bacterial origin (E. coli) widely used in the treatment of acute lymphoblastic leukemia in children and adults.
INCIDENCE
Highest of all antimitotic agents. Intravenous route: 15 to 33%. Intramuscular route: 6 to 18%. Deaths reported.
RISK FACTORS
Intravenous use. Hiatus of 1 month or more between two courses. Non-association with prednisone and vincristine. Prior exposure months or years previously.
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General: anaphylactic shock. Cutaneous: pruritus, rash, urticaria, angioedema. Respiratory: laryngospasm, bronchospasm.
DIAGNOSTIC METHODS
Cutaneous testing. Ineffective (false positive and negative). Specific IgE. Increased specific IgE antibodies found in patients in whom Lasparaginase infusions are followed by allergic reactions. Specific IgM and IgG (microtiter solid-phase radioimmunoassay). High titers of IgG3 or IgG4 anti L-asparaginase may predict Lasparaginase allergy. Complement activation (C3d). L-asparaginase-specific IgG antibodies bind and activate the complement system.
MECHANISMS
IgE-mediated hypersensitivity: a few cases. Complement activation induced by formation of immune complexes of L-asparaginase and specific IgM and IgG class antibodies. Leukotriene production by bone marrow-derived mast cells.
MANAGEMENT
Avoidance, but hypersensitivity reactions to L-asparaginase do not impact on the remission duration in adults with acute lymphoblastic leukemia. Use of alternative formulations: L-asparaginase derived from Erwinia chrysantemia: fewer anaphylactic reactions and no cross-reactivity with Escherichia coli L-asparaginase Polyethyleneglycol-L-asparaginase: lower immunogenicity. Premedication (epinephrine).
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Desensitization (in a 2 - year -old child with myelogenous leukemia). From 1.2 U/hour over 4.2 hours to 1200 U/hour over 3.8 hours.
REFERENCES
Larson R.A, Fretzin M.H, Dodge R.K, Schiffer C.A, Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia, Leukemia. , 1998; 12 (5): 660-5 Bonno M, Kawasaki H, Hori H, Umemoto M, Komada Y, Sakurai M, Rapid desensitization for L-asparaginase hypersensitivity, J. Allergy. Clin. Immunol., 1998; 101 (4.1): 571-12 Stone H.D Jr, Dipiro C, Davis P.C, Meyer C.F, Wray B.B, Hypersensitivity reactions to Escherichia Coli derived polyethylene glycolated-asparaginase associated with subsequent immediate skin-test reactivity to E. Coli - derived granulocyte colony stimulating factor, J. Allergy. Clin. Immunol., 1998; 101 (3): 429-31 Ettinger L.J, Kurtzberg J, Voute P.A, Jurgens H, Halpern S.L, An openlabel multicenter study of polyethyleneglycol-L-asparaginase for the treatment of acute lymphoblastic leukemia, Cancer, 1995; 75 (5): 1176-81 Fabry U, Korholz D, Jurgens H, Gobel U, Wahn V, Anaphylaxis to Lasparaginase during treatment for acute lymphoblastic leukemia in children. Evidence of a complement activated mechanism, Pediatr. Res., 1985; 19 (4): 400-8
AZATHIOPRINE
Azathioprine is an imidazole analogue of 6-mercaptopurine. This immunosuppressive agent has become the mainstay of therapy for rheumatological and dermatological conditions, and inflammatory bowel diseases.
INCIDENCE
Hypersensitivity reactions to azathioprine: more than 50 patients reported (up to 1998) in English medical literature.
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RISK FACTORS
Presence of fever, gastrointestinal symptoms, or exacerbation of the underlying disease upon initiation of the drug are risk factors for a hypersensitivity reaction. Concomitant use of corticosteroids (hypotension).
(within 4 weeks of initiation of the treatment) General: fever (38/49), hypotension (4/49), tachycardia (2/49). Cutaneous: urticaria (8/49), maculopapular eruption (3/49), erythema multiforme, erythema nodosum, purpura, petechiae. Respiratory: dyspnea (5/49), pneumonitis (3/49), cough (1/49). Gastrointestinal: nausea (21/49), vomiting (21/49), diarrhea (10/ 49), jaundice (3/49), pancreatitis (3/49), hepatitis (3/49). Musculoskeletal: arthralgia (7/49), myalgia (6/49), rhabdomyolysis (1/49). Neurological: headache (7/49), meningismus (3/49), peripheral neuropathy (2/49), seizure (1/49). Renal: oliguria (3/49), acute interstitial nephritis (1/49).
DIAGNOSTIC METHODS
No antibodies to azathioprine or its metabolites have been found. Recurrence of symptoms with drug re-challenge (to be performed with extreme caution).
MECHANISMS
Unknown. Role of the imidazole side-chain?
MANAGEMENT
Avoidance, especially if the initial dose of the medication elicits a febrile or systemic response.
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REFERENCES
Fields C.L, Robinson J.W, Roy T.M, Ossorio M.A, Byrd R.P Jr, Hypersensitivity reaction to azathioprine, South. Med. J., 1998; 91 (5): 471-4 Jones J.J, Ashworth J, Azathioprine-induced shock in dermatology patients, J. Am. Acad. Dermatol., 1993; 29 (5.1): 795-6 Rosenthal E, Azathioprine shock, Postgrad. Med. J., 1986; 62 (729): 677-8
BLEOMYCIN
Cytostatic agent produced by a strain of Streptomyces verticillus. Bleomycin inhibits cell cleavage by blocking the uptake of thymidine by DNA and leading to weakening and break-up of DNA chains.
INCIDENCE
Fever: 20 to 25% of patients. Fulminant reactions: 1 to 8% of patients. Deaths reported.
RISK FACTORS
Lymphoma (for fulminant reactions). Intravenous administration.
General: fever, hypotension. Cutaneous: pruritus, flagellate dermatitis, angioedema, toxic epidermal necrolysis, erythematous rash. Respiratory: eosinophilic pneumonia, fibrosis.
DIAGNOSTIC METHODS
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MECHANISMS
Non immunological mechanisms are likely.
MANAGEMENT
Antihistamines and corticosteroids are sometimes effective.
REFERENCES
Haerslev T, Avnstorp C, Joergensen M, Sudden onset of adverse effects due to low-dosage bleomycin indicates an idiosyncratic reaction, Cutis., 1993; 52 (1): 45-6 Yousem S.A, Lifson J.D, Colby T.V, Chemotherapy-induced eosinophilic pneumonia. Relation to bleomycin, Chest., 1985; 88 (1): 103-6 Khansur T, Little B, Tavassoli M, Fulminant and fatal angioedema caused by bleomycin treatment, Arch. Intern. Med., 1984; 144 (11): 2267
BUSULFAN
Alkylating agent able to act selectively against the myeloid cell line used in the treatment of chronic leukemia, polycythemia vera, and thrombocythemia.
INCIDENCE
Uncommon.
Cutaneous (main manifestations): bullous eruptions, urticaria. Respiratory: interstitial pneumonia (often severe), pulmonary fibrosis.
DIAGNOSTIC METHODS
MECHANISMS
Undetermined.
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MANAGEMENT
Avoidance.
REFERENCES
Akoun G, Milleron B, Mayaud C, Pulmonary changes caused by cytostatic drugs, Ann. Med. Interne.(Paris), 1985; 136 (8): 671-6 Leyden M.J, Manoharan A, Allopurinol-type rash due to busulphan , Lancet., 1978; 2 (8093): 797
CYCLOSPORINE
Cyclosporine is a potent immunosuppressive agent used to prevent rejection of transplanted organs.
INCIDENCE
23 cases of hypersensitivity have been reported (17 in patients, 5 in normal volunteers).
General: anaphylactic shock. Respiratory: dyspnea, bronchospasm. E.N.T.: laryngospasm. Cutaneous: erythematous skin rash (generalized or mainly on face and trunk), urticaria, pruritus, periorbital edema. In the 17 patients reported: 5/17 no previous exposure, 12/17 previous exposure to cyclosporine or cremophor EL (15 intravenous route, 2 oral route).
DIAGNOSTIC METHODS
Cutaneous testing is seldom performed: 2/17 patients had positive skin-tests. Provocation challenge: oral or intravenous.
MECHANISMS
The organic solvent (cremophor E.L.) contained in the intravenous solution (not in oral form) has been implicated.
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IgE-mediated hypersensitivity (positive skin-tests, no specific IgE found).

Complement activation. Direct histamine release.
MANAGEMENT
Use alternative formulations of cyclosporine: oral solution (cyclosporine 100 mg/ ml): Sandimmune (diluent: polyoxyethylated oleic glycerides). oral soft gelatin capsule: Sandimmune (diluent: polyoxyethylated glycolysed glycerides) oral solution microemulsion: Neoral (diluent: polyoxyl 40 hydrogenated castor oil) oral soft gelatin capsule microemulsion: Neoral (diluent: polyoxyl 40 hydrogenated castor oil). The soft, corn oil-based gelatin capsule appears to be the safest formulation of cyclosporine. If high-dose intravenous cyclosporine is used: cyclosporine solutions are incompatible with polyvinyl chloride (PVC) plastics and must be prepared in non-PVC plastic bags, glass bottles or polypropylene syringes. Tubing used for the infusion must not contain PVC. cyclosporine should be diluted to 0.5 to 2.5 mg/ ml with 5% dextrose or 0.9% sodium chloride. After adding cyclosporine to the carrier fluid, the infusion must be mixed thoroughly by shaking or swirling the bottle. The infusion fluid must appear homogenous. the tubing system must be primed with 0.9% saline or 5% dextrose. high-dose cyclosporine should not be administered to the patient unless the patient has received appropriate corticosteroid and antihistamine premedication . During the first ten minutes of the first and second cyclosporine infusions, supervision by medical personnel with proper resuscitation skills is advisable.
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REFERENCES
Volcheck G.W, Van Delenn R.G, Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and review, Ann. Allergy. Asthma. Immunol., 1998; 80 (2): 159-63 Liau-Chu M, Theis J.G.W, Koren G, Mechanism of anaphylactoid reactions: improper preparation of high-dose intravenous cyclosporine leads to bolus infusion of cremophor EL and cyclosporine, Ann. Pharmacother., 1997; 31: 1287-91 Boehnke-Michaud L, Methods for preventing reactions secondary to cremophor EL, Ann. Pharmacother., 1997; 31: 1402-4 Theis J.G.W, Liau-Chu M, Chan H.S, Doyle J, Greenberg M.L, Koren G, Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: the causative role of improper dissolution of cremophor EL, J. Clin. Oncol., 1995; 13 (10): 2508-16
CYTARABINE
Antimitotic antimetabolite agent. This hydrosoluble pyrimidic nucleoside-resembling cytidin inhibits desoxycytidin synthesis by a competitive mechanism. It is used in the treatment of acute leukemia and some solid tumors.
INCIDENCE
Type I reactions: uncommon. Cytarabine syndrome: up to 21% of treated patients in some reports. Toxic conjunctivitis: uncommon. Neutrophilic eccrine hidradenitis: uncommon. Palmar-plantar syndrome: rare.
Type I reactions: dyspnea, chest pain, fever, angioedema, urticaria, hypotension. Cytarabine syndrome: fever, rigors, diaphoresis, myalgia, arthralgia, maculopapular rash, hypotension, conjunctivitis. Palmar-Plantar erythema: +/- generalized erythematous maculopapular rashes.
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Neutrophilic eccrine hidradenitis: tender, erythematous, indurated lesions (trunk + upper extremities).
DIAGNOSTIC METHODS
Type I reactions. Cutaneous testing. Prick-tests are negative. A few cases of positive intradermal skin-tests at a concentration of 4 g/ml. Presence of specific IgE antibodies: in some patients with anaphylactic shock. Specific histamine release.
MECHANISMS
Type I reactions: IgE-mediated hypersensitivity is suggested by immediately positive intradermal skin tests, detection of IgE antibodies and passive cutaneous anaphylaxis. Cytarabine syndrome, toxic conjunctivitis, neutrophilic eccrine hidradenitis: direct toxicity is likely.
MANAGEMENT
Type I reactions. Desensitization. Adults (1 case): starting with 10 ml of 0,002% cytarabine up to 200 mg of cytarabine in 500 cc of saline. Children (1 case): 200 g to 45 mg in 13 hours. Other reactions. Pretreatment with corticosteroids is sometimes helpful.
REFERENCES
Blanca M. Torres M.T, Giron M, Corzo J.L, Martinez-Valverde A,Successful administration of cytarabine after a previous anaphylactic reaction , Allergy.1997; 52: 1009-1011 Weiss R.B, Hypersensitivity reactions Sem. Oncology.1992; 19 (5): 458-77
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Berkowitz F.E, Wehde S, Ngwenya E.T, Anaphylactic shock due to cytarabine in a leukemic child, Am. J. Dis. Child., 1987; 141: 1000-1 Markman M, Howell S.B, King M, Pfeifle C, Nasserman S.I.,Anaphylactic reaction to cytarabine: in vitro evidence that the immune response is IgEmediated. Med. Ped. Oncol. 1984; 12: 2013 Rassiga A.L, Schwartz H.J, Forman W.B, Crum E.D, Cytarabine induced anaphylaxis demonstration of antibody and successful desensitization, Arch. Intern. Med. 1980; 140: 425-8
DACARBAZINE
Dacarbazine (DTIC) is an imidazole carboxamide used in the treatment of malignant melanoma, sarcomas, Hodgkins disease and neuroblastoma.
INCIDENCE
Anaphylactic shock: one case. More common for photosensitivity and hepatitis.
General: anaphylactic shock (one case). Cutaneous: photosensitivity, localized skin reaction, pruritus, erythema, edema. Hepatic: allergic hepatitis (allergic hepatic veno-occlusive disorder: Budd-Chiari syndrome).
DIAGNOSTIC METHODS
None.
MECHANISMS
Unknown.
MANAGEMENT
Avoidance.
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REFERENCES
Serrano G, Aliaga A, Febrer I, Dacarbazine induced photosensitivity , Photodermatology, 1989; 6: 140-1 Abhyankar S, Rao S.P, Pollio L, Miller S.T, Anaphylactic shock due to dacarbazine, Am. J. Dis. Child., 1988; 142 (9): 918 Mc Clay E, Lusch C.J, Mastrangelo M.J, Allergy-induced hepatic toxicity associated with dacarbazine, Cancer Treat. Rep, 1987; 71 (2): 219-20 Koehn G.G, Balizet L.B, Unusual local cutaneous reaction to dacarbazine, Arch. Dermatol., 1982; 118 (12): 1018-9
DIAZIQUONE
Diaziquone is an aziridinylbenzoquinone alkylating agent used in various carcinomas.
INCIDENCE
1 to 2%.
(occurring after several courses of diaziquone) General: anaphylactic shock. Cutaneous: pruritus, urticaria. Respiratory: bronchospasm.
DIAGNOSTIC METHODS
Recurrence of hypersensitivity reactions with drug re-challenge (3/3).
MECHANISMS
The solvent: N,N-dimethylacetamide could be involved in hypersensitivity reactions.
MANAGEMENT
Avoidance. No protocols for prophylactic premedication have been yet published.
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REFERENCES
Weiss R.B, Hypersensitivity reactions, Semin.Oncol., 1992; 19 (5): 45877 Posada J.G, ODwyer P.J, Hoth D.F, Anaphylactic reactions to diaziquone, Cancer. Treat. Rep., 1984; 68 (10): 1215-7 Budman D.R, Schulman P, Vinciguerra V, Weiselberg L, Degnan T.J, Anaphylactoid reactions to AZQ, Cancer Chemother. Pharmacol., 1982; 8 (3): 317
EPIDOPHYLLOTOXINS
ETOPOSIDE
Semi-synthetic derivative of podophyllotoxin, active against a number of tumors: germ cell neoplasms, small cell lung carcinoma and malignant lymphoma.
INCIDENCE
93 cases reported up to 1996. 3 deaths. High incidence in children with Hodgkins disease.
RISK FACTORS
Intravenous route.
Hypotension, bronchospasm, facial flushing, exanthema, dyspnea, fever, chills, tachycardia, chest tightness, cyanosis, hypertension (rare).
Urticaria is uncommon. DIAGNOSTIC METHODS

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MECHANISMS
Non specific histamine release. The role of polysorbate 80 (Tween 80) used as an excipient in the parenteral formulation is doubtful.
MANAGEMENT
Lowering of the infusion rate. Continuing administration without modification (65% successful) Premedication with antihistamines and/ or corticosteroids.
REFERENCES
Hoetelmans R.M., Schornagel J.H, ten Bokkel Huinink W.W, Beijnen J.H, Hypersensitivity reactions to etoposide, Ann. Pharmacother, 1996; 30 (4): 367-71 Hudson M.M, Weinstein H.J,Donaldson S.S, Greenwald C, Kun L, Tarbell N.J, Humphrey W.A, Rupp C, Marina N.M, Wilimas J, Link M.P, Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkins disease, J. Clin. Oncol., 1993; 11 (6): 1080-4 Kellie S.J, Crist W.M, Pui C.H, Crone M.E, Fairclough D.L, Rodman J.H, Hypersensitivity reactions to epidophyllotoxins in children with acute lymphoblastic leukemia, Cancer. 1991; 67: 1070-5 Eschalier A, Lavarenne J, Burtin C, Renoux M, Chapuy E, Rodriguez M, Study of histamine release induced by acute administration of anti tumor agents in dogs, Cancer Chemother. Pharmacol., 1988; 21: 246-50
TENIPOSIDE
Semisynthetic derivative of podophyllotoxin which interacts with type II topoisomerase to induce DNA cross-links and double-strand breaks.
INCIDENCE
2 to 11%. 41% of children with acute lymphoblastic leukemia treated with intensive multiagent chemotherapy.
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RISK FACTORS
Children with neuroblastoma or brain tumors. High doses (children): 1500 to 2000 mg/ m2.
(often on the first dose) General: hypotension, oliguria, intravascular hemolysis, sweating, palor, fever. Respiratory: chest pain, wheezing. Cutaneous: flushing, urticaria, angioedema.
DIAGNOSTIC METHODS
In vitro histamine release from basophil leukocytes: non-specific histamine release. One case with IgG 1 antibody to teniposide.
MECHANISMS
Cremophor EL is thought to be the culprit (see cremophor EL).
MANAGEMENT
Premedication with diphenydramine +/- corticosteroids is useful. Etoposide does not usually cross-react.
REFERENCES
Kellie S.J, Crist W.M, Pui C.H, Crone M.E, Fairclough D.L, Rodman J.H, Rivera G.K, Hypersensitivity reactions to epipodophyllotoxins in children with acute lymphoblastic leukemia, Cancer. , 1991; 67 (4): 1070-5 Siddall S.J, Martin J, Nunn A.J, Anaphylactic reactions to teniposide, Lancet., 1989; 1 (8634): 394 Nolte H, Carstensen H, Hertz H, VM-26 (teniposide)-induced hypersensitivity and degranulation of basophils in children, Am. J. Pediatr. Hematol. Oncol., 1988; 10 (4): 308-12 ODwyer P.J, King S.A, Fortner C.L, Leyland-Jones B, Hypersensitivity reactions to teniposide (VM-26): an analysis , J. Clin. Oncol., 1986; 4 (8): 1262-9
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5-FLUOROURACIL
Pyrimidine analogue used for the treatment of several types of malignancies. Topical 5-FU is widely used for the treatment of actinic keratosis and warts in some countries.
INCIDENCE
Unknown.
RISK FACTORS
Seborrheic dermatitis (palmar-plantar dermatitis). Iterative long-term topical applications.
Anaphylactic shock (4 cases reported). Angioedema. Palmar-plantar dermatitis. Contact eczema by topical application, pigmentation abnormalities, phototoxicity and photosensitization.
DIAGNOSTIC METHODS
Cutaneous testing: one case with intradermal test positive (anaphylactic shock).
Patch-tests and photopatch-tests with 0.5-1% 5-FU in pet.

No specific IgE found.
MECHANISMS
IgE-mediated hypersensitivity (one case of anaphylactic shock). Probable direct cytotoxic effect of 5 FU (palmar-plantar dermatitis).
MANAGEMENT
Avoidance.
REFERENCES
Nadal C, Pujol R.M, Randazzo L, Marchello E, Alomar A, Systemic contact dermatitis from 5-Fluorouracil, Contact. Dermatitis., 1996; 35: 124-5
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Milla Santos A, Sanchiz Medina F, Anaphylactic reaction following i.v administration of 5-fluorouracil (letter), Cancer. Treat. Rep., 1986; 70 (11): 1346 Sridhar K.S, Allergic reactions to 5-fluorouracil infusion, Cancer., 1986; 58: 862-4 de Beer R, Kabakow B, Anaphylactoid reactions associated with intravenous administration of 5-fluorouracil, N.Y. State. J. Med., 1979; 79: 1750-1
HYDROXYUREA
Antimetabolite acting primarily on cells in S phase. It is used in patients with myeloproliferative disorders.
INCIDENCE
Cutaneous manifestations: 10 to 35% of patients. Fever: 15 cases published (up to 1997).
General: fever, appearing within the first few weeks after first exposure; disappearing rapidly after discontinuation. Cutaneous: generalized dryness and scaling (xerosis), dermatomyositis-like eruption (dorsal hands), cutaneous atrophy, hyperpigmentation of skin and nails, ulcerative lichen planus-like dermatitis, fixed drug eruption (rare), oral or leg ulceration.
Respiratory: alveolitis (rare). DIAGNOSTIC METHODS

Skin biopsy: epidermal thickening, flattening of the dermoepidermal junction, basal layer degeneration, colloid body formation.
MECHANISMS
Cutaneous reactions: Lichenoid hypersensitivity reaction? Hydroxyurea toxicity on the basal layer of the epidermis?
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MANAGEMENT
Hydroxyurea can be continued if necessary with no worsening of cutaneous lesions.
REFERENCES
van der Klooster J.M, Sucec P.M, Stiegelis W.F, Hagenbeek A, Fever caused by hydroxyurea: a report of three cases and review of the literature, Neth. J. Med., 1997; 51 (3): 114-8 Senet P, Aractingi S, Porneuf M, Perrin P, Duterque M, Hydroxyurea induced dermatomyositis-like eruption , Br. J. Dermatol., 1995; 133 (3): 455-9 Lossos I.S, Matzner Y, Hydroxyurea-induced fever: case report and review of the literature, Ann. Pharmacother., 1995; 29 (2): 132-3 Kelly R.I, Bull R.H, Marsden A, Cutaneous manifestations of long-term hydroxyurea therapy, Australas. J. Dermatol., 1994; 35 (2): 61-4
METHOTREXATE
Folic acid antagonist used in the treatment of several neoplasms and inflammatory disorders.
INCIDENCE
Anaphylactic shock: fewer than 20 cases reported.
General: anaphylactic shock. Cutaneous: pruritus, urticaria, angioedema, cutaneous vasculitis, severe epidermal toxicity. Respiratory: acute pneumonitis, bronchospasm. Hematological: pancytopenia, agranulocytosis, hemolytic anemia.
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-test: with methotrexate 10 mg/ ml. One positive case (anaphylactic shock).
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Intradermal test: 0,1 ml of 25 mg/ ml solution of methotrexate. One case positive complicated by syndromic reaction (anaphylactic shock). No specific IgE found. No specific histamine release shown. Drug induced lymphocyte stimulation test (DLST): positive in 2 cases of pancytopenia, and one case of agranulocytosis. IgG3 antibody in a case of hemolytic anemia.
MECHANISMS
Type I reactions: anaphylaxis, urticaria, angioedema. Type II reactions: hemolytic anemia. Type III reactions: acute pneumonitis, cutaneous vasculitis.
MANAGEMENT
If no alternative therapy exists and there is a non life-threatening hypersensitivity reaction, re-challenge may be considered. Most of the time (92%) there are recurrent symptoms despite premedication. Desensitization is sometimes used (one successful case beginning with 0.1 mg up to 25 mg in 60 hours).
REFERENCES
Alkins S.A, Byrd J.G, Morgan S.K, Ward F.T, Weiss R.B, Anaphylactoid reactions to methotrexate , Cancer. 1996; 77 (10): 2123-6 Vega A, Cabanas R, Contreras J, Lopez-Casana J, Lopez-Serrano C, Pascual C, Martinez-Alzamora F, Anaphylaxis to methotrexate: a possible IgEmediated mechanism, J. Allergy. Clin. Immunol., 1994; 94 (2.1): 268-70 Cohn J.R, Cohn J.B, Fellin F, Cantor R, Systemic anaphylaxis from low dose methotrexate , Ann.Allergy., 1993; 70 (5): 384-5 Gluck-Kuyt I, Irwin L.E, Anaphylactic reaction to high dose methotrexate , Cancer. Treat. Rep., 1979; 63: 797-8
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MITOMYCIN
Antitumor antibiotic derived from Streptomyces caespitosus; widely used for treatment and prevention of superficial bladder cancer (intravesical instillation).
INCIDENCE
Cutaneous side-effect: 9% of patients treated with intravesical instillations.
RISK FACTORS
Association with vincristine, bleomycin or doxorubicin.
Cutaneous: vesicular dermatitis of the hands, the genitals, and feet. More diffuse reactions involving the trunk. Respiratory: interstitial lung disease.
DIAGNOSTIC METHODS
Cutaneous testing. Skin tests: one immediately positive intradermal skin test reported in a patient who presented an immediate reaction. Patch-tests (concentration ranging from 0.06% to 0.6% in water or in petrolatum) positive in patients with contact allergy.
MECHANISMS
Presence of CD I + has been shown in bladder epithelium. Eczematous eruptions are type IV hypersensitivity reactions; mediated transvesically.
MANAGEMENT
Avoidance. Topical corticosteroids may be useful.
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REFERENCES
de Groot A.C, Conemans J.M, Systemic allergic contact dermatitis from intravesical instillation of the antitumor antibiotic mitomycin C, Contact. Dermatitis., 1991; 24 (3): 201-9 Colver G.B, Inglis J.A, Mc Vittie E, Spencer M.J, Tolley D.A, Hunter J.A, Dermatitis due to intravesical mitomycin C: a delayed-type hypersensitivity reaction ?, Br. J. Dermatol., 1990; 122 (2): 217-24 Nissenkorn I, Herrod H, Soloway M.S, Side effects associated with intravesical mitomycin, J. Urol., 1981; 126 (5): 596-7
MITOXANTRONE
Mitoxantrone (DHAD) has been synthesized by systematic substitution on the basic anthraquinone nucleus. It is used in the treatment of refractory cancers (advanced breast cancer).
INCIDENCE
Less than 1%.
General: anaphylactic shock.
Cutaneous: rashes (vesicular and erythematous), facial edema. DIAGNOSTIC METHODS

Skin biopsy: leukocytoclastic vasculitis in a case of erythematous vesicular rash.
MECHANISMS
Unknown.
MANAGEMENT
Avoidance.
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REFERENCES
Taylor W.B, Cantwell B.M, Roberts J.T, Harris A.L, Allergic reactions to mitoxantrone, Lancet, 1986; 1 (8495): 1439 Anderson K.C, Cohen G.I, Garnick M.B, Phase II trial of mitoxantrone, Cancer. Treat. Rep, 1982; 66 (11): 1929-31
PENTOSTATIN
Pentostatin (2'-deoxycoformycin) is an antibiotic produced by culture broths of Streptomyces antibioticus, and widely used as antineoplastic agent (lymphoid malignancies, mycosis fungoids, chronic lymphocytic leukemia).
INCIDENCE
0.5 to 1 %.
RISK FACTORS
Concomitant use of allopurinol.
General: anaphylactic shock, fever. Cutaneous: pruritus, rash, flushing, edema, dryness of the chest and limbs. Respiratory: cough, pulmonary infiltrates. Hematological: eosinophilia.
DIAGNOSTIC METHODS
Hypersensitivity vasculitis involving arteries and veins in the heart, spleen, cerebral cortex (autopsy). Recurrence of reactions with drug re-challenge.
MECHANISMS
Concomitant administration of allopurinol to prevent hyperuricemia secondary to tumor lysis could enhance pentostatin toxicity. Pentostatin is formulated using mannitol and sodium hydroxide.
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MANAGEMENT
Avoidance of systematic use of allopurinol.
REFERENCES
ODwyer P.J, King S.A, Eisenhauer E, Grem J.L, Hoth D.F, Hypersensitivity reactions to deoxycoformycin, Cancer. Chemother. Pharmacol., 1989; 23 (3): 173-5 Steinmetz J.C, DeConti R, Ginsburg R, Hypersensitivity vasculitis associated with 2-deoxycoformycin and allopurinol therapy, Am. J. Med., 1989; 86 (4): 498-9
PLATINUM COMPOUNDS
CARBOPLATIN
Mainstay therapy in ovarian and testicular carcinoma but also in brain tumors in children (pilocytic astrocytoma).
INCIDENCE
Unusual (< 8% of patients). Increase with the number of courses in adults (6% at cycle 6 to 67% by cycle 10) with ovarian carcinoma. 10 of 150 children with brain tumors.
RISK FACTORS
Occupational exposure to platinum salts(?)
General: anaphylactic shock. Cutaneous: pruritus, urticaria, diffuse erythema. Respiratory: dyspnea, bronchospasm, cyanosis. Digestive: vomiting.
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DIAGNOSTIC METHODS
Cutaneous testing Intradermal skin-tests positive at 0,1 mg/ ml and 1 mg/ ml in a few patients. No specific IgE found.
MECHANISMS
IgE-mediated hypersensitivity in some cases (platinum is a tetravalent inorganic molecule that readily complexes with proteins to form antigens).
Direct histamine release. MANAGEMENT

Pre-treatment with corticosteroids and antihistamines (sometimes ineffective in preventing IgE-mediated reactions). Desensitization. Many protocols have been reported:
In children:
rush protocol: Premedication with prednisolone 12 h and 1 h before, diphenydramine 30 minute before and ranitidine 30 minute before. Then: 1 - 2.5 - 5 - 10 - 25 and 50 mg of carboplatin infused at 1 mg/ min every 15 minutes. The remainder of the dose at 200 mg/ hr. slow protocol: 0.1 - 0.2 - 0.5 - 1 - 2 - 3 - 4 - 5 - 7.5 - 10 and 15 mg at 1 mg/ min every 15 minutes. Then: 100 mg/ hr for one hour then remainder of the dose at 200 mg/ hr.
In adults:
rush protocol (4 hours): 350 mg/ m2 carboplatin in 100 ml aqueous dextrose solution (D5W) 0.1 ml - 1 ml - 10 ml diluted in 100 ml D5W over one hour each. The remainder of the dose over one hour.
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slow protocol (81 hours): 0.4 mg carboplatin / 150 ml over 1.5 hour. 4 mg carboplatin / 150 ml over 15 hours. 40 mg carboplatin / 150 ml over 15 hours. 355 mg carboplatin / 500 ml over 50 hours.
REFERENCES
Broome C.B, Schiff R.I, Friedman H.S, Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions, Med. Pediatr. Oncol., 1996; 26 (2): 105-10 Goldberg A, Confino-Cohen R, Fishman A, Beyth Y, Altaras M, A modified prolonged desensitization protocol in carboplatin allergy, J. Allergy. Clin. Immunol., 1996; 98: 841-3 Windom H.H, Mac-Guire W, Hamilton R.G, Adkinson Jr N.F, Anaphylaxis to carboplatin. A new platinum chemotherapeutic agent, J. Allergy. Clin. Immunol., 1992; 90: 681-3
CISPLATIN
Cytostatic agent able to inhibit DNA synthesis selectively and specifically. Most active agent in germ-cell tumors and osteogenic carcinoma.
INCIDENCE
Common in the 1970s studies: 6 to 14% (six or more doses of cisplatin). Far less frequent in the 1980s: only 3 or 4 cisplatin courses in testicular carcinoma; and common use of diphenydramine and dexamethasone in emesis prevention.
RISK FACTORS
Concurrent use of other drugs (bleomycin, actinomycin, vinblastine, cyclophosphamide). Intravesical use: incidence 10 to 25% (especially if > 8 courses). Intraperitoneal use: if large doses and high infusion time ratio (>2,2).
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Occupational exposure to platinum salts(?).
General: anaphylactic shock (deaths reported). Cutaneous (most common): pruritus, urticaria, rash, flush. Respiratory: dyspnea, bronchospasm. Digestive: vomiting. Hematological: hemolytic anemia (or false positive direct antiglobulin test).
DIAGNOSTIC METHODS
Cutaneous testing. Prick-test: 0,1 mg/ ml Intradermal-test: 0,001 mg/ ml; 0,01 mg/ ml; 0,1 mg/ ml. Few patients positive to I.D. 0,1 mg/ ml. Histamine release.
One case with positive histamine release test. MECHANISMS

IgE-mediated hypersensitivity in some cases (cisplatin acts as a hapten bound to serum proteins). Direct release of vasoactive substances.
MANAGEMENT
Pretreatment with corticosteroids and antihistamines (sometimes ineffective in preventing IgE-mediated reactions). Desensitization: a few cases reported. After premedication with hydroxyzine and methylprednisolone, gradual increase of doses from 1 mg to 80 mg at 30 min intervals. Cross-reactivity with other platin derivatives (carboplatin, iproplatin and DACPP) is likely.
REFERENCES
Hebert M.E, Blivin J.L., Kessler J, Soper J.T, Oleson J.R.,Anaphylactoid reactions with intraperitoneal cisplatin, Ann. Pharmacother., 1995; 29: 260-3
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Goldberg A, Altaras M.M., Mekori Y.A, Beyth Y, Confino-Cohen R., Anaphylaxis to cisplatin: diagnosis and value of pretreatment in prevention of recurrent allergic reactions. Ann. Allergy., 1994; 73: 271-2 Ter-Schiphorst C, Bousquet J, Menardo J.L, Piquemal M, Bataille A, Michel F.B., Desensibilisation spcifique au cis-dichloro-diamino-platinum (D.D.P:) chez un malade allergique, Presse. Med., 1986; 15 (26): 1242.
PROCARBAZINE
Cytostatic agent derived from methylhydralazine. Mainly used in the treatment of lymphoma and brain tumors.
INCIDENCE
Severe allergic reactions: 2%, severe toxic effects: 2%, lifethreatening allergic reactions: 1% in Hodgkins disease. Much higher (25%) in patients with brain tumors.
RISK FACTORS
Brain tumors, especially when anticonvulsant therapy is used.
General: fever. Respiratory: cough, dyspnea, acute pulmonary infiltrates, pleural effusion. Cutaneous: pruritus, urticaria, maculopapular rash (+++), angioedema, fixed drugeruption, toxic epidermal necrolysis.
DIAGNOSTIC METHODS
No in vivo or in vitro method is currently available for diagnosis other than re-challenge (which is hazardous: life-threatening pneumonitis published).
MECHANISMS
Classical complement pathway activation is possible. Procarbazine oxidation to a reactive intermediate is enhanced by phenobarbital.
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MANAGEMENT
Avoidance. Use non enzyme-inducing anticonvulsants. Corticosteroids are useful in the management of respiratory manifestations.
REFERENCES
Lehmann D.F, Hurteau T.E, Newman N, Coyle T.E, Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors, Clin. Pharmacol. Ther., 1997; 62 (2): 225-9 Coyle T, Bushunow P, Winfield J, Wright J, Graziano S, Hypersensitivity reactions to procarbazine with mechlorethamine, vincristine, and procarbazine chemotherapy in the treatment of glioma, Cancer, 1992; 69 (10): 2532-40 Brooks B.J Jr, Hendler M.B, Alvarez S, Ancalmo N, Grinton S.F, Delayed life-threatening pneumonitis secondary to procarbazine , Am. J. Clin. Oncol., 1990; 13 (3): 244-6 Glovsky M.N, Braunwald J, Opelz G, Alenty A, Hypersensitivity to procarbazine associated with angioedema, urticaria and low serum complement activity, J. Allergy. Clin. Immunol., 1976; 57 (2): 134-40
TAXANES
DOCETAXEL
Docetaxel, the new chemotherapeutic agent (taxoids) derived from the needles of the European yew (Taxus baccata); shows significant antitumor activity in phase II trials of ovarian, breast and non small cells lung cancer.
INCIDENCE
Cutaneous manifestations (erythema, pruritus, dry skin, macular eruptions, swelling, burning, desquamation): 64.3%. Grade III: 6.4%; grade IV: 1.7%. Fever: 35.8%. Grade III: 2.8%; grade IV: 0.2%.
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Hypersensitivity reactions: 31.3 % (usually occurring in the first or second course). Mild: pruritus, flushing, rash, fever, chills. Severe: hypotension, dyspnea, bronchospasm, general urticaria or angioedema. Grade III: 6.7%; grade IV: 0.6%.
General: hypotension, fever, chills. Cutaneous: erythrodysesthesia, solitary erythematous to edematous plaque in the infusionarm proximal to the site of infusion, pruritus, urticaria, angioedema, flushing. Respiratory: dyspnea, bronchospasm.
DIAGNOSTIC METHODS
Skin biopsy (erythrodysesthesia): epidermal dysmaturation with necrotic keratinocytes or sparse superficial perivascular lymphocytic infiltration with eosinophils, focal vacuolar alteration or plain perivascular lymphocytic inflammation.
MECHANISMS
Non-specific release of vasoactive mediators following mast-cell degranulation is likely.
MANAGEMENT
The usefulness of premedication with antihistamines and corticosteroids is controversial. Oral pretreatment 12 hours and 3 hours before infusion of docetaxel with 32 mg of methyprednisolone, 10 mg of cetirizine and 1 mg of ketotifen limits the development of acute hypersensitivity reactions (28% -> 7.7%). Classical prophylactic medication: dexamethasone 8 mg 13 hours, 7 hours, 1 hour before the administration of docetaxel; clemastine 1 mg 13 hours, 7 hours, 1 hour, before the administration of docetaxel; followed by dexamethasone 8 mg p.o. twice daily for 3 days.
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Sodium cromoglycate (400 mg orally x 4 daily) could be an alternative to corticosteroids and conventional antihistamines in the treatment of taxoid-induced acute hypersensitivity reactions. Skin toxicity is not prevented by corticosteroids and antihistamines. Treatment with an ointment of glycerin and chlorhexidine is simple, and improves the condition in most patients.
REFERENCES
Westermann A.M, ten Bokkel Huinink W.W, Rodenhuis S, Successful docetaxel re-challenge with cromoglycate after major sensitivity reactions, Ann. Oncol., 1996; 7 (1): 104 Cortes J.E, Pazdur R, Docetaxel, J. Clin. Oncol., 1995; 13 (10): 2643-55 Zimmermann G.C, Keeling J.H, Burris H.A, Cook G, Irvin R, Kuhn J, Mc Collough M.L, Von Hoff D.D, Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent, Arch. Dermatol., 1995; 131 (2): 202-6 Schrijvers D, Wanders J, Dirix L, Prove A, Vonck I, van Oosterom A, Kaye S, Coping with toxicities of docetaxel (Taxotere), Ann. Oncol., 1993; 4 (7): 610-11
PACLITAXEL
A member of a new class of antineoplastic agents (taxanes), paclitaxel is a natural diterpene product, isolated from the bark of Taxus brevifolia. Clinically active in ovarian, breast and non-small lung cancer.
INCIDENCE
Severe reactions: 2%. Hypersensitivity reactions: > 10%.
Bronchospasm, dyspnea (81%). Urticaria, erythematous rash (74%). Hypotension (41%). Angioedema (19%). Pneumonitis (in previously irradiated patients).
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DIAGNOSTIC METHODS
Basophil histamine release: non IgE-mediated response.
MECHANISMS
The vehicle (cremophor EL + ethanol) is likely to be responsible.
MANAGEMENT
Premedication is effective. Numerous prophylactic regimens have been published: 1 20 mg dexamethasone orally 12 hours and 6 hours before paclitaxel, and 20 mg I.V just before treatment + 50 mg diphenhydramine orally 12 hours and 6 hours before paclitaxel, and 50 mg I.V just before treatment + 25 mg ephedrine sulfate orally one hour before paclitaxel (if possible). 2 5 to 20 mg dexamethasone I.V + 50 mg diphenhydramine I.V + 300 mg cimetidine or 50 mg ranitidine I.V 30 minutes before paclitaxel. 3 20 mg dexamethasone I.V just before paclitaxel + 50 mg orphenadrine I.M, and 300 mg cimetidine I.V one hour before paclitaxel. Desensitization: 1/100000 (1, 2, 4, 8 ml) to 1 ml undiluted solution, then continuous infusion. Alternative formulations of paclitaxel: polyethylene glycol (decreases the antitumor activity of taxol) cyclodextrins (renal and hemolytic toxicity) polyvinylpyrrolidone nanoparticles (improvement in antitumor efficacy) phospholipid suspensions: liposomes (increased efficacy) prodrugs. Clinical efficacy needs to be established.
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REFERENCES
Szebeni J, Muggia F.M, Alving C.R, Complement activation by cremophor EL as a possible contributor to hypersensitivity to paclitaxel: an in vitro study, J. Natl. Cancer. Inst., 1998; 90 (4): 300-6 Bookman M.A, Kloth D.D, Kover P.E, Smolinski S, Ozols R.F, Short-course intravenous prophylaxis for paclitaxel-related hypersensitivity reactions, Ann. Oncol., 1997; 8 (6): 611-4 Meerum-Terwogt J.M, Nuijen B, Ten Bokkel Huinink W.W, Beijnen J.H, Alternative formulations of paclitaxel, Cancer Treat. Rev., 1997; 23 (2): 87-95 Essayan D.M, Kagey-Sobotka A, Colarusso P.J, Lichtenstein L.M, Ozols R.F, King E.D, Successful parenteral desensitization to paclitaxel, J. Allergy. Clin. Immunol, 1996; 97: 42-6 Boehm D.K, Maksymiuk A.W, Paclitaxel premedication regimens (letter), J. Natl. Cancer. Inst., 1996; 88 (7): 463-5 Gennari A, Salvadori B, Tognoni A, Conte P.F, Rapid intravenous premedication with dexamethasone prevents hypersensitivity reactions to paclitaxel (letter), Ann. Oncol., 1996; 7 (9): 978-9 Weiss R.B, Donehower R.C, Wiernik P.H, Ohnuma T, Gralla R.J, Trump D.L, Baker J.R Jr, Van Echo D.A, Von Hoff D.D, Leyland-Jones B, Hypersensitivity reactions from taxol, J. Clin. Oncol., 1990; 8 (7): 1263-8
THIOTEPA
Alkylating agent acting upon synthesis of desoxyribonucleoproteins. Used in the treatment of ovarian, breast cancer and bladder tumors (intravesical instillation).
INCIDENCE
3% of intravesical infusions.
RISK FACTORS
Bladder instillation.
General: fever. Cutaneous: pruritus, urticaria. angioedema.
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DIAGNOSTIC METHODS
MANAGEMENT
Avoid use.
REFERENCES
Lee M, Sharifi R, Generalized hypersensitivity reaction to intravesical thiotepa and doxorubicin, J. Urol., 1987; 138 (1): 1434. Hu K.N, Kim A, Khan A.S, Soroff H, Gonder M, Combined thiotepa and mitomycin C instillation therapy for low-grade superficial bladder tumor, Cancer, 1985; 55 (8): 1654-8
VINCA ALKALOIDS
VINBLASTINE VINCRISTINE VINDESINE
Plant alkaloids frequently used in current chemotherapy protocols.
INCIDENCE
Exceptional for anaphylaxis. More common for bronchospasm. Deaths reported.
RISK FACTORS
Associated treatment with mitomycin (respiratory manifestations).
General: anaphylactic shock (vincristine). Cutaneous: erythrodermia, localized epidermal necrolysis Respiratory: acute respiratory failure (vinblastine), bronchospasm, pleural effusion.
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DIAGNOSTIC METHODS
No in vivo or in vitro method is currently available for diagnosis. Pulmonary function tests show obstructive patterns.
MECHANISMS
Undetermined.
MANAGEMENT
Avoidance. Premedication with corticosteroids may be useful.
REFERENCES
Thomas P, Pradal M, Le Caer H, Montcharmont D, Vervloet D, Kleisbauer J.P, Bronchospasme aigu du lassociation alcalode de la pervenchemitomycine, Rev. Mal. Resp., 1993; 10: 268-71 Rivera M.P, Kris M.G, Gralla R.J, White D.A, Incidence and syndrome of acute shortness of breath following vinca alkaloids in patients receiving mitomycin, Proc. Ann. Meet Am. Soc. Clin. Oncol., 1990; 9: A1246. Ballen K.K, Weiss S.T, Fatal acute respiratory failure following vinblastine and mitomycin administration for breast cancer , Am. J. Med. Sci.1988; 295 (6): 558-60 Bhardwaj B, Kalra S.K, Gupta G, Fatal anaphylaxis following intravenous vincristine (letter), Indian Pediatr., 1986; 23 (11): 961 Luedke D, McLaughlin T.T, Daughaday C, Luedke S, Harrison B, Reed G, Martello O, Mitomycin C and Vindesine associated pulmonary toxicity with variable clinical expression, Cancer, 1985; 55: 5425 Dyke R.W, Acute bronchospasm after vinca alkaloids in patients previously treated with mitomycin, New Eng. J. Med., 1984; 310 (6): 389.
ANCILLARY DRUGS
5 HYDROXYTRYPTAMINE 3 RECEPTOR ANTAGONISTS
Granisetron, ondansetron and tropisetron are used for prevention of nausea and vomiting associated with cancer chemotherapy.
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INCIDENCE
Uncommon. Ondansetron: 24 cases (FDA 1994). Tropisetron: 11 cases.
RISK FACTORS
Previous reaction with another 5 HT 3 receptor antagonist.
Differentiate from non-allergic side-effects (headache, gastrointestinal symptoms). Anaphylactic reactions. Rashes, Facial edema. Bronchospasm. Chest pain. Arrhythmias.
DIAGNOSTIC METHODS
Drug re-challenge: positive.
MECHANISMS
Unknown.
MANAGEMENT
Avoidance of all 5 HT 3 receptor antagonists due to effects of drug class.
REFERENCES
Frigerio C, Buchwalder P.A, Spertini F, Ondansetron: reasons to be restrictive, Lancet., 1996; 347: 1484-5 Kataja V, de Bruijn K.M, Hypersensitivity reactions associated with 5 hydroxytryptamine 3 receptor antagonists: a class effect ?, Lancet, 1996; 347: 584-5 Kossey J.L, Kwok K.K, Anaphylactoid reactions associated with ondansetron, Ann. Pharmacother., 1994; 28 (9): 1029-30
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MESNA
Mesna (2 -mercaptoethane sulphonate), a thiol compound is used to prevent hemorrhagic cystitis, complication of cyclophosphamide treatment.
INCIDENCE
Severe reactions: 3/83. All reactions: 4/31.
Macular pruriginous rash. Fever. Urticaria.
DIAGNOSTIC METHODS
2 cases with delayed type patch-tests reactions. No specific IgE found.
MECHANISMS Unknown. MANAGEMENT

Benefits of mesna outweigh the risk of allergic reactions. Corticosteroids may be useful.
REFERENCES
DCruz D, Haga H.J, Hughes G.R, Allergic reactions to mesna (letter; comment), Lancet., 1991; 338 (8768): 705-6 Seidel A, Andrassy K, Ritz E, Ksser U, Lemmel E.M, Allergic reactions to mesna (letter) (see comments), Lancet., 1991; 338 (8763): 381-2 Pratt C.B, Sandlund J.T, Meyer W.H, Cain A.M, Mesna-induced urticaria, Drug. Intell. Clin. Pharm., 1988; 22: 914
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DRUGS USED IN CARDIOLOGY
V DRUGS USED IN CARDIOLOGY
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ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACE)

The ACE inhibitors appear to be an attractive choice for managing hypertension and congestive heart failure at all stages.
INCIDENCE
Cough: mean 15%. post-marketing surveillance: 1 - 3%. uncontrolled retrospective studies: 6 - 15%. controlled studies: 20%. Rash: 1.3 to 6%. Angioedema 1/1000 to 7/1000. Dyspnea and wheezing: ten times less frequent than cough in reports of adverse respiratory reaction.
RISK FACTORS
Women (cough), non smokers (cough). Idiopathic angioedema (angioedema). Black Americans, Hong-Kong Chinese (cough). Asthma is not a risk factor for cough.
Respiratory. nasal congestion, post-nasal drip, sinusitis hypersensitivity pneumonitis cough: non productive, dry, tickling. Worse in supine posi tion and at night. Pre-existing cough may be exacerbated. Average time of onset: one week; for as long as the drug is taken; disappearing on average 3-6 days after drug withdrawal. Cutaneous.
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Rash: maculopapular eruption predominantly occurring on the arms and upper torso, accompanied by pruritus. Usually occurring within the first four weeks of therapy, but more often within the first few days; often transitory, lasting for only a few hours or days and rarely a cause of discontinuation of treatment. Higher incidence with captopril is related to excessively high doses (600 to 1200 mg/ day) in the first studies. The rash is sometimes specific to a particular ACE inhibitor. Angioedema: evolving face, lips, tongue. May be associated with respiratory distress. Often after first dose or within the first few days of treatment. Enalapril: 1/1000 during the first week.
DIAGNOSTIC METHODS
Cutaneous testing (anaphylactic or cutaneous reactions) Intradermal: 0.05 ml of pure captopril: 0.1/1/10 mg/ ml. Check results after 15 minutes. Positive in 60% of patients with cutaneous manifestations. Patch tests: pure captopril in vaseline 0.1%; 1 and 10% applied to the patients back. Check results after 48 and 72 hours. Positive in 30% of patients with cutaneous manifestations. Skin biopsy: vasculitis with leukocyte infiltration in patients with cutaneous lesions. Respiratory function tests: bronchial hyperresponsiveness to histamine or metacholine is sometimes found in patients who develop cough with ACE inhibitors. Drug re-challenge.
MECHANISMS
Cough. Captopril increases plasma levels of prostaglandins. PGE directly stimulates unmyelinated afferent vagal C fibers, the initial chemical mediator of the cough reflex in the lung. Accumulation of bradykinin which stimulates the release of tachykinins including substance P and neurokinin A.
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Tachykinin stimulates the C fibers whose activation causes cough. Thromboxane A2 is implicated in ACE induced cough. The mechanism of ACE inhibitor-induced coughing may involve substance P mediated airway priming but the final triggering of the ACE inhibitor-induced cough is unlikely to be due to this peptide. Substance P is metabolized by ACE in tissues, and ACE inhibitors have previously been shown to decrease its metabolism. Substance P is important in neurogenic inflammation and has a functional relationship via C fibers with mast cells in various tissues, including lung and skin. Pulmonary accumulation of bradykinin may be a mediator of ACE inhibitor-induced coughing. Bradykinin is known to activate afferent sensory C fibers via type J receptors which cause coughing. Conversely bradykinin could increase the formation of prostaglandins and leukotrienes. Angioedema. Inhibition of ACE and/ or related enzymes in the kinine-kallikrein system blocks bradykinin metabolism. In addition, a decrease in bradykinin degradation increases the synthesis of bradykinin and/ or related kinines.
MANAGEMENT
Use another antihypertensive agent (especially if skin-tests are positive: high predictive value) lozartan (angiotensine 2 antagonist) which does not induce cough, but a few cases of angioedema. Sodium cromoglycate reduces cough scores of 50% by its inhibitor effect on the tachykinin-induced activation of C fibers. Other drugs are now available: ozagrel (thromboxane A2 synthetase inhibitor), which is effective in the treatment of cough induced by ACE inhibitors.
REFERENCES
Umemura K, Nakashima M, Saruta T, Thromboxane A2 synthetase inhibition suppresses cough induced by angiotensin converting enzyme inhibitors, Life Sci., 1997; 60 (18): 1583-8
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Elliott W.J, Higher incidence of discontinuation of angiotensin converting enzyme inhibitors due to cough in black subjects, Clin. Pharmacol. Ther., 1996; 60 (5): 582-8 Semple P.F, Putative mechanisms of cough after treatment with angiotensin converting enzyme inhibitors, J. Hypertens. Suppl., 1995; 13 (S3): S17-21 Wood R, Bronchospasm and cough as adverse reactions to the ACE inhibitors captopril, enalapril and lisinopril. A controlled retrospective cohort study, Br. J. Clin. Pharmacol., 1995; 39 (3): 265-70 Lunde H, Hedner T, Samuelsson O, Ltvall J, Andren L, Lindholm L, Wiholm B.E, Dyspnoea, asthma and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors, B.M.J, 1994; 308 (6920): 18-21 Parish R.C, Miller L.J, Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update, Drug Safety., 1992; 7 (1): 14-31
ATROPINE
Atropine is a widely used premedication drug for the prevention of vagal bradycardia and especially in strabismus surgery.
INCIDENCE
Uncommon for anaphylactic shock.
General: anaphylactic shock. Cutaneous: erythematous rashes (face, neck, chest).
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests at 1/100 are positive in a few cases. Specific IgE has not been detected. The Prausnitz-Kstner test is positive in a few cases.
MECHANISMS
Positive results of skin tests and Prausnitz-Kstner test suggest an IgE-mediated mechanism.
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MANAGEMENT
Avoidance. Strabismus surgery may be performed with hyoscine or glycopyrronium after skin tests.
REFERENCES
Moyano P, Ribas M, Ricos M, Giralt P, Gancedo V.A, Anestesia en dos casos de alergia a la atropina en la cirurgia del estrabismo, Rev. Esp. Anestesiol. Reanim., 1997; 44 (7): 290-1 Aguilera L, Martinez-Bourio R, Cid C., Arino J.J, Saez de Eguilaz J.L, Arizaga A, Anaphylactic reaction after atropine, Anaesthesia., 1988; 43 (11): 955-7. Dundee J.W, Mirakhur R.K, Hypersensitivity to atropine, Br. J. Anaesthesia, 1978; 50: 866.
BETA-BLOCKERS
Family of drugs widely used to treat arterial hypertension and angina, as well as for local treatment of glaucoma. Three problems: Beta-blockers and asthma. Beta-blockers and anaphylactic shock. Beta-blockers and local allergic effect.
INCIDENCE
One 40 or 80 mg tablet of propranolol can induce bronchoconstriction in 50% of asthmatics, but the rate is probably much lower with cardioselective beta-blockers. Bronchoconstriction also occasionally occurs in patients with chronic bronchitis. 13 deaths and 200 major reactions to timolol maleate eye drops have been reported in asthmatics in the USA. Beta-blockers and anaphylactic shock: unknown. Beta-blockers in eye-drops are widely used for the treatment of glaucoma; the local allergic effect has recently been recognized.
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Asthma, bronchospasm, dyspnea, apnea in children, respiratory arrest. Anaphylactic shock to beta-blockers is characterized by bradycardia, despite collapse and poor response to epinephrine. Eczema of the eyelids, contact conjunctivitis with beta-blockers containing eye-drops.
DIAGNOSTIC METHODS
Beta-blockers and asthma: clinical signs and spirometric data. Beta-blockers and anaphylactic shock: clinical signs. Beta-blockers and eczema: patch-tests 0.5% aq. or pure eye-drops.
MECHANISMS
The mechanism underlying the ability of beta-blockers to produce bronchoconstriction remains unclear. Beta-blockers and anaphylactic shock: beta-blockers inhibits the production of cyclic AMP (by reducing intracellular levels) and lower the threshold of mediator release by mastocytes and basophils. Beta-blockers decrease endogenous adrenaline secretion by blocking beta-2-receptors at synapses, and inhibit beta 1 effects of exogenous and endogenous adrenaline on the heart. In contact allergy, beta-blockers have a very close structure; most of them cross-react. This may be due to a common aldehyde after primary metabolism.
MANAGEMENT
Beta-blockers and asthma: If a beta-blocker must be administered to an asthmatic pa tient, use a selective beta 1 agent, if necessary determined by quantitative measurement of cardioselectivity: Clinical surveillance and spirometry at the time of administration. Administration in hospital: Day 1: Day 2: 1/10th of the dose. 1/5th of the dose.
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Day 3: Day 4:
1/2 of the dose. full dose.
If beta-blocker eye drops must be administered to an asthmatic patient, first test tolerance, e.g. to timolol: instillation of one drop of timolol collyre at 0.50% in each eye followed by second instillation 20 minutes later; clinical surveillance (chest auscultation, pulse and arterial blood pressure) at start then at 15, 30, 60 and 120 minutes; perform spirometry at the same time. The best agent available at the present time is a beta 1 selective product: betaxolol. Beta-blockers and anaphylactic shock: Curative treatment: refractory to adrenaline; use of isoprenaline, dopamine, or glucagon; need for blood volume expansion (6 to 7 l). Preventive treatment: Skin-test and desensitization under beta-blockers is prohibited. For anesthesia, either discontinue beta-blockers 48 hours before surgery, or perform an isoprenalin test during surgery (seldom done). Beta-blockers and contact eczema with eye-drops: avoidance. The risk of recurrence is high if another local betablocker is used.
REFERENCES
Giordano-Labadie F, Lepoittevin J.P, Calix I, Bazeix J, Allergie de contact aux bloqueurs des collyres: allergie croise ? , Ann. Dermatol. Venereol., 1997; 124: 322-4 Tattersfield A.E, Beta adrenoreceptor antagonists and respiratory disease, J. Cardiovasc. Pharmacol., 1986; 8 (S 4), 35-9. Dunn T.L, Gerber M.J, Shen A.S, Fernandez E, Iseman M.D, Cherniack R.M, The effect of topical ophthalmic instillation of timolol and betaxolol on lung function in asthmatic subjects , Am. Rev. Respir. Dis., 1986; 133: 264-8. Benitah E, Nataf P, Herman D, Accidents anaphylactiques chez des patients traits par btabloquants. A propos de 14 observations , Thrapie, 1986; 41: 139-42.
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CALCIUM CHANNEL BLOCKERS

Widely used in the treatment of arterial hypertension. There are 3 groups of calcium channel blockers: phenylalkylamines, dihydropyridines, benzothiazepines.
INCIDENCE
Of the 315 cases of possible diltiazem-induced adverse reactions that were reported by the Health Protection Branch, 151 (48%) were cutaneous. The number of diltiazem-induced cutaneous events was significantly higher than those induced by either nifedipine or verapamil. However, no difference was found in the proportion of serious cutaneous adverse events between the three drugs.
Cutaneous: acute generalized exanthematous pustulosis (AGEP): 5 cases .Occurring 8.4 (+/- 2.2) days after initiation of the treatment, and clearing 10 (+/-1.8) days after discontinuation. Serious cutaneous reactions: erythema multiforme, StevensJohnsons syndrome, toxic epidermal necrolysis, hypersensitivity syndrome reaction (1-17 days after initiation of therapy). Less severe reactions: fixed drug eruptions, maculopapular rashes, photosensitivity, non-thrombocytopenic purpura, urticarial vasculitis.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-test or intradermal skin tests: sometimes positive in diltiazeminduced cutaneous reactions. Drug re-challenge with nifedipine or verapamil in diltiazem reactor patients is rarely positive. Similarly nifedipine-reactive patients have usually tolerated diltiazem. Conversely, one patient with non thrombocytopenic purpura due to nifedipine had a similar eruption with diltiazem; another one with pruritic exanthema after diltiazem had a recurrence after amlodipine.
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MECHANISMS
The mechanism of adverse reactions from diltiazem and other calcium channel blockers is unknown. Because the spectrum of cutaneous reactions is extensive, it is likely that the pathophysiology differs with each reaction.
MANAGEMENT
In case of calcium inhibitor allergy the use of a such treatment, even from another group, requires careful monitoring.
REFERENCES
Knowles S, Gupta A.K, Shear N.H, The spectrum of cutaneous reactions associated with diltiazem: three cases and a review of the literature, J. Am. Acad. Dermatol., 1998; 38: 201-6 Baker B.A, Cacchione J.G, Cross-sensitivity between diltiazem and amlodipine, Ann. Pharmacother., 1994; 28: 118-9 Stern R, Khalsa J, Cutaneous adverse reactions associated with calcium channel blockers, Arch. Intern. Med., 1989; 149: 829-32
FUROSEMIDE
Furosemide or chloro-4-furfurylamino-2-sulfamoyl-5-benzoic acid is a widely used Henles loop diuretic.
INCIDENCE
Exceedingly rare for anaphylactic reactions. 0.5% for mild cutaneous reactions.
General: anaphylactic shock. Cutaneous: pruritus, urticaria, periorbital edema, eczematous rash, vasculitis, lichenoid eruption, vesiculo-bullous eruption, Stevens Johnsons syndrome. Respiratory: acute pulmonary edema. Digestive: pancreatitis, hepatitis.
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DIAGNOSTIC METHODS
Cutaneous testing. Prick-tests: negative; Intradermal at 1%: positive for furosemide as well as for chlorothiazide, bumetanide and sulfamethoxazoletrimethoprim. One case with delayed positivity (10th hour).
MECHANISMS
Type I suspected on a basis of immediate positive skin tests. Type III suspected in pancreatitis and hepatitis.
MANAGEMENT
Avoidance. No cross reactivity between furosemide and sulfonamides. Bumetanide may be used as replacement therapy in furosemide induced vasculitis.
REFERENCES
Gratadour P, Guillaume C, Bui-Xuan B, Godard J, Vedrinne J.M, Motin J, Absence dallergie croise entre furosemide et bumetanide, Presse. Med., 1990; 19 (32): 1504 Breuil K, Patte F, Meurice J.C, Vandel B, Pineau-Drouin D, Allergie de mcanisme non-immediat au furosemide, Rev. fr. Allergol., 1989; 29 (3): 150-1. Hansbrough J.R, Wedner H.J, Chaplin D.D, Anaphylaxis to intravenous furosemide, J. Allergy Clin. Immunol., 1987; 80 ( 4): 538-41 Thestrup-Pedersen K, Adverse reactions in the skin from antihypertensive drugs, Dan. Med. Bull., 1987; 34 (S1): 3-5 Tuzel I.H, Comparison of adverse reactions to bumetamide and furosemide, J. Clin. Pharmacol., 1981; 21: 615-9
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PRAZOSIN
Prazosin is a derivative of quinazoline. It is an antihypertensive drug that produces vasodilatation by blocking post-synaptic alpha receptors.
INCIDENCE
Urticaria: 0.3% of subjects treated. Anaphylactic shock: one case reported.
General: anaphylactic shock Cutaneous: urticaria, angioedema. Respiratory: bronchospasm.
DIAGNOSTIC METHODS
Cutaneous testing: prick tests are very hazardous (one collapse reported). No specific IgE found.
MECHANISMS
Undetermined.
MANAGEMENT
Avoidance.
REFERENCES
Chodosh S, Tuck J, Pizzuto D, Prazosin in hypertensive patients with chronic bronchitis and asthma: a brief report, Am. J. Med., 1989; 86 (1 B): 91-3 Ruzicka T, Ring J, Hypersensitivity to prazosin, Lancet, 1983; 1 (8322): 473-4.
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DYES, PRESERVATIVES, ANTISEPTICS
VI DYES, PRESERVATIVES, ANTISEPTICS
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CARBOXYMETHYL-CELLULOSE
Carboxymethylcellulose sodium is a highly viscous material used in pharmaceutical preparations as a suspending agent to promote dissolution of compounds with poor water solubility (barium enema, corticosteroids).
INCIDENCE
Infrequent. Described with barium enema (differentiate from other ingredients: methylparaben, latex, carrageenan) and corticosteroids (cortivazol, prednisolone acetate, triamcinolone acetonide).
General: anaphylactic shock. Respiratory: bronchospasm. Cutaneous: pruritus, urticaria, angioedema.
DIAGNOSTIC METHODS
Cutaneous testing Skin-prick tests: 1%. Intradermal skin-tests: 1/100000 to 1/10000. Scratch-tests: positive with the drug and carboxymethylcellulose. Specific IgE: one case. Specific histamine release: 2 cases.
MECHANISMS
IgE-mediated hypersensitivity.
MANAGEMENT
Avoidance is extremely difficult due to the extensive use of carboxymethylcellulose (drugs and foods).
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REFERENCES
Muroi N, Nishibori M, Fujii T, Yamagata M, Hosoi S, Nakaya N, Saeki K, Henmi K, Anaphylaxis from the carboxymethylcellulose component of barium sulfate suspension, N. Engl. J. Med., 1997; 337 (18): 1275-7 Patterson D.L, Yunginger J.W, Dunn W.F, Jones R.T, Hunt L.W, Anaphylaxis induced by the carboxymethylcellulose component of injectable triamcinolone acetonide suspension (Kenalog), Ann. Allergy. Asthma. Immunol., 1995; 74 (2): 163-6 Beaudouin E, Kanny G, Gueant J.L, Moneret-Vautrin D.A, Anaphylaxie la carboxymethylcellulose: propos de deux cas de chocs des corticodes injectables, Allerg. Immunol. (Paris)., 1992; 24 (9): 333-5
CHLORHEXIDINE
Biguanide antiseptic and disinfectant active against a broad spectrum of bacteria, mycobacteria, viruses and fungi.
INCIDENCE
50 cases reported between 1967 and 1984: 22 with hypotension, 13 with dyspnea, 9 with anaphylactic shock, 4 with cyanosis.
RISK FACTORS
For anaphylactic reactions: contact dermatitis to chlorhexidine.
General: anaphylactic shock. Respiratory: bronchospasm, occupational asthma. Cutaneous: pruritus, erythema, urticaria, contact dermatitis, photosensitive dermatitis, fixed drug eruption. Anaphylactic reactions have been reported after urinary catheterization, disinfection of a drain insertion site, topical application of a dressing on a burn, and placement of a central venous catheter.
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DIAGNOSTIC METHODS
Cutaneous testing. Skin- prick tests: 0.005% to 0.05%. Intradermal skin-tests: 0.02 ml at 0.0002% to 0.002% concentrations. Positive in anaphylaxis cases. Patch-tests 1%: positive in contact dermatitis. Specific IgE (RAST). Histamine release test.
MECHANISMS
IgE-mediated hypersensitivity.
MANAGEMENT
Avoidance in allergic patients. Do not use chlorhexidine gluconate on mucosa. Use at lowest bactericidal concentration (0.05%) on wound surfaces.
REFERENCES
Ebo D.G, Stevens W.J, Bridts C.H, Matthieu L, Contact allergic dermatitis and life-threatening anaphylaxis to chlorhexidine, J. Allergy. Clin. Immunol, 1998; 101 (1.1): 128-9 Oda T, Hamasaki J, Kanda N, Mikami K, Anaphylactic shock induced by an antiseptic-coated central venous catheter, Anesthesiology., 1997; 87 (5): 1242-4 Ramselaar C.G, Craenen A, Bijleveld R.T, Severe allergic reaction to intraurethral preparation containing chlorhexidine, Br. J. Urol., 1992; 70 (4): 451-2 Okano M, Nomura M, Hata S, Okada N, Sato K, Kitano Y, Tashiro M, Yoshimoto Y, Hama R, Aoki T, Anaphylactic symptoms due to chlorhexidine gluconate, Arch. Dermatol., 1989; 125: 50-2.
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CHLOROBUTANOL
Preservative with hypnotic, sedative, antiseptic and anesthetic properties used in many externally applied products as well as in drugs (vasopressin, heparin, oxytocin).
INCIDENCE
Uncommon. One death reported.
General: anaphylactic shock. Cutaneous: pruritus, maculopapular eruption.
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests using chlorobutanol at 0.5%. One positive result was reported in a patient with a maculopapular eruption. One positive scratch test in a patient with anaphylactic shock. Intravenous challenge with chlorobutanol was positive in a patient 5 minutes after 1 ml of 1/1000 chlorobutanol solution.
MECHANISMS
Undetermined.
MANAGEMENT
Avoid use of drugs containing this preservative.
REFERENCES
Maycock E.J, Russell W.C, Anaphylactoid reaction to Syntocinon*, Anaesth. Intensive. Care. , 1993; 21 (2): 211-2 Hofman H, Goerz G, Plewig G, Anaphylactic shock from chlorobutanolpreserved oxytocin, Contact Dermatitis, 1986; 15 (4): 241-2 Slater R.M, Bowles B.J.M, R, Pumphrey R.S.H, Anaphylactoid reaction to oxytocin in pregnancy, Anaesthesia, 1985; 40: 655-6
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Itabashi A, Katayama S, Yamaji T, Hypersensitivity to chlorobutanol in DDAVP solution, Lancet, 1982; 1 (8263): 108 Dux S, Pitlik S,Perry G, Rosenfeld J.B, Hypersensitivity reaction to chlorbutol-preserved heparin, Lancet, 1981 1 (8212):149.
CREMOPHOR E.L.
Non ionic surfactant. polyoxyethylated castor oil used to dissolve water insoluble drugs. Greater specific gravity than water, and high viscosity.
INCIDENCE
Adverse reactions have been described with numerous drugs. ALTHESIN (alphaxalone), EPONTOL (propanidid): withdrawn from the market, DIPRIVAN (propofol), DAKTARIN (miconazole), KONAKION (vitamin K1), STESOLID MR (diazepam): reformulated without cremophor E.L. SANDIMMUNE (cyclosporine), TAXOL (paclitaxel), VUMON (teniposide), DIDEMNIN B (didemnin B): currently in use.
General: anaphylactic shock. Respiratory: bronchospasm. Cutaneous: urticaria, generalized erythema.
DIAGNOSTIC METHODS
Cutaneous testing. A few cases with positive intradermal tests with cremophor 0.2 mg/ml to 20 mg/ml. No specific IgE found.
MECHANISMS
IgE-mediated hypersensitivity (few cases). Non IgE-mediated hypersensitivity (IgG 4). Complement activation (+++). Non specific histamine release.
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MANAGEMENT
Avoid use as excipient if possible. In the case of intravenous cyclosporine: proper mixing during the preparation of the infusion, and avoidance of polyvinylchlorure in the set-up. This could be extrapolated to other drugs containing cremophor E.L .
REFERENCES
Volcheck G.W, Van Dellen R.G, Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and review, Ann. Allergy. Asthma. Immunol., 1998; 80 (2): 159-63 Michaud L.B, Methods for preventing reactions secondary to cremophor E.L, Ann. Pharmacother., 1997; 31 (11): 1402-4 Mounier P, Laroche D, Divanon F, Mosquet B, Vergnaud M.C, Esse-Comlan A, Piquet M.A, Bricard H, Reactions anaphylactoides une solution polyvitamine injectable contenant un cremophore, Therapie. , 1995; 50 (6): 571-3 Dorr R.T, Pharmacology and toxicology of cremophor E.L diluent, Ann. Pharmacother., 1994; 28 (5 s): S11-14 Bowers V.D, Locker S, Ames S, Jennings W, Corry R.J, The hemodynamic effects of cremophor E.L, Transplantation., 1991; 51 (4): 847-50
ERYTHROSINE
Erythrosine is a tetraiodofluoresceine-resembling eosine used as a food and drug colorant. It belongs to the azoic-class of coloring agents, is soluble in water, binds strongly to serum proteins in vitro and presents little toxicity while supplying a high level of iodine.
INCIDENCE
Uncommon.
General: anaphylactic shock, serum sickness. Cutaneous: chronic urticaria, photosensitization, angioedema. Respiratory: asthma. E.N.T.: chronic rhinitis.
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DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-test using an aqueous solution at a concentration of 1.5 mg/ml give positive results in 35 to 70% of patients with immediate or delayed reactions to erythrosine. Precipitating antibodies in patients with serum sickness. Detection of IgE antibodies by RAST is successful in 70% of patients with immediate reactions. Re-challenge with surveillance of target organ:
MECHANISMS
Immediate IgE-mediated hypersensitivity is involved in most cases (immediate positive skin tests, detection of specific IgE antibodies). Immune complex-mediated hypersensitivity has been implicated in patients with serum sickness.
MANAGEMENT
Value of challenge tests in conjunction with RAST and skin test. For cutaneous manifestations, an elimination diet of several weeks, followed by reintroduction of the coloring agent in capsule form gives clear and irrefutable results.
REFERENCES
Vesely B, Bodmer R, Guerin B, Girard J.P, Manifestations cliniques lerythrosine. Etude du rle des mcanismes dhypersensibilit, Rev. fr. Allergol., 1985; 1 (25) 7-11.
ETHYLENEDIAMINE
Ethylenediamine is used as a binding agent (creams, eye drops, aminophylline, enema) conferring greater solubility and reducing the alkalinity of the drug. Aminophylline is a complex of 2 theophylline molecules to one ethylenediamine molecule.
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INCIDENCE
Ethylenediamine sensitivity: 13% in patients with contact dermatitis.
(allergic reaction may occur with intravenous aminophylline and oral formulations or suppositories) Manifestations usually appear 24 to 48 hours after intake of the drug, but delays of 6 to 8 hours have also been reported. General: anaphylactic shock, fever, headache, myalgia. Respiratory: bronchospasm, occupational asthma in exposed subjects to ethylenediamine vapors. Cutaneous: pruritus, urticaria, maculopapular rash, angioedema, periorbital edema, exfoliative dermatitis, erythroderma, contact dermatitis (occupational in pharmacists).
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests: aminophylline 1%, ethylenediamine 0.1% and 1%. Patch-tests: aminophylline 1% pet. , ethylenediamine 1% pet. No specific IgE found.
Specific histamine-release positive in one case. MECHANISMS

Possible IgE-mediated hypersensitivity in few cases Type IV cellular reaction. Sensitization to ethylenediamine is particularly common with topical drugs. Acetylation is one of the major metabolic pathways for ethylenediamine.
MANAGEMENT
Ethylenediamine-sensitive patients can develop allergy to piperazine (antihelminthic agent); to ethanolamine group antihistamines (clemastine, carbinoxamine, diphenhydramine,
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hydroxyzine); to triethanolamine containing creams and to ethylenediamine antihistamines (tripelennamine hydrochloride, antazoline phosphate). Use an ethylenediamine-free theophylline.
REFERENCES
Urbani C.E, Urticarial reaction to ethylenediamine in aminophylline following mesotherapy, Contact. Dermatitis, 1994; 31 (3): 198-9 Eedy D.J, Angioneurotic oedema following piperazine ingestion in an ethylenediamine-sensitive subject, Contact. Dermatitis, 1993; 28 (1): 48-9 de la Hoz B, Perez C, Tejedor M.A, Lazaro M, Salazar F, Cuevas M, Immediate adverse reaction to aminophylline , Ann. Allergy., 1993; 71 (5): 452-4 Thompson P.J, Gibb W.R.G, Cole P, Citron K.M, Generalized allergic reactions to aminophylline, Thorax, 1984; 39 (8):600-3. Elias J.A, Levinson A.I, Hypersensitivity reactions to ethylenediamine in aminophylline, Am. Rev. Respir. Dis., 1981; 123 (5): 550-2.
MERCURY ANTISEPTICS
Widely used antiseptics: mercurochrome, thiomersal, phenylmercuric acetate.
INCIDENCE
Systemic reactions are uncommon. Delayed cutaneous reactions are common.
General: anaphylactic shock. Respiratory: bronchospasm. Cutaneous: acute urticaria, facial edema, contact dermatitis. E.N.T.: laryngeal edema.
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DIAGNOSTIC METHODS
Prick and intradermal tests with mercury chloride, mercury nitrate, phenylmercury acetate, mercurochrome, thiomersal, thiosalicylic acid. Results may be positive following an acute reaction. Patch-test may be positive in patients with contact dermatitis (thiomersal).
MECHANISMS
IgE-mediated hypersensitivity may be implicated in immediate reactions. One positive Prausnitz-Kstner test has been reported. Cell-mediated hypersensitivity in patients with contact dermatitis.
MANAGEMENT
Avoid use. In addition to products for external use, some vaccines also contain mercury antiseptics (antituberculosis, antihepatitis B).
REFERENCES
A. Torres, Anaphylactic hypersensitivity to mercurochrome (merbrominum), Ann. Allergy, 1985, 54, 230232. S. Rietschel, Ocular inflammation in patients using soft contact lenses, Arch. Dermatol., 1982, 118, 147148.
PARABENS
These methyl, ethyl, propyl, and butyl esters of hydroxybenzoic acid have bacteriostatic and fungicide properties and are the most widely used preservatives in food, cosmetics and medications (more than 300 pharmaceutical categories).
INCIDENCE
0.8% of chronic dermatitis (skin tests). 3% of delayed cutaneous manifestations. 0.9% of drug allergies.
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RISK FACTORS
Damaged skin (leg ulcer, stasis dermatitis). Previous sensitization by substances with a para-amine function. Localization on the face or the neck.
After topical use: contact eczema After oral use: Eczema-like eruptions, pruritus, urticaria. Insidious chronic dermatitis is frequent especially if corticosteroids are associated. After systemic administration. Cutaneous: erythema, urticaria, pruritus, angioedema. Respiratory: dyspnea, bronchospasm, worsening of ongoing asthma.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests are often positive in patients with contact dermatitis. Parabens mix belongs to the European patchtests standard series and contains 3% of methyl, ethyl, propyl and butyl para-hydroxybenzoates. Intradermal skin-tests should be performed with a 5% concentration of methylparaben, ethylparaben, propylparaben, and butylparaben in order to avoid false negatives. A few positive results have been reported in patients with immediate reactions.
MECHANISMS
IgE-mediated hypersensitivity is suggested by the following findings: positive Prausnitz-Kstner tests reported in several cases, immediately positive intradermal skin tests. However, IgE antibodies have never been detected. Cell-mediated hypersensitivity is responsible for contact dermatitis. Cross-sensitivity may occur between parabens and molecules possessing a free amine group in the para position ( benzocaine,
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para-phenylendiamine and sulfonamides). The only difference between such products and parabens is the presence of a hydroxy instead of an amine group in the para position. Cross reactivity between p. amine and p. hydroxyl compounds has been documented.
MANAGEMENT
Avoidance is difficult.
REFERENCES
Verhaeghe I, Dooms-Goossens A, Multiple sources of allergic contact dermatitis from parabens , Contact. Dermatitis, 1997; 36 (5): 269-70 Rycroft R.J.G, Menne T, Frosch P.J, Textbook of contact dermatitis, 2nd Ed.Springer-Verlag Berlin, 1995; 437-8 Fisher A.A, The parabens: paradoxical preservatives Cutis, 1993; 51 (6): 405-6 Chichmanian R.M, Mignot G, Spreux A, Cassuto D, Manassero J, Manifestations allergiques multiples. Rle dun excipient, Thrapie, 1985; 40: 365-7. Nagel J.E, Fuscaldo J.T, Fireman P, Paraben allergy, JAMA, 1977; 237: 1594-5.
POVIDONE
Povidone or polyvinyl pyrrolidone is a polymer with a molecular weight ranging from 10000 to 700000, comparable to plasma proteins and used as excipient in topical, oral, and parenteral pharmaceutical products.
INCIDENCE
Rare.
General: anaphylactic shock Cutaneous: urticaria, contact dermatitis. Respiratory: asthma (hair spray).
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Ocular: conjunctivitis (intraocular lenses). E.N.T: rhinorrhea.
DIAGNOSTIC METHODS
Cutaneous testing. Basophil degranulation test. Histamine release test. Provocation challenge.
MECHANISMS
Non specific histamine release. IgE-mediated hypersensitivity. Povidone 10 has been shown to be a potent activator of suppressor T-cells, whereas povidone 40 and 60 are able to activate B-cells.
MANAGEMENT
Avoidance.
REFERENCES
Gonzalo Garijo M.A, Duran Quintana J.A, Bobadilla Gonzalez P, Maiquez Asuero P, Anaphylactic shock following povidone, Ann. Pharmacother., 1996; 30 (1): 37-40 Moneret-Vautrin D.A, Mata E, Gerard H, Trechot M, Allergie probable la polyvidone, responsable dun accident un produit iod de contraste: propos dun cas dasthme aprs hysterosalpingographie, Allerg. Immunol. (Paris), 1989; 21: 196-9 Ameille J, Pages M.G, Capron F, Proteau J, Rochemaure J, Pathologie respiratoire induite par linhalation de laque capillaire, Rev. Pneumol. Clin., 1985; 41: 325-30
POVIDONE IODINE
Povidone iodine is widely used as an antiseptic.
INCIDENCE
Rare.
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Cutaneous: contact eczema.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests: positive with Betadine solution, Betadine ointment, Betadine scrub 2% in water, povidone iodine 10% in pet. negative with potassium iodide 5, 10, 15, 20% in pet. negative with iodine tincture (open test).
MECHANISMS
Type IV hypersensitivity.
MANAGEMENT
Avoidance.
REFERENCES
van Ketel W.G, van der Berg W.H.H.W, Sensitization to povidone-iodine, Dermatol. Clin., 1990; 8 (1): 107-9 Ancona A, Suarez de la Torre R, Macotela E, Allergic contact dermatitis from povidone-iodine, Contact Dermatitis, 1985; 13: 66-8
SULFITES
Sulfites are used in the pharmaceutical and food industry for their antioxidizing and antibacterial properties. SO2: sulfurous anhydride. Na2SO3: sodium sulfite. NaHSO 3: sodium bisulfite. Na2S 2O 5: sodium metabisulfite. K2S2O5: potassium metabisulfite.
INCIDENCE
< 2% in the general population. 4 to 8% of asthmatics are sulfites sensitive 1.7% of positive sodium metabisulfite patch-tests in patients with eczematous dermatitis
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The majority of sulfite reactions are dietary; 3% of total reactions are attributed to drugs.
RISK FACTORS
Aspirin intolerance? Steroid dependent asthma.
(reported with: novocaine, lidocaine, gentamicin, metoclopramide, vitamin B injection preparations, doxycycline) Anaphylactic shock. Asthma (steroid-dependent chronic asthma). Urticaria, angioedema, periorbital edema, contact dermatitis. Laryngeal edema, nasal pruritus, rhinorrhea.
MODE OF EXPOSURE
Food: preservative in dried food (e.g. fish), bleaching agent in codfish filets, dried fruits, fresh grapes, candies, vegetables, shrimps, wine, beer, cider, fruit and vegetable juice. Drug: at least 1000 sulfite-containing drugs in USA (aminoglycosides, local anesthetics with epinephrine, corticosteroids, antifungal creams).
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests (1 to 10 mg/ml), intradermal skin-tests (5 mg/ml), delayed skin-tests with sulfite solution 2% are usually negative. Patch-tests with sodium metabisulfite 1% in petrolatum are used in the diagnosis of contact allergy. Challenge tests. Oral challenge tests: 5,10,25,50,100 mg dissolved in 20 ml of 0.5% citric acid positive in 20% of steroid-dependent asthmatic children. Inhalation challenge tests. Subcutaneous challenge tests (do not exceed 10 mg): not always positive in sulfite-sensitive individuals.
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MECHANISMS
Several hypotheses: IgE-mediated hypersensitivity (positive skin-tests, positive transfer-tests, no specific IgE found) Inhalation of sulfur dioxide (bronchoconstriction) Direct nervous stimulation by SO2 Direct membrane toxicity Sulfite oxidase deficiency Delayed contact sensitivity in contact eczema.
MANAGEMENT
Cyanocobalamin is effective in preventing clinical sulfite reactions. Avoid use: Foods: easy if the presence of sulfites is indicated on the package label. If not, a detection band can be used, but false negative results are frequent. Drugs: see the drug listing, or use detection band.
REFERENCES
Miltgen J, Marotel C, Natali F, Vaylet F, LHer P, Aspects cliniques et diagnostic de lintolrance aux sulfites. A propos de 9 patients., Rev. Pneumol. Clin., 1996; 52 (6): 363-71 Peroni D.G, Boner A.L, Sulfite sensitivity , Clin.Exp.Allergy., 1995; 25 (8): 680-1 Vena G.A, Foti C, Angelini G, Sulfite contact allergy, Contact Dermatitis, 1994; 31 (3): 172-5 Lodi A, Chiarelli G, Mancini L.L, Crosti C, Contact allergy to sodium sulfite contained in an antifungal preparation, Contact Dermatitis, 1993; 29 (2): 97 Sanz J, Martorell A, Torro I, Carlos-Cerda J, Alvarez V, Intolerance to sodium metabisulfite in children with steroid-dependent asthma, J. Investig. Allergol. Clin. Immunol, 1992; 2 (1): 36-8 Smolinske S.C Review of parenteral sulfite reactions, J. Toxicol. Clin. Toxicol., 1992; 30 (4): 597-606
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TARTRAZINE
Tartrazine is an azo dye used in many foods an drugs including antibiotics, antihistamines, steroids, bronchodilators and antidepressants (imipramine, desipramine, amitriptyline).
INCIDENCE
0.1 to 6 subjects /1 000.
General: anaphylactic shock. Respiratory: bronchospasm. Cutaneous: urticaria (acute and chronic), angioedema, fixed drug eruption, contact dermatitis, allergic vasculitis. E.N.T.: rhinitis.
DIAGNOSTIC METHODS
The oral challenge with tartrazine is a only reliable method of accurate diagnosis: Urticaria: tartrazine 1,5,25 and 50 mg at 30 minute intervals. Asthma: tartrazine 0,1 mg to 50 mg at 30 minute intervals.
MECHANISMS
Direct histamine release?
MANAGEMENT
Tartrazine free diet and avoidance of all drugs containing tartrazine. If symptoms improve, re-challenge with tartrazine. Reappearance of symptoms is sufficient proof of tartrazine hypersensitivity. In obscure cases, perform oral challenge. No cross reaction has been demonstrated between tartrazine and aspirin with regard to respiratory symptoms. Consequently, no avoidance of tartrazine in aspirin-allergic patients unless an adverse reaction has been observed in challenge tests.
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REFERENCES
Orchard D.C, Varigos G.A, Fixed drug eruption to tartrazine, Austral. J. Dermatol., 1997; 38 (4): 212-4 Dipalma J.R, Tartrazine sensitivity, Am. Fam. Physician., 1990; 42 (5): 1347-50 Stevenson D.D, Simon R.A, Lumry W.R, Mathison D.A, Adverse reactions to tartrazine, J. Allergy Clin. Immunol., 1986; 78: 182-91. Collins-Williams C, Clinical spectrum of adverse reactions to tartrazine, J. Asthma, 1985; 22 (3): 139-43.
THIMEROSAL
Thimerosal, or thiomersal, or merthiolate (sodiumethylmercurithiosalicylate) has been used as a preservative in vaccines and topical medication for years. It is bacteriostatic against Gram+ and bacteria, and active against fungi and yeast.
INCIDENCE
1 to 25% of positive patch-tests to thimerosal in patients with contact allergy. 10% of patients with positive patch-tests to thimerosal show adverse reactions to thimerosal containing vaccines.
RISK FACTORS
Young adults (greater exposure to vaccines containing thimerosal?)
Possible sources of thimerosal (0.001 to 0.1%). Vaccines: diphtheria, tetanus, pertussis, mumps, hepatitis B, influenza, tick-borne encephalitis, staphylococcus, sal monella, meningococcus A. Immunoglobulins: RhoD for example. Extracts and diluents for: intracutaneous allergy tests, intracutaneous testing for candida, coccidioidin, histoplas min, mumps, hyposensitization therapy
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Blood and plasma products Topical medications: eyes, ENT area, skin Storing and cleaning solutions for soft contact lenses. Disinfectant for skin and mucous membranes Cosmetic creams and lotions, toothpastes, mouthwashes, pesticides. Persistent local reactions to vaccines. Generalized urticaria, generalized exanthematic eruptions. Asthma (one case). Contact dermatitis. Contact urticaria. Keratoconjunctivitis (contact lens wearers). Acute laryngeal obstruction (throat spray). Prolonged external otitis (topical ear treatment).
DIAGNOSTIC METHODS
Patch-tests with: thimerosal 0.05% in pet. (0.1% is irritant) thiosalicylic acid 0.1% in pet. ethylmercurychloride 0.05% in pet 3 groups of patients are to be considered positive to thimerosal, but negative to mercurials and thiosalicylic acid positive to thimerosal and thiosalicylic acid, but negative to other mercurials positive to thimerosal and some other mercurials, but negative to thiosalicylic acid.
MECHANISMS
The ethylmercury radical appears to be the allergenic determinant. The high frequency of patch-test reactions to thimerosal is due to sensitization by thimerosal containing vaccines. There is a cross-reactivity between thiosalicylate and a degraded photoproduct of (sensitization to thimerosal with photosensitivity to piroxicam).
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MANAGEMENT
Hypersensitivity to thimerosal does not imply true mercury allergy. A positive patch-test with thimerosal should often be regarded as an accidental finding with no clinical relevance. A history of ocular sensitivity to thimerosal does not preclude hepatitis B vaccine administration. Replace thimerosal in soft contact lenses care with sterile singleunit preservative-free saline with thermal disinfection or use special preservative-free care system containing only a low concentration (0.6%) of hydrogen peroxide.
REFERENCES
Luka R.E, Oppenheimer J.J, Miller N, Rossi J, Bielory L, Delayed hypersensitivity to thimerosal in Rho (D) immunoglobulin, J. Allergy. Clin. Immunol., 1997; 100 (1): 138-9 Gonalo M, Figueiredo A, Gonalo S, Hypersensitivity to thimerosal: the sensitizing moiety, Contact. Dermatitis, 1996; 34: 201-3 vantVeen A.J, van Joost T, Sensitization to thimerosal (merthiolate) is still present today, Contact. Dermatitis, 1994; 31 (5): 293-8 Cirne de Castro J.L, Freitas J.P, Menezes-Brandao F, Themido R, Sensitivity to thimerosal and photosensitivity to piroxicam, Contact. Dermatitis, 1991; 24 (3): 187-92 Aberer W, Vaccination despite thimerosal sensitivity, Contact. Dermatitis, 1991; 24: 6-10
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PRODUCTS USED IN DIALYSIS
VII PRODUCTS USED IN DIALYSIS
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CUPRAMMONIUM CELLULOSE HEMODIALYZERS

Dialyzers prepared with raw cellulose, copper, ammoniac, and other chemical products.
INCIDENCE
3.3/year/1000 patients. First-use syndrome: 3 to 5% of dialysed patients.
RISK FACTORS
Use of new cellulose. Insufficient rinsing before dialysis. Previous exposure to the same type of hemodialyzer. Atopy (more rapid onset and more pronounced complement activation).
First-use syndrome: chest and back pain, hypotension, nausea, vomiting, abdominal cramps, shortness of breath. General: hypotension. Respiratory: dyspnea, wheezing. Cutaneous: pruritus, urticaria, edema. Digestive: nausea, vomiting, abdominal pain.
MECHANISMS
Complement activation via the alternative pathway. Ethyleneoxide has an increased allergenicity after contact with cuprammonium cellulose dialyzers.
MANAGEMENT
Use of reused dialyzers lower complement activation.
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REFERENCES
Kraske G.K, Shinaberger J.H, Klaustemeyer W.B, Severe hypersensitivity reaction during hemodialysis, Ann. Allergy. Asthma. Immunol., 1997; 78 (2): 217-20 Rockel A, Klinke B, Hertel J, Baur X, Thiel C, Abdelhamid S, Fiegel P, Walb D, Allergy to dialysis materials, Nephrol. Dial. Transplant., 1989; 4 (7): 646-52 Daugirdas J.T, Ing T.B, Roxe D.M, Severe anaphylactoid reactions to cuprammonium cellulose hemodialyzers, Arch. Intern. Med., 1985; 145: 489-94. Bhat K, Lee S.M.K, Lozano J, Anaphylactic reaction on subsequent exposure to cuprophan hollow-fiber dialyzer: a case report, Ann. Allergy, 1984; 52: 282. Hakim R.M, Breillatt J, Lazarus J.M, Port F.K, Complement activation and hypersensitivity reactions to dialysis membranes, N. Engl. J. Med., 1984; 311: 1178-82
ETHYLENE OXIDE
Ethylene oxide is a gas capable of killing microorganisms by the alkylation of the sulfur-containing proteins. Since it is a highly inflammable gas, it is used in association with both CO2 (90%) and fluoric hydrocarbons. In such conditions, ethylene oxide sterilizes at a temperature of 40 and a humidity of 40% within 4 hours. It is used to sterilize various medical instruments and supplies that would not tolerate sterilization by heat.
INCIDENCE
Severe but non-fatal reactions: 4.2 out of 1000000 dialyzers sold. 4/100000 hemodialysis sessions with hollow-fiber dialysers.
RISK FACTORS
Atopy. Use of cuprammonium cellulose dialyzers. Frequent exposure (spina-bifida).
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General: anaphylactic shock Cutaneous: urticaria, angioedema, itching, flushing. Respiratory: bronchospasm. ENT: rhinitis. Other: local intra-articular reactions (reconstructive knee surgery); sterile shunt malfunction.
DIAGNOSTIC METHODS
Cutaneous testing with ETO-HSA. Skin prick-tests: 1 mg/ ml then; Intradermal skin-tests: 0.02 ml ETO-HSA 10 g/ml; 100g/ml; 1mg/ ml. Positive predictive value: 80%. Negative predictive value: 96%. Specific IgE (ELISA, RAST). Correlation between ETO-specific IgE and allergic symptoms during dialysis.
MECHANISMS
The quantity of ETO remaining in the dialyzer after washing can interact with human albumin and induce the formation of allergens with a cross-linking agent.
MANAGEMENT
Sterilization by heat is not possible. Catheters should be washed in a physiologic solution then left in a well-ventilated place in order to remove all trace of the ethylene oxide used (not always feasible). In Japan, the use of steam or gamma radiation made adverse reactions to ethylene oxide disappear. Frequent reuse of compatible membranes (cheaper and safer). Rinsing of the blood compartment and all lines of a cuprammonium cellulose dialyzer with 2 liters of sterile saline. Rinsing of the dialysate compartment with 10 liters of dialysate.
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REFERENCES
Kraske G.K, Shinaberger J.H, Klaustermeyer W.B, Severe hypersensitivity reaction during hemodialysis, Ann. Allergy. Asthma. Immunol., 1997; 78 (2): 217-20 Purello DAmbrosio F, Savica V, Gangemi S, Ricciardi L, Bagnato G.F, Santoro D, Cuzzocrea S, Bellinghieri G, Ethylene oxide allergy in dialysis patients, Nephrol. Dial. Transplant., 1997; 12 (7): 1461-3 Pittman T, Kiburz J, Steinhardt G, Krock J, Gabriel K, Ethylene oxide allergy in children with spina bifida, J. Allergy. Clin. Immunol., 1995; 96:486-8 Pittman T, Wiliams D, Rathore M, Knutsen A.T, Mueller K.R, The role of ethylene oxide allergy in sterile shunt malfunctions, Br. J. Neurosurg., 1994; 8 (1): 41-5 Grammer L.C, Roberts M, Wiggins C.A, Fitzsimons R.R, Ivanovich P.T, Roxe D.M, Patterson R, A comparison of cutaneous testing and ELISA testing for assessing reactivity to ethylene oxide-human serum albumin in hemodialysis patients with anaphylactic reactions, J. Allergy. Clin. Immunol., 1991; 87: 674-6 Rckel A, Klinke B, Hertel J, Baur X, Thiel C, Abdelhamid S, Fiegel P, Walb D, Allergy to dialysis materials, Nephrol. Dial. Transplant., 1989; 4 (7): 646-52
FORMALDEHYDE
The simple formaldehyde molecule is a highly sensitizing molecule that is the underlying cause of contact dermatitis in many patients. Exposure to formaldehyde gas at work and in the home (insulation with urea-formol foam) can lead to the development of asthma. It is also used for sterilization, notably of dialyzers, as an antibiotic additive in grooming products (toothpaste, shampoo, soaps) and in certain medications (antihepatitis B vaccine, certain allergoids).
INCIDENCE
Anaphylactic shock is uncommon (hemodialysis and dentistry). Contact dermatitis is frequent.
RISK FACTORS
Previous exposure to formaldehyde.
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Differentiate from irritation syndrome (ocular, nasal, bronchial). General: anaphylactic shock. Cutaneous: urticaria, angioedema, contact dermatitis, polymorphous erythema, maculopapular rash on the face and in the mouth (dentistry). Respiratory: bronchospasm. E.N.T.: rhinorrhea.
DIAGNOSTIC METHODS
Cutaneous testing. prick-tests using formaldehyde solutions at 0.1 and 1% are often positive in subjects presenting immediate reactions. Results should be read immediately (20 minutes). patch-tests using a formaldehyde solution at 1% are often positive in subjects with contact dermatitis (high doses are irritating and should not be used). Specific IgE antibodies against formaldehyde can often be detected by RAST or ELISA in subjects with immediate manifestations.
MECHANISMS
IgE-mediated hypersensitivity (anaphylactic shock). Cell-mediated hypersensitivity (contact dermatitis). Type III: IgG antibodies against formaldehyde/serum albumin conjugates have been detected in patients exposed through the respiratory or parenteral route.
MANAGEMENT
Avoid using dialysis membranes sterilized with formaldehyde in patients with previous allergic skin reactions to formaldehyde. Perform an intradermal test with antihepatitis B vaccine in patients presenting contact dermatitis to formaldehyde (risk of generalized urticaria or eczema).
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REFERENCES
Wantke F, Hemmer W, Haglmuller T, Gotz M, Jarisch R, Anaphylaxis after dental treatment with a formaldehyde-containing tooth-filling material, Allergy, 1995; 50 (3): 274-6 Bousquet J, Michel F.B, Allergy to formaldehyde and ethyleneoxide, Clin. Rev. Allergy, 1991; 9: 357-70. Bardana E.J Jr, Montanaro A, Formaldehyde: an analysis of its respiratory, cutaneous and immunologic effects, Ann. Allergy., 1991; 66 (6): 441-52 Maurice F, Rivory J.P, Larsson P, Bousquet J, Anaphylactic shock caused by formaldehyde in a patient undergoing long term hemodialysis, J. Allergy Clin. Immunol., 1986; 77 (4): 594-7.
IRON DEXTRAN
Intravenous iron dextran is used in the treatment of anemia in patients with end-stage renal disease when oral iron therapy fails to maintain adequate iron reserves. The typical treatment regimen consists of 10 doses of 100 mg of iron dextran injected during hemodialysis treatment.
INCIDENCE
0.1% of dextran injections (in non uremic patients). 0.6% of patients (non uremic). 4.7% in uremic patients.
RISK FACTORS
History of drug allergy (OR: 2.4). History of multiple drug allergy (OR: 5.5).
Immediate General: hypotension, cardiac arrest. Cutaneous: itching, swelling, flushing. Respiratory: chest pain, dyspnea, wheezing. Digestive: nausea, diarrhea, dyspepsia.
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Delayed (4 to 48 hours after iron administration; may last for 3 to 7 days) Lymphadenopathy, myalgia, arthralgia, fever, headache.
DIAGNOSTIC METHODS
No specific reports concerning iron dextran.
MECHANISMS
Poorly studied. The same mechanisms could be involved as were reported concerning dextrans used as plasma expanders.
MANAGEMENT
A test dose of 25 mg of iron dextran is commonly recommended, but only 40% of all anaphylactoid reactions occur with the test dose. In one case, iron dextran was administered to a patient who reacted to the test dose after premedication with corticosteroids, antihistamines, ephedrine, hapten inhibition and desensitization: Day 1: 50 mg/ 100 ml rate: 20 ml/ h Day 2: 100 mg/ 250 ml rate: 40 ml/ h 24 hours later 200 mg/ 250 ml rate: 50 ml/h6 hours later Day 3: 400 mg then 500 mg 24 hours later 500 mg then 250 mg
REFERENCES
Fishbane S, Ungureanu V.D, Maesaka J.K, Kaupke C.J, Lim V, Wish J, The safety of intravenous iron dextran in hemodialysis patients , Am. J. Kidney. Dis., 1996; 28 (4): 529-34 Monaghan M.S, Glasco G, St John G, Bradsher R.W, Olsen K.M, Safe administration of iron dextran to a patient who reacted to the test dose , South. Med. J., 1994; 87 (10): 1010-2 Novey HS, Pahl M, Haydik I, Vaziri N.D, Immunologic studies of anaphylaxis to iron dextran in patients on renal dialysis, Ann. Allergy., 1994; 72 (3): 224-8 Fleming L.W, Stewart W.K, Parratt D, Dextran antibodies, complement conversion and circulating immune complexes after intravenous iron dextran therapy in dialysed patients, Nephrol. Dial. Transplant., 1992; 7: 35-9
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Hamstra R.D, Block M.H, Schocket A.L, Intravenous iron dextran in clinical medicine, J.A.M.A, 1980; 243: 1726-31
POLYACRYLONITRILE AN 69 MEMBRANE
Hemodialysis is a safe procedure. Hypersensitivity during hemodialysis can sometimes be due to the membrane.
INCIDENCE
Unknown.
RISK FACTORS
Concomitant use of ACE inhibitors.
CLINICAL MANIFESTATIONS (onset within 20 minutes after starting dialysis)

Major criteria: dyspnea, angioedema, burning/ heat sensation at the access site or throughout the body. Minor criteria: urticaria, rhinorrhea, lacrimation, itching, abdominal cramps.
DIAGNOSTIC METHODS
Increased bradykinin in samples obtained from afferent blood line of patients.
MECHANISMS
Contact of plasma with negatively charged AN 69 membrane initiates the contact phase of coagulation and leads to the activation of the Hageman factor and conversion of prekallikrein to kallikrein, which cleaves bradykinin from the high molecular weight kininogen. Normally kininogen is almost completely cleared by the kininases during its passage in the lung circulation. This does not occur in
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patients with ACE inhibitors; leading to bradykinin accumulation and development of anaphylactoid reactions.
MANAGEMENT
Avoidance of the association of AN 69 membrane with ACE inhibitors. Nevertheless, anaphylactoid reactions have been reported with AN 69 membranes without ACE inhibitor association.
REFERENCES
Tielemans C, Gastaldello K, Goldman M, Vanherweghem J.L, Acute hemodialysis membrane-associated reactions, Nephrol. Dial. Transplant, 1996; 11 (S2): 112-5 Verresen L, Fink E, Lemke H.D, Vanrenterghem Y, Bradykinin is a mediator of anaphylactoid reactions during hemodialysis with AN 69 membranes, Kidney.Int., 1994; 45: 1497-1503
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DIAGNOSTIC AGENTS
VIII DIAGNOSTIC AGENTS
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DIAGNOSTIC AGENTS
FLUORESCEIN
Angiography using fluorescein is a valuable tool for the ophthalmologist in investigating vascular disease in general, and chorioretinitis in particular. However this useful method is not free from risk.
INCIDENCE
All adverse reactions: (IV administration): 0.6 to 16.1%. (oral administration): 0.9%. Flushing, itching, hives: 0.5 to 0.6%. Anaphylaxis: 0 to 0.2% (deaths reported).
RISK FACTORS
Previous reaction during fluorescein angiogram. Black females (urticaria in one study).
General: anaphylactic shock Respiratory: bronchospasm. E.N.T.: sneezing (early symptom of allergy). Cutaneous: pruritus, urticaria, angioedema.
DIAGNOSTIC METHODS
Cutaneous testing. False positive in intradermal skin-tests. A positive prick-test with 10% fluorescein solution could predict anaphylactoid reaction to intravenous injection of fluorescein. No specific IgE found. Mechanisms Unknown. Non-specific histamine release?
MANAGEMENT
Premedication may be useful (controversial). Desensitization (0.1 ml 1/1 000 to 1 ml pure) is poorly used.
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DIAGNOSTIC AGENTS
REFERENCES
Matsuura M, Ando F, Fukumoto K, Kyogane I, Torii Y, Matsuura M, Usefulness of the prick-test for anaphylactoid reaction in intravenous fluorescein administration (article in Japanese), Nippon. Ganka. Gakkai. Zasshi., 1996; 100 (4): 313-7 Jennings B.J, Mathews D.E, Adverse reactions during retinal fluorescein angiography, J. Am. Optom. Assoc., 1994; 65 (7): 465-71 Rohr A.S, Pappano J.E Jr, Prophylaxis against fluorescein-induced anaphylactoid reactions, J. Allergy. Clin. Immunol., 1992; 90 (3.1): 407-8 Kwiterovich K.A, Maguire M.G, Murphy R.P, Schachat A.T, Bressler N.M, Bressler S.B, Fine S.L, Frequency of adverse systemic reactions after fluorescein angiography. Results of a prospective study, Ophtalmology., 1991; 98 (7): 1139-42
GASTROINTESTINAL CONTRAST MEDIA

Significant anaphylactoid reactions to gastrointestinal contrast media are rare.
INCIDENCE
One severe anaphylactoid reaction/ 2.5 million procedures.
RISK FACTORS
Unknown. One case with allergy to fish, peanuts (barium preparation).
Anaphylactic shock. Respiratory distress, chest tightness, stridor, bronchospasm, laryngeal edema.
DIAGNOSTIC METHODS
None.
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DIAGNOSTIC AGENTS
MECHANISMS
Numerous components of the gastrointestinal media may be involved: Ancillary supplies (latex) Barium sulfate (unlikely) Water-soluble gastrointestinal agents: gastrografin (sodium and meglumine diatrizoate solution); hypaque (sodium diatrizoate solution). Increased gastrointestinal permeability has sometimes been demonstrated.
MANAGEMENT
Avoidance of the same agent, if a subsequent examination is necessary.
REFERENCES
Seymour P.C, Kesack C.D, Anaphylactic shock during a routine upper gastrointestinal series, Am. J. Roentgenol., 1997; 168 (4): 957-8 Miller S.H, Anaphylactoid reaction after oral administration of diatrizoate meglumine and diatrizoate sodium solution, Am. J. Roentgenol., 1997; 168 (4): 959-61 Skucas J, Anaphylactoid reactions with gastrointestinal contrast media (comment), Am. J. Roentgenol, 1997; 168 (4): 962-4
INDOCYANINE GREEN
Used in the diagnosis and management of choroidal vasculature affections. Indocyanine green is a tricarbocyanine organic dye with less than 5% of iodine (for stabilization).
INCIDENCE
0.05% to 0.07%. One death reported during cardiac catheterization with indocyanine green.
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DIAGNOSTIC AGENTS
Anaphylactic shock Pruritus. Wheezing.
DIAGNOSTIC METHODS
None.
MECHANISMS
Anaphylaxis may be related to the iodine additive, or to the dye itself.
MANAGEMENT
Avoidance.
REFERENCES
Olsen T.W, Lim J.I, Capone A Jr, Myles R.A, Gilman J.P, Anaphylactic shock following indocyanine green angiography (letter), Arch. Ophtalmol., 1996; 114 (1): 97 Hope-Ross M, Yannuzzi L.A, Gradoudas E.S, Adverse reactions due to indocyanine green, Ophtalmology., 1994; 101: 529-33 Obana A, Miki P, Hayashi K, Survey of complications of indocyanine green angiography in Japan, Am. J. Ophtalmol., 1994; 118: 749-53 Wolf S, Arend O, Schulte K, Reim M, Severe anaphylactic reaction after indocyanine green fluorescence angiography, Am. J. Ophtalmol., 1992; 114: 638-9 Benya R, Quintana J, Brundage B, Adverse reactions to indocyanine green. A case report and review of the literature, Cathet. Cardiovasc. Diagn., 1989; 17: 231
IODINATED CONTRAST MEDIA

Iodinated radiographic contrast media are widely used. Reactions from intravascular injection are usually mild and self-treated. Radiographic contrast media can be divided into 4 categories:
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DIAGNOSTIC AGENTS
Ionic monomers (highest osmotoxicity: ratio 1.5; highest carboxyl group toxicity) Diatrizoate, iothalamate, ioxythalamate, iodamide, metrizoate. Ionic dimers (lower osmotoxicity: ratio 3; lower carboxyl group toxicity) Ioxaglate. Non ionic monomers (same osmotoxicity as ionic dimers; no carboxyl group toxicity). 4 hydroxyl groups: metrizamide, iopromide. 5 hydroxyl groups: iopentol, iopamidol, iomeprol, ioxitol. 6 hydroxyl groups: iohexol, ioversol. Non ionic dimers (lowest osmotoxicity; no carboxyl group toxicity). 9 hydroxyl groups: iodixanol. 12 hydroxyl groups: iotrolan.
INCIDENCE
Acute reaction rates: High osmolarity contrast media (HOCM): Mild: 2.5 to 12.66% Moderate: 0.22 to 1.2% Severe: 0.04 to 0.4% Low osmolarity contrast media Mild: 0.58 to 3.13% Moderate: 0.04 to 0.11% Severe: 0 to 0.016%. Risk of repeated reaction: 17 to 35%. Death HOCM: 1/10931 to 1/117000. LOCM: 0 to 1/168363. Delayed reactions: 5 to 30% with ionic monomers. 5 to 15% with non-ionic monomers. No significant association with immediate reactions, allergy, previous adverse reaction to contrast media. May be over estimated due to false delayed adverse reactions resulting from clinical methodology (questionnaire).
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DIAGNOSTIC AGENTS
RISK FACTORS
Asthma: relative risk of any reaction: 1.2 to 2.5 relative risk of severe reaction: 5.1 to 8.4 A patient with peak expiratory flow less than 400 l/ min 10 minutes before injection runs a 3.8 times higher risk of developing an adverse reaction to intravascular injection of contrast media. Food or medication allergies: relative risk of any reaction: 1.6 to 3 relative risk of severe reaction: 2.3 to 3.2 Previous contrast reaction: relative risk of any reaction: 3.3 to 6.9 relative risk of severe reaction: 4.5 to 10.9 Atopy Concomitant use of interleukin 2 increases incidence and severity of delayed reactions (fever, chills, rigors, flushing, dizziness, hypotension). Beta-adrenergic blockers: relative risk 2.7 Female gender is associated with greater risk of anaphylactoid reactions and severe anaphylactoid reactions Cardiac diseases Sea-food allergy or povidone-iodine allergy are not risk factors.
Differentiate from other cardiac or non cardiac manifestations: vasovagal response, cardiogenic shock, myocardial infarction, cardiac tamponade, cardiac rupture, hypovolemia, sepsis or other drug intolerance. Minor reactions Pruritus, urticaria (limited), erythema: no treatment. Moderate reactions Urticaria (diffuse), angioedema, laryngeal edema, bronchospasm: treatment. Severe reactions Cardiovascular shock, respiratory arrest, cardiac arrest: hospitalization.
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DIAGNOSTIC AGENTS
Differentiate from non-idiosyncratic manifestations: warmth, metallic taste in the mouth, nausea, vomiting, contrast-induced renal failure. Delayed reactions (at least 30 minutes after contrast media injection). Flu-like syndrome: fatigue, weakness, upper respiratory tract congestion, fever, chills, nausea, vomiting, diarrhea, abdominal pain, rash, dizziness, headache.
DIAGNOSTIC METHODS
A few reports state that anaphylactoid reactions could be IgEmediated: one case with positive intradermal reaction to meglumine and sodium diatrizoate (1/100) and positive human basophil degranulation test (HBDT).
MECHANISMS
Not fully known, but hyperosmolarity is crucial. The chemotoxicity, osmotoxicity and iontoxicity of contrast media influence cell membranes of blood cells, platelets, endothelial cells and mast cells leading to release of vasoactive substances (histamine, leukotrienes, prostaglandines) and structural changes in molecules of the complement, coagulation, fibrinolytic, or kinin system leading to activation and creation of bradykinin, anaphylatoxins. Antigen-antibody interaction, if any is exceptional. The role of 2 mercaptobenzothiazole (MBT) used in the manufacture of rubber and present in disposable plastic syringes has seldom been advocated.
MANAGEMENT
Universal premedication with corticosteroids Methylprednisolone 32 mg 12 h and 2 h before injection of conventional ionic contrast media decreases the frequency of all reactions from 9% to 6.4% and of severe reactions requiring treatment from 2% to 1.2%.
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DIAGNOSTIC AGENTS
Patients with history of prior reactions to contrast media 1- Use a low osmolarity RCM. 2- Prednisone: 50 mg 13 hours, 7 hours and 1 hour before the procedure. 3- Diphenydramine: 50 mg intramuscular 1 hour before the procedure. 4- Ephedrine: 25 mg p.o 1 hour before the procedure (optional). 1+2+3: 0.7% reactions 1+2+3+4: 0% reaction Use of anti H2 histamine is optional and controversial. Hydroxyzine 100 mg p.o 12 hours before intravenous injection of the ionic dimer ioxaglate decreases the rate of reactions from 12.5% to 1% in low-risk patients. Emergency pre-treatment in previous reactors Intravenous hydrocortisone 100-250 mg q 4 hours until completion of the procedure. Diphenydramine p.o, i.m, i.v, 1 hour before the procedure. Iopamidol causes fewer allergic-type adverse events but more flushing than ioxaglate in patients with asthma or atopic disease. Pre-testing with an intravenous injection of a small amount of contrast media is not useful in predicting severe reactions to ionic or non-ionic contrast media. In patients at risk of anaphylactoid reactions to radiographic contrast media 1- Evaluate the necessity of a procedure requiring RCM. 2- Administration of a LOCM to patients with prior severe anaphylactoid reactions to HOCM. 3- Have emergency equipment available. 4- Use a pre-treatment protocol. 5- Discontinue beta-blockers if possible
REFERENCES
Cohan R.H, Ellis J.H, Iodinated contrast material in uroradiology. Choice of agent and management of complications, Urol. Clin. North. Am., 1997; 24 (3): 471-91 Simon M.R, Allergic-type adverse reactions to low-osmolarity contrast media in patients with a history of allergy or asthma, Invest. Radiol., 1995; 30 (5): 285-90
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DIAGNOSTIC AGENTS
Lang D.M, Alpern M.B, Visintainer P.F, Smith S.T, Gender risk for anaphylactoid reaction to radiographic contrast media, J. Allergy. Clin. Immunol., 1995; 95 (4): 813-7 Almen T, The etiology of contrast medium reactions, Invest. Radiol., 1994; 29 (S1): S37-45 Bertrand P.R, Soyer P.M, Rouleau P.J, Alison D.P, Billardon M.J, Comparative randomized double-blind study of hydroxyzine versus placebo as premedication before injection of iodinated contrast media, Radiology., 1992; 184 (2): 383-4 Greenberger P.A, Patterson R, The prevention of immediate generalized reactions to radiocontrast media in high-risk patients , J. Allergy. Clin. Immunol., 1991; 87 (4): 867-72 Katayama H, Yamagushi K, Kozuka T, Takashima T, Seez P, Matsuura K, Adverse reactions to ionic and non ionic contrast media. A report from the Japanese committee on the safety of contrast media, Radiology, 1990; 175: 621-8 Lasser E.C, Berry C.C, Talner L.B, et al., Pretreatment with corticosteroids to alleviate reactions to intravascular contrast material, N. Eng. J. Med., 1987; 317: 245-9
PARAMAGNETIC CONTRAST AGENTS

Gadolinium chelates used as contrast agents for magnetic resonance (MR) imaging are considered to be relatively safe. Gadopentetate dimeglumine, gadoteridol, gadoterate meglumine.
INCIDENCE
Gadopentetate dimeglumine. Adverse reactions 2.4% (rash: 0.09%, urticaria: 0.07%, anaphylactic shock: 3/million. Adverse reactions in asthmatic patients: 3.7%. Adverse reactions in allergic patients: 3.7%. Adverse reactions in patients with a history of reaction to MR imaging contrast agent: 21.3% Adverse reactions to iodinated contrast agent: 6.3% Deaths reported.
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DIAGNOSTIC AGENTS
RISK FACTORS
Asthma, allergy, previous reaction to MR imaging contrast agent, previous reaction to iodinated contrast agent. Rapid injection is not an adverse reaction risk factor.
Anaphylactic shock Bronchospasm. Pruritus, facial and lingual edema, urticaria, maculopapular exanthema.
DIAGNOSTIC METHODS
None.
MECHANISMS
Paramagnetic contrast agents are ionic or non-ionic. Although not yet fully understood, the same mechanisms as iodinated contrast agents could be involved.
MANAGEMENT
No premedication data published.
REFERENCES
Nelson K.L, Gifford L.M, Lauber-Huber C, Gross C.A, Lasser T.A, Clinical safety of gadopentetate dimeglumine, Radiology., 1995; 196 (2): 439-43 Witte R.J, Anzai L.L, Life-threatening anaphylactoid reaction after intravenous gadoteridol administration in a patient who had previously received gadopentetate dimeglumine, Am. J. Neuroradiol., 1994; 15 (3): 523-4 Shellock F.G, Hahn H.P, Mink J.H, Itskovich E, Adverse reaction to intravenous gadoteridol (see comments), Radiology., 1993; 189 (1): 151-2 Baxter A.B, Lazarus S.C, Brasch R.C, In vitro histamine release induced by magnetic resonance imaging and iodinated contrast media, Invest. Radiol., 1993; 28 (4): 308-12 Niendorf H.P, Dinger J.C, Haustein J, Cornelius I, Alhassan A, Clauss W, Tolerance data of Gd-DTPA: a review, Eur. J. Radiol., 1991; 13 (1): 15-20
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DIAGNOSTIC AGENTS
PATENT BLUE DYE

Patent blue is an aniline dye (alphazurin 2 G) used to stain the lymphatic channels prior performing lymphangiography.
INCIDENCE
0.1 to 2.5% of lymphography procedures. About 30 allergic reactions and 25 cases of anaphylactic shock have been reported. No deaths reported.
RISK FACTORS
Exposure to tryphenylmethane dyes: textile industry, cosmetics, print shops, farms, pharmaceutical plants, food processing plants, plaque-disclosing agents in dentistry.
General: anaphylactic shock. Cutaneous: pruritus, urticaria, angioedema, contact dermatitis. Respiratory: bronchospasm.
DIAGNOSTIC METHODS
Cutaneous testing. In the course of routine preliminary testing: 0.14 to 3.5% of patients were positive to an intradermal skin-test. 2.7% were positive to a prick-test. 0.3% were positive to a patch-test. Scratch, prick, and especially intradermal skin tests, using 1/100000 to 1/100 dilutions. Positive results are often observed in patients presenting immediate generalized reactions. IgE antibodies have never been detected by RAST. Histamine release from leukocytes incubated with patent blue.
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DIAGNOSTIC AGENTS
MECHANISMS
Possible IgE-mediated hypersensitivity in some cases. Non-specific histamine release. Indirect histamine release with activation of the alternative complement pathway.
MANAGEMENT
Predictive skin testing does not detect latent patent blue sensitivity in all cases. Lymphangiography is seldom performed nowadays. If absolutely necessary : perform lymphangiography without visualization of lymphatic vessels , use Evans blue (but contact dermatitis has been reported).
REFERENCES
Belhaouari M, Marty M.H, Sorbette F, Vitry A, Accidents au bleu patent observs durant la lymphographie, Therapie, 1989; 44 (5): 377-8 Pevny I, Carl H, Allergy to dyes used in lymphangiography , Contact Dermatitis, 1985; 12 (1): 54-5 Dubost J.L, Chevallier H, Les accidents allergiques au blue patent violet. Mcanismes, frquence et traitement, Phlbologie, 1982; 35 (3): 739-46 Kalimo K, Jansen C.T, Kormano M, Sensitivity to patent blue dye during skin-prick testing and lymphography. A retrospective and prospective study , Radiology., 1981; 141 (2): 365-7
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DIAGNOSTIC AGENTS
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ENZYMES
IX ENZYMES
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ENZYMES
APROTININ
Aprotinin is a naturally occurring polybasic polypeptide serine protease inhibitor, purified from cattle lungs. It is used in cardiac surgical procedures. It decreases blood loss and transfusion requirements (30 to 40%) by its antifibrinolytic effect, platelet preservation, anti-inflammatory effect and possible preventive action on CNS injury.
INCIDENCE
0.5% of allergic reactions. 2.1% to 5.8% if re-exposure. Between 1964 and 1993: 26 cases have been reported (3 deaths).
RISK FACTORS
Interval of less than 200 days between two aprotinin exposures; especially 35 days to 2 months.
General: anaphylactic shock. Respiratory: bronchospasm. Cutaneous: localized or generalized urticaria.
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests, then intradermal skin tests from 1/1000 to 1/10: a few cases with positive skin tests after an allergic reaction. Specific IgE and IgG After 48 months, 50% of all patients still show measurable levels of IgG antiaprotinin. IgE and IgG antiaprotinin are found in 55% of patients with allergic reactions and 32% of non-reactors. Thus, clinical value is not clearly established.
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ENZYMES
MECHANISMS
IgE-mediated hypersensitivity. Non-specific histamine release.
MANAGEMENT
Do not use aprotinin in non-cardiovascular surgery Delay the first bolus injection of aprotinin until the surgeon is ready to begin cardiopulmonary bypass. Test dose of 10000 KIU of aprotinin in all patients with aprotinin treatment. H1/H2 blockade (clemastine 0.03 mg/kg + cimetidine 5 mg/kg) in cases of known or possible previous exposure. Avoidance of re-exposure within the first 6 months after the previous exposure to aprotinin. Use predictive skin-tests in patients with previous exposure or beefallergic. Other antifibrinolytics are available (tranexamic acid).
REFERENCES
Dobkowski W.B, Murkin J.M, A risk-benefit assessment of aprotinin in cardiac surgical procedures, Drug. Saf, 1998; 18 (1): 21-41 Dietrich W, Spath P, Ebell A, Richter J.A, Prevalence of anaphylactic reactions to aprotinin: analysis of two hundred forty-eight re-exposures to aprotinin in heart operations, J. Thorac. Cardiovasc. Surg., 1997; 113 (1): 194-201 Scheule A.M, Jurmann M.J, Wendel H.P, Haberle L, Eckstein F.S, Ziemer G, Anaphylactic shock after aprotinin re-exposure: time course of aprotininspecific antibodies, Ann. Thorac. Surg., 1997; 63 (1): 242-4 Cottineau C, Moreau X, Drouet M, De Brux J.L, Brenet O, Delhumeau A, Choc anaphylactique lors de lutilisation de laprotinine fortes doses en chirurgie cardiaque, Ann. Fr. Anesth. Reanim., 1993; 12 (6): 590-3 Yanagihara Y, Shida T, Immunological studies on patients who received aprotinin therapy, Arerugi., 1985; 34 (9): 899904.
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ENZYMES
CHYMOPAPAIN
Chymopapain is a proteolytic enzyme with a molecular weight of 27 000 D. It is extracted from a fraction of non-crystallized latex from a tropical tree: Carica papaya. Since 1965 it has been used to treat herniated discs (chemonucleolysis). Because they have the same antigenic determinants, papain and chymopapain exhibit cross-reactivity (chymopapain is the major active component of papain). Chymopapain is more soluble and has greater proteolytic activity than papain.
INCIDENCE
Incidence: 0.44 to 2% of chemonucleolysis procedures. Incidence of severe anaphylactic reactions: 0.18% to 0.45% at the first injection; 9 to 17% after a second injection. 8 deaths reported before 1974, 7 deaths from 1982 to 1991.
MODES OF SENSITIZATION TO PAPAIN

Food: Papaya in any form, pineapple (bromelain), various mixed foods (appetizer mixes, yogurt), beverages containing exotic fruits, beer, Coca-Cola, meat tenderizer containing papain. Drugs containing papain: digestive aids, ENT solutions, antiinflammatory drugs, contact lens cleaning solutions, detergents, ointments containing papain. Occupational: inhalation of airborne papain and bromelain.
RISK FACTORS
Atopy (O.R 13.8). Exposure to papain (O.R 7.3).
Immediate (within 30 minutes after injection of the test dose or total dose): discomfort, pruritus, urticaria, angioedema, fatal anaphylactic shock. Delayed (up to 2 weeks after chemonucleolysis): urticaria, angioedema, serum sickness.
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ENZYMES
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests: chymopapain 1 mg/ml to 10 mg/ml (one case of anaphylaxis during cutaneous testing). Specific IgE (UniCAP/Pharmacia CAP System).
MECHANISMS
IgE-mediated hypersensitivity is responsible for most reactions. This is suggested by previous history, immediately positive skin tests, and detection of IgE antibodies. Activation of the alternate complement route by the enzyme or activation of the normal complement route by chymopapain specific IgG immune complexes. Non-specific histamine release. Autoimmune responses against proteoglycans derived from mucopolysaccharide protein complexes which are produced in great quantity during the 24 hours after injection into the disc.
MANAGEMENT
In high risk patients (atopy and/ or exposure to papain) before first chemonucleolysis, and in all patients before second chemonucleolysis: predictive skin prick-tests. Excellent negative predictive value. If the skin test is negative: chemonucleolysis; if the skin test is positive: surgery. Surgery is indicated in patients with a history of allergic reaction during previous chemonucleolysis. The choice of anesthesia remains controversial. In America, local anesthesia is advocated, while in France general anesthesia is usually performed.
REFERENCES
Moneret-Vautrin D.A, Feldmann L, Kanny G, Baumann A, Roland J, Pere P, Incidence and risk factors for latent sensitization to chymopapain: predictive skin-prick tests in 700 candidates for chemonucleolysis, Clin.Exp.Allergy., 1994; 24 (5): 471-6
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ENZYMES
Nordby E.J, Wright P.H, Schofield S.R, Safety of chemonucleolysis. Adverse effects reported in the United States, 1982-1991., Clin. Orthop., 1993; 293: 122-34 Grammer L.C, Schafer M, Bernstein D, Bernstein I.L, Cogen F, Dolovich J, Schatz M, Zeiger R, Shaughnessy J.J., Gutt L, Roberts M, Patterson R, Prevention of chymopapain anaphylaxis by screening chemonucleolysis candidates with cutaneous chymopapain testing., Clin. Orthop. 1988; 234: 12-15.
STREPTOKINASE
Streptokinase is a 47000 D protein produced by Beta hemolytic streptococci. Once bonded with plasminogen the streptokinaseplasminogen complex cleaves arginine 560 on free plasminogen molecules from free plasma. Clinical uses of streptokinase include the treatment of acute myocardial infarction, deep venous thrombosis, arterial thrombosis and embolism.
INCIDENCE
ISIS-2 trial: 4.4% of allergic reactions to streptokinase. ISIS-3 trial: 3.6% of allergic reactions to streptokinase. GUSTO-1 trial: 5.7% of allergic reactions to streptokinase (0.6% anaphylaxis).
RISK FACTORS
Previous exposure to streptokinase: topical (6 months), antithrombotic use (4 years).
Anaphylactic shock. Bronchospasm, ARDS. Rash, periorbital swelling. rhinorrhea, sneezing. Delayed reactions: fever, arthralgias, myalgias, cutaneous eruptions, renal abnormalities.
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ENZYMES
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests with streptokinase 300 000 IU/ml. Intradermal skin tests: 0.02 ml of 3 IU and 10 IU streptokinase. Some cases positive in patients with anaphylaxis. Serologic methods. Precipitating antibodies . Antistreptokinase IgE, IgG, IgM (ELISA). Antistreptokinase IgG (fluorimetric assay; fibrinplate assay). Lymphocyte transformation test (one case).
MECHANISMS
Complement activation. Human albumin, phosphate buffers, and sodium glutamate are contained in streptokinase preparations. IgE-mediated hypersensitivity: positive skin-tests, specific IgE. Type III hypersensitivity: serum sickness, vasculitis, glomerulonephritis. The presence of antistreptokinase antibodies in high titers may lead to a lower rate of coronary reperfusion if streptokinase is reused.
MANAGEMENT
Use alteplase or urokinase in patients previously exposed to streptokinase. The biologic efficacy of streptokinase is not compromised by an allergic reaction. The precise relation between streptokinase allergy, antibody titers, and clinical outcome requires further studies. Hydrocortisone and antihistamines appear to have no protective effect against hypotensive reactions. Perform an intradermal skin-test with 100 IU of streptokinase before intravenous use. If positive do not use streptokinase; a negative skin-tests is predictive of safe administration of streptokinase.
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ENZYMES
Rapid enzyme immunoassay of antistreptokinase antibodies in human plasma (in 30 minutes) should allow the best thrombolytic therapy for the patient.
REFERENCES
Tsang T.S, Califf R.M, Stebbins A.L, Lee K.L, Cho S, Ross A.M, Armstrong P.W, Incidence and impact on outcome of streptokinase allergy in the GUSTO-1 trial, Am. J. Cardiol., 1997; 79 (9): 1232-5 Jennings K, Antibodies to streptokinase (editorial), B.M.J, 1996; 312 (7028): 393-4 Lee H.S, How safe is the re-administration of streptokinase ?, Drug Safe., 1995; 13 (2): 76-80 Lynch M, Pentecost B.L, Littler W.A, Stockley R.A, The significance of anti-streptokinase antibodies , Clin. Exp. Immunol., 1994; 96 (3): 427-31 Lee H.S, Yule S, Mc Kenzie A, Cross S, Red T, Davidson R, Jennings K, Hypersensitivity reactions to streptokinase in patients with high pre-treatment anti-streptokinase antibody and neutralization titres (see comments), Eur. J. Heart., 1993; 14 (12): 1640-3 Dykewicz M.S, Mc Grath K.C, Davison R, Kaplan K.J, Patterson R, Identification of patients at risk for anaphylaxis due to streptokinase, Arch. Intern. Med., 1986; 146 (2): 3057.
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HORMONES
X HORMONES
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HORMONES
ADENOCORTICOTROPHIC HORMONE (ACTH) TETRACOSACTRIN

ACTH is used for routine laboratory evaluation of adrenocortical function. For many practitioners, ACTH is the product of choice for patients with multiple sclerosis, Wests syndrome, ulcerative colitis and tumoral cerebral edema.
INCIDENCE
Formerly common when natural ACTH was used. Much lower with tetracosactrin (synthetic ACTH peptide). Deaths reported.
General: anaphylactic shock. Respiratory: bronchospasm. Cutaneous: angioedema, maculopapular erythema, urticaria.
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests: ACTH 10 U/ ml; tetracosactrin 100 g/ ml. Intradermal skin-tests: ACTH 0.1 U/ ml; tetracosactrin 1 g/ ml. Detection of IgE antibodies against ACTH has been reported in many cases and against corticotrophin, one case using RAST and ELISA. Challenge is hazardous.
MECHANISMS
IgE-mediated hypersensitivity: Tetracosactrin is less allergenic than ACTH. This may be due to the absence of the terminal 15 AA chain in tetracosactrin.
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HORMONES
Effect of the primary, secondary and quaternary antigenic determinants depends on their spatial configuration in the molecule. This may explain the different cutaneous reactions to A.C.T.H. and tetracosactrin. This may also explain the high incidence of allergic reactions with depot tetracosactrin whose quaternary structure is alte red by the presence of zinc atom.
MANAGEMENT
If tetracosactrin is absolutely necessary, desensitization can be used: 0.01 mg subcutaneously then 0.01 mg intravenously then 0.10 mg intravenously then 0.40 mg intravenously during 4 hours. These injections should be administered at 20-minute intervals.
REFERENCES
Lee T.M, Grammer L.C, Shaughnessy M.A, Patterson R, Evaluation and management of corticotrophin allergy, J. Allergy Clin. Immunol., 1987; 79 (6): 964-88. Hashimoto K, Takahara J, Takaya Y, Yunoki S, Ofuji T, Anaphylactic shock after synthetic adrenocorticotrophin-(1-18) in a patient with isolated adrenocorticotrophin and beta-lipotropin deficiency, J. Clin. Endocrinol. Metab., 1980; 51 (5): 1175-9 Sonneville A, Garrigue M.A, Sabbah A,Baudouin J, Muh J.P, Hypersensibilit immdiate au tetracosapeptide, Rev. fr. Allergol., 1977; 17 (1): 43-6.
CALCITONIN
Cacitonin is a 32 amino acid polypeptide synthesized by the parafollicular cells of the thyroid. It inhibits bone resorbtion and increases urinary calcium and phosphor output. Three types of calcitonin are used, i.e. natural porcine, synthetic salmon and synthetic human calcitonin, for the treatment of Pagets disease, hypercalcemia, hyperparathyroidism, and osteoporosis.
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HORMONES
INCIDENCE
Reported incidence varies from 6% to less than 1/30000.
General: anaphylactic shock. Cutaneous: pruritus, rash, angioedema, urticaria. Respiratory: bronchospasm.
DIAGNOSTIC METHODS
Skin tests: scratch and intradermal (1/1000 and 1/100) were positive in one patient presenting anaphylactic shock with porcine calcitonin. In vitro tests: detection of IgE against porcine calcitonin (RAST) was positive in one case.
MECHANISMS
Immediate IgE hypersensitivity.
MANAGEMENT
Avoidance. Use other types of calcitonin (synthetic salmon or human calcitonin). Negative skin-tests do not exclude allergic manifestations induced by calcitonin.
REFERENCES
Piccone U, Pala M, Caprari M, Schock anafillattico da calcitonina. Descrizione di un caso e revisione della letteratura, Minerva Cardioangiol., 1994; 42 (9): 435-41 Cuskey J, Dubois L, du Buske L, Induction of urticaria and angioedema by synthetic salmon calcitonin, J. Allergy Clin. Immunol., 1991; 87 (1): A359. Pirson F, Tafforeau M, Birnbaum J, Vervloet D, Charpin J, Raction anaphylactique la calcitonine, Rev. fr. Allergol., 1988; 28 (3): 2489.
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HORMONES
CORTICOSTEROIDS
Glucocorticoids are steroids with 21 carbon atoms. They are derived from sterane, pentacyclic carbure. Paradoxically, although widely used for inflammatory and allergic manifestations, they can cause allergic symptoms.
INCIDENCE
Uncommon for systemic reactions: fewer than one hundred cases reported since 1957 (10 deaths published after methylprednisolone pulse therapy). Common for contact dermatitis: 0.2 to 4.8% prevalence in patients attending clinics for patch testing (corticosteroid contact dermatitis will be explored in the next chapter).
RISK FACTORS
Female gender. Age 30 to 60 years. Aspirin intolerance (for bronchospasm due to hydrocortisone). Intravenous administration. Atopic background (controversial). Chronic dermatitis requiring topical therapy over an extended period (for corticosteroid contact allergy).
Drugs involved: hydrocortisone (46%), methylprednisolone (31%), prednisolone (11%), dexamethasone (9%), prednisone (3%). Immediate: anaphylactic shock, urticaria, angioedema, bronchospasm. Generalized delayed systemic reactions: generalized dermatitis, exanthematous rashes with focal bullae and purpura. Allergic contact dermatitis: worsening or lack of response of dermatitis to treatment, perinasal dermatitis, worsening of perennial rhinitis.
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HORMONES
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests: sometimes positive. Intradermal skin-tests: positive in 50% of the cases with immediate hypersensitivity. Patch-tests: budesonide (1% eth) + tixocortol pivalate (1% pet) positive in 91.3% of corticosteroid contact allergic subjects. Skin-tests with the excipient may be positive (carboxymethylcellulose). Specific IgE antibodies: one case (methylprednisolone). Challenge tests may be useful but hazardous.
MECHANISMS
Unclear. IgE-mediated hypersensitivity: one case report. Preservatives and excipients have been implicated: parabens, sulfites, carboxymethylcellulose. Possible role of contaminants and metabolites. Possible role of steroid salts (hydrocortisone esters). Most cases involve a non-allergic mechanism. In patients with aspirin intolerance, hydrocortisone inhibits arachidonic acid release by phospholipids and thus deprives the airways of the cycloxygeneation products (PGE2, prostacycline) which play an important role in bronchodilatation.
MANAGEMENT
Do not use hydrocortisone in patients with aspirin intolerance. When possible, administer orally rather than intravenously. If use is absolutely necessary, perform desensitization to hydrocortisone starting with 15 g and ending with 100 mg in 46 days.
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HORMONES
REFERENCES
Figueredo E, Cuesta-Herranz J, de Las Heras M, Lluch-Bernal M, Umpierrez A, Sastre J, Anaphylaxis to dexamethasone , Allergy., 1997; 52: 877 Moreno-Ancillo A, Martin-Munoz F, Martin-Barroso J.A, Diaz-Pena J.M, Ojeda J.A, Anaphylaxis to 6-alpha-methylprednisolone in an eight-yearold child, J. Allergy Clin. Immunol., 1996; 97: 1169-71 Whitmore S.E, Delayed systemic allergic reactions to corticosteroids , Contact. Dermatitis., 1995; 32 (4): 193-8 Reveilleau-Richard S, Navarre C, Castot A, Hypersensibilits aux glucocorticodes: reflexions partir dun chantillon de cas rapports dans la litterature, Therapie. , 1995; 50 (5): 439-46 Boffa M.J, Wilkinson S.M, Beck M.H, Screening for corticosteroid contact hypersensitivity, Contact. Dermatitis, 1995; 33 (3): 149-51 Clee M.D, Ferguson J, Browning M.C.K, Jung R.T, Clark R.A, Glucocorticod hypersensitivity in an asthmatic patient: presentation and treatment, Thorax., 1985; 40 (6): 477-8
TOPICAL CORTICOSTEROIDS
Widely used drugs in dermatology. Allergy to hydrocortisone has been reported for the first time in 1959. There are 4 chemical/structural classes of corticosteroids. A: hydrocortisone, prednisolone, tixocortol pivalate B: acetonides (triamcinolone, desonide, budesonide) C: betamethasone, dexamethasone, desoxymethasone, fluocortolone D: esters: hydrocortisone-17-butyrate, betamethasone-vale rate, betamethasone-dipropionate, carbonates, carboxylates.
INCIDENCE
0.4% to 6.4% of positive patch-tests to different topical corticosteroids in populations with contact dermatitis. 189/7238 patients (2.6%) in a multicentre European study.
RISK FACTORS
Long term application of topical corticosteroids (leg ulcers, atopic dermatitis, psoriasis, lichen planus).
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HORMONES
The diagnosis of topical corticosteroid allergy is often difficult due to the anti-inflammatory action on cutaneous lesions and their delayed appearance. Increased eczema despite well-conducted topical treatment Eczematization of chronic dermatosis (seborrheic dermatitis, leg ulcers, psoriasis) Reactivation of eczema following oral, parenteral or intraarticular administration of a corticosteroid. Anaphylaxis, urticaria, angioedema following parenteral ad ministration of a corticosteroid.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests must be read at 48 and 96 hours, but also at day 7 or 10 (delayed reactions due to the anti-inflammatory effects of the topical corticosteroids). Interpretation of the tests is often difficult due to vasoconstriction or vasodilatation effects. In dubious cases, a repeated open application test with the corticosteroid preparation or a serial dilution of patch testing may be useful. Among the corticosteroids, budesonide and tixocortol pivalate give the highest positive patch-tests (1.4%); followed by hydrocortisone17-butyrate (1%). Clobetasol propionate and betamethasone valerate have the lowest frequency.
MECHANISMS
Delayed contact hypersensitivity. Topical corticosteroids should be included in standard patch testing: budesonide, tixocortol pivalate, hydrocortisone-17-butyrate are the best candidates.
MANAGEMENT
Avoidance. Cross-reactivity between corticosteroids may be found in patch testing but is not always clinically relevant.
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HORMONES
REFERENCES
Pons-Guiraud A, Allergie aux dermocorticodes, Objectif. Peau., 1996; 4: 433-5 Dooms-Goossens A, Andersen K.E, Brandao F.M, Bruynzeel D, Burrows D, Camarasa J, Ducombs G, Frosch P, Hannuksela M, Lachapelle J.M, Lahti A, Menne T, Wahlberg J.E, Wilkinson J.D, Corticosteroid contact allergy: an ECDRG multicentre study, Contact. Dermatitis, 1996; 33: 40-4 Lepoittevin J.P, Drieghe J, Dooms-Goossens A, Studies in patients with corticosteroid contact allergy: understanding cross-reactivity among different steroids, Arch. Derm., 1995; 131: 31-7 Coopman F, Degreef H, Dooms-Goossens A, Identification of cross-reaction patterns in contact dermatitis from topical corticosteroids, Br. J. Dermatol., 1989; 121: 27-34
GNRH ANALOGUES
These drugs are used to induce ovulation and in treatment of endometriosis, polycystic ovary disease, precocious puberty, and prostate cancer. Tripterolin, Gonadorelin, Buserelin, Leuprorelin (leuprolide), Nafarelin, Goserelin.
INCIDENCE
Local reactions: 0 to 13%. General reactions are rare.
RISK FACTORS
Route of administration (constant infusion > intermittent use). Length of treatment.
General: anaphylactic shock. Cutaneous: flush, pruritus, local erythema, urticaria, vasculitis (sometimes delayed) Respiratory: sneeze, bronchospasm.
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HORMONES
DIAGNOSTIC METHODS
Cutaneous testing. Skin-prick tests positive in various concentrations for gonadorelin, buserilin, goserilin, leuprorelin. Specific IgE (RAST): a few cases published. Specific IgG (RIA): controversial role. MIF one case positive with triptorelin Skin-biopsy: one case of allergic vasculitis with triptorelin.
MECHANISMS
IgE-mediated hypersensitivity (immediate positive skin tests, specific IgE). Type III reaction (one case). Non-specific histamine release.
MANAGEMENT
Avoidance of all GnRHs.
REFERENCES
Raj S.G, Karadsheh A.J, Guillot R.J, Raj M.H, Kumar P, Case report: systemic hypersensitivity reaction to goserelin acetate , Am. J. Med. Sci., 1996; 312 (4): 187-90 Amichai B, Grunwald M.H, Halevy S, Allergic vasculitis induced by Decapeptyl*: confirmation by macrophage migration inhibition factor (MIF) test, Eur. J. Obstet. Gynecol. Reprod. Biol., 1993; 52 (3): 217-8 Letterie G.S, Stevenson D, Shah A, Recurrent anaphylaxis to a depot form of GnRH analogue, Obstet. Gynecol., 1991; 78 (5.2): 943-6 Foster W.G, Jarrell J.F, Dolovich J, Yung-Lai E.V, Immunoglobulin-mediated hypersensitivity in response to long-term treatment with gonadorelin hydrochloride (Factrel) in a female patient, Am. J. Obstet. Gynecol., 1989; 160 (4): 979-83 Mac Leod T.L, Eisen A, Sussman G.L, Anaphylactic reaction to synthetic luteinizing hormone-releasing hormone, Fertil. Steril., 1987; 48 (3): 500-2.
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HORMONES
HEPARIN
Heparin is a highly acidic, anionic, sulfated mucopolysaccharide obtained from beef lung or beef and porcine intestinal mucosa and is highly antigenic. Heparin is widely used in surgery (cardiopulmonary bypass) and in medicine to treat deep venous thrombosis and pulmonary embolism.
INCIDENCE
Heparin associated thrombocytopenia: 1 to 5% of patients receiving unfractioned heparin for at last 5 days. Skin-necrosis: uncommon. Type I manifestations: exceptional.
RISK FACTORS
Female gender and obesity (delayed allergic skin reactions).
I Heparin associated thrombocytopenia (HAT). Type I: moderate and transient decline in platelet count, occurring to 2 to 4 days after heparin administration (platelet sequestration?). Type II: severe (often < 50000 platelets/ mm3), developing 6 to 12 days after start of heparin therapy and often complicated by venous and arterial thromboembolic events (immunological mechanism). II Immediate hypersensitivity reactions. Anaphylactic shock Bronchospasm Urticaria Rhinitis, conjunctivitis
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HORMONES
III Skin-necrosis. With or without thrombocytopenia. 5 to 9 days after beginning of the treatment; indurated erythema occurring at the injection sites with subsequent skin-necrosis. IV Delayed allergic skin-reactions. 57 cases described (1996) with unfractioned heparins 10 cases described (1996) with low weight molecular heparins Infiltrative plaque after deep injection, eczematous lesion after superficial injection; occurring 10 days after initiation of therapy.
DIAGNOSTIC METHODS
I Thrombocytopenia. Heparin-induced platelet activation test (HIPA) Stagnation point flow adhesioaggregometry (SPAA) These techniques must be performed to confirm the responsibility of heparin in thrombocytopenia (IgG antibodies) and also with the substitutes: low molecular weight heparins or heparinoid before using them. II Cutaneous reactions. Prick-tests and intradermal skin-tests are sometimes positive in immediate cutaneous reactions (urticaria). Patch-tests are often negative in delayed allergic skin-reactions. Subcutaneous injection of 0.1 ml, or pure heparin is often the better test. It must be read at 30 minutes, 2 days, 4 days. Skin-biopsies show type III histologic lesions in skin-necrosis and type IV histologic lesions in delayed allergic skin-lesions.
MECHANISMS
Platelets of patients with peripheral arterial disease are hypersensitive to heparin in vitro and in vivo. Low molecular weight heparins show in vitro and in vivo crossreactivity with unfractioned heparin, and must only be used after immunological exclusion of cross-reactivity. Sensitization to heparin may occur with other polysulfated glycosaminoglycans.
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HORMONES
Type I: immediate reactions (urticaria). Type II: thrombocytopenia. Type III: skin-necrosis. Type IV: delayed skin reactions. Reactions to preservatives (chlorocresol, chlorbutanol) were reported in the Seventies.
MANAGEMENT
Thrombocytopenia. Immediate discontinuation of heparin. Substitution with low molecular weight heparin or heparinoid (danaparoid sodium), if in vitro aggregation test is negative. Use warfarin or coumadin therapy. Vena cava filters are sometimes useful (pulmonary embolism). Heparin allergy. In a patient with history indicating possible heparin allergy, numerous alternatives exist: use bovine lung heparin, if there is a reaction to porcine gut heparin (one case) use low molecular weight heparin or heparinoids (beware of cross-reactivity) use thrombin inhibitors: ancrod (thrombin-like enzyme extracted from the venom of Malayan pit viper), argatro ban, hirudin. use iloprost in cardiopulmonary by-pass or dialysed patients DESENSITIZATION is possible (2 cases reported), and if no other possibilities. I Intravenous desensitization: D1: 100 IU/1000 ml saline/24 hours. D2: 1000 IU/1000 ml saline/24 hours. D3: 5000 IU /1000 ml saline/24 hours. Then 5000 IU subcutaneously twice daily until surgery.
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HORMONES
II Subcutaneous and intravenous desensitization: D1: 50 IU S.C After 40 minutes: 250 IU S.C After 40 minutes: 500 IU S.C D2: 500 IU S.C After 40 minutes: 1500 IU S.C After 40 minutes: 3000 IU S.C D3: 500 IU I.V After 40 minutes: 1500 IU I.V After 40 minutes: 3000 IU I.V D4 5000 IU I.V
REFERENCES
Tholl U, Greinacher A, Overdick K, Anlauf M, Life-threatening anaphylactic reaction following parathyroidectomy in a dialysis patient with heparininduced thrombocytopenia, Nephrol. Dial. Transplant., 1997; 12 (12): 27505 Smith R.E, Townsend G.E, Berry B.R, Bowen T, Enoxaparin for unstable angina and ancrod for cardiac surgery following heparin allergy, Ann. Pharmacother., 1996; 30 (5): 476-80 Reininger C.B, Greinacher A, Graf J, Lasser R, Steckmeier B, Schweiberer L, Platelets of patients with peripheral arterial disease are hypersensitive to heparin, Thromb. Res., 1996; 81 (6): 641-9 Bircher A.J, Itin P.H, Tsakiris D.A, Surber C, Delayed hypersensitivity to one low-molecular-weight heparin with tolerance of other low-molecularweight heparins, Br. J. Dermatol., 1995; 132 (3): 461-3 al-Eryani A.Y, al-Momen A.K, Fayed D.F, Allam A.K, Successful heparin desensitization after heparin-induced anaphylactic shock, Thromb. Res., 1995; 79 (5.6): 523-6 Patriarca G, Rossi M, Schiavino D, Schinco G, Fais G, Varano C, Schiavello R, Rush desensitization in heparin hypersensitivity: a case report, Allergy., 1994; 49 (4): 292-4
INSULIN
Immunological responses to insulin are responsible for 2 principal syndromes: insulin allergy and insulin resistance. The prevalence
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HORMONES
of insulin allergy has decreased considerably since human recombinant insulins became available.
INCIDENCE
Historically: 50% of patients using impure insulin preparation. Less than 1% of de novo human insulin treated patients.
RISK FACTORS
Atopy (controversial) . Previous allergies (controversial). Insulin factors: purity, species (bovine > pork > human), physical properties (pH), retarding agents (Zn, protamine). Individual factors: age, immunological background (HLA DR 2, 3, 4), presence of insulin antibodies. Mode of insulin administration: SC > IV, insulin pumps, interrupted insulin therapy.
I/ Local (2-3% in patients treated with highly purified pork or human insulin). Immediate (within minutes of injection): pain + itching accompanied by erythema and swelling < 1 hour. Biphasic (immediate + late phase response): starting at 4 hours and persisting 1-3 days. Intermediate (Arthus reaction): onset at 4-8 hours, peaks at 12 hours, induration with pruritus. Delayed (tuberculin-like): onset at 12 hours, peaks at 24-48 hours, induration with erythema and pruritus. II/ Systemic. Anaphylactic shock. Bronchospasm. General urticaria, angioedema, periorbital edema. Serum sickness, generalized lymphadenopathy. Immunological insulin resistance.
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HORMONES
DIAGNOSTIC METHODS
Cutaneous testing (40% of patients receiving insulin without clinical allergy develop positive immediate skin-tests to the insulin used for treatment). Cutaneous testing allows assessment of the less immunogenic insulin. Skin-prick tests: insulins 40 UI/ ml, protamine sulfate 10 mg/ ml . Intradermal skin-tests: 0.02 to 0.05 ml of different insulins (5 U/ ml). Specific IgE (RAST, ELISA) Low concentrations of IgE anti-insulin are present in the serum of many patients treated with insulin and do not correlate with allergic reactions. High titers of IgE are frequently present in systemic insulin allergy. Protamine-specific IgE (UniCAP/Pharmacia CAP System) are positive in a few patients with allergy to insulins containing protamine . Specific IgG (ELISA) High titers of insulin IgG antibodies are found in patients with insulin resistance. This requires a quantitative assay of the insulin binding capacity of the serum (if greater than 5 U/l of plasma = insulin resistance)
MECHANISMS
IgE-mediated hypersensitivity (local reactions: immediate or biphasic; general reactions: anaphylactic shock, urticaria). Type III reactions (antigen-antibody initiated complement fixation, leukocyte attraction and inflammatory response): Arthus, adenopathies, serum sickness, immunological insulin resistance). Type IV reactions: rare. Antigenic characteristics. Differences in primary amino acid sequence from human insulin Altered tertiary structure Dimer and aggregate formations
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HORMONES
Non-insulin protein contaminants (proinsulin, peptides, glucagon, microbial contaminants) Non-protein additives (zinc, protamine, preservatives, buffers). Antigenicity of human semi-synthetic insulin is probably due to a tertiary structure change and to shared antigen determinants with pork and beef insulins. Most cases of allergy to human insulin have histories of animal insulin exposure. Differences in amino acid sequences of the various exogenous is one of the major contributors to exogenous insulin allergy. Porcine and bovine insulins differ from human insulin by 1 and 3 amino acids. Allergy occurs more often with bovine insulin than with porcine insulin therapy. The insulin molecule has well-identified immunogenic epitopes which map at A.A positions A1, A6, A chain loop (A8-A11), A1920-21, B-3 and B-30. A few papers reported allergy to protamine, present in NPH insulin and protamine-zinc insulin as the cause of generalized allergic reactions to insulin (clinically: absence of previous local reactions, severity of reactions, refractory period of weeks or months between reactions). Insulin syringes and insulin vial stoppers containing latex and may lead to allergic reactions in patients with diabetes. Different from contact allergy due to glue components in infusion sets of insulin pumps: epoxyresin.
MANAGEMENT
I/ Local reactions. Reassure the patient, use antihistamines, use several injection sites, switch to a more purified form of insulin. II/ Generalized reactions. If insulin treatment is absolutely necessary and skin-tests are positive; desensitize to the least reactive regular insulin preparation.
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HORMONES
If the patient is medically stable: give 1/2 dose of insulin.increase insulin dose 5 Uq 12 h until control is achieved.continue NPH or lente insulin q12 h If the patient is medically unstable: rapid desensitization protocol; for example: 0.02 ml (0.05 U/ ml) ID to 0.08 ml (50 U/ ml); then follow with double dose SC q 4 h until control is established. LISPRO (analog of human insulin) with reversed position of amino acids lysine 28 and proline 29 on the insulin Beta chain, remains in a monomeric state and has lowest immunogenicity. It has been successfully used in allergy to other insulins and in immunemediated insulin resistance cases.
REFERENCES
Frigerio C, Aubry M, Gomez F, Graf I, Dayer E, de Kalbermatten N, Gaillard R.C, Spertini F, Desensitization-resistant insulin allergy, Allergy, 1997; 52 (2): 238-9 Kumar D, Lispro analog for treatment of generalized allergy to human insulin, Diabetes Care. , 1997; 20 (9): 1357-9 Lebovitz H.E, Insulin allergy and insulin resistance, Curr. Ther. Endocrinol. Metab., 1997; 6: 500-4 Blanco C, Castillo R, Quiralte J, Delgado J, Garcia I, de Pablos P, Carrillo T, Anaphylaxis to subcutaneous neutral protamine Hagedorn insulin with simultaneous sensitization to protamine and insulin, Allergy, 1996; 51 (6): 421-4 Goldfine A.B, Kahn C.R, Insulin allergy and insulin resistance, Curr. Ther. Endocrinol. Metab., 1994; 5: 461-4 Dykewicz M.S, Kim H.W, Orfan N, Yoo T.J, Lieberman P, Immunologic analysis of anaphylaxis to protamine component in neutral protamine Hagedorn human insulin, J. Allergy. Clin. Immunol., 1994; 93 (1.1): 117-25 Schernthaner G, Immunogenicity and allergenic potential of animal and human insulins, Diabetes Care., 1993; 16 Suppl 3: 155-65
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HORMONES
PROTAMINE
Strongly alkaline polycationic molecule used to neutralize the anticoagulant effect of heparin or to slow the absorption of insulin. It is purified commercially from salmon milt.
INCIDENCE
2,9% to 26,6% of insulin diabetic patients with NPH insulin or PZ insulin have reactions to intravenously administered protamine versus 0,76% to 0,4% of non diabetic patients. Pulmonary vasoconstriction: 1,2%
RISK FACTORS
Single-dose intravenous protamine results in protamine specific IgE or IgG antibody production in 28% of patients. Seroconversion is associated with male gender and insulin-dependent mellitus; these patients may be at increased risk on subsequent exposure. Insulin dependent diabetic patients treated with NPH or PZI: the presence of IgE to protamine leads to a relative risk of 95 if protamine is used; the presence of IgG to protamine leads to a relative risk of 38. In patients with no prior exposure to SC protamine insulin preparations, the presence of IgG to protamine leads to a relative risk of 25. Previous protamine exposure. Vasectomy and fish allergy are not risk factors.
CLINICAL MANIFESTATIONS.
Anaphylactic shock. Systemic hypotension +/- pulmonary vasoconstriction. Urticaria, rash. Bronchospasm.
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HORMONES
DIAGNOSTIC METHODS
Cutaneous testing (controversial). Intradermal skin-tests with 1 g/ ml and 10 g/ ml protamine give false positive results. Skin-prick tests positive at 10 mg/ ml in one patient with NPH insulin allergy. Protamine specific antibody assays. Solid phase immunoassay (IgE, IgG). ELISA (IgE, IgG): false positive results. RAST (IgE, IgG).
MECHANISMS
IgE or IgG-mediated hypersensitivity (with or without complement activation unrelated to rate of administration). Complement activation (by heparin-protamine complexes or by interaction with protamine-antiprotamine IgG antibody complexes leading to generation of C3a, C4a, C5a). Direct non-immunological histamine release. Inhibition of serum carboxypeptidase. Potentiation of IgE-mediated histamine release. Augmentation in thromboxane A2 and 6 ketoprotaglandin F1 alpha, causing pulmonary arterial pressure elevation.
MANAGEMENT
Use of ancrod or hirudin instead of heparin. Use of hexadimethrine in place of protamine. Use of adjuncts to promote hemostasis (antifibrinolytics, aprotinin). Premedication with antihistamines and steroids reduces the severity of an allergic reaction (controversial)
REFERENCES
Nyhan D.P, Shampaine E.L, Hirshman C.A, Hamilton R.G, Frank S.M, Baumgartner W.A, Adkinson N.F Jr, Single doses of intravenous protamine result in the formation of protamine-specific IgE and IgG antibodies, J. Allergy. Clin. Immunol., 1996; 97 (4): 991-7
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HORMONES
Horrow J.C, Pharo G.H, Levit L.S, Freeland C, Neither skin-tests nor serum enzyme-linked immunosorbent assay tests provide specificity for protamine allergy, Anesth. Analg., 1996; 82 (2): 386-9 Dykewicz M.S, Kim H.W, Orfan N, Yoo T.J, Lieberman P, Immunologic analysis of anaphylaxis to protamine component in neutral protamine Hagedorn human insulin, J. Allergy Clin. Immunol., 1994; 93 (1.1): 117-25 Weiss M.E, Adkinson N.F Jr, Allergy to protamine, Clin. Rev. Allergy, 1991; 9 (3-4): 33955 Vincent G.M, Janowski M, Menlove R, Protamine allergy reactions during cardiac catheterization and cardiac surgery: risk in patients taking protamineinsulin preparations, Cathet. Cardiovasc. Diagn., 1991; 23 (3): 164-8
PSEUDOEPHEDRINE
Many drugs contain cathecholamine derivatives (local anesthetics, eye drops with neosynephrine, nasal vasoconstrictives).
INCIDENCE
Low.
Urticaria, eczema (oral absorption of pseudoephedrine), fixed drug eruption, scarlatin-like rash. Acute conjunctivitis with eczema of the eyelids (neosynephrine containing eye drops).
DIAGNOSTIC METHODS
Cutaneous testing. Prick-tests and patch-tests with pseudoephedrine 1%, 5% in water or pet. (patch-tests).
MECHANISMS
Immediate hypersensitivity is exceptional. Delayed contact hypersensitivity is more frequent. Mechanism is unknown in toxic shock syndrome and in most rashes.
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HORMONES
MANAGEMENT
Avoidance. Cross-reactivity may exist among cathecholamine derivatives. There are 2 types of derivatives: ephedrine, pseudoephedrine and norephedrine derived from a molecular structure of phenyl propanolamine type. These molecules have a very close structure and can cross-react. epinephrine and phenylephrine do not seem to cross-react with the first group. Thus sensitization to pseudoephedrine does not contra-indicate the use of eye drops containing neosynephrine and the use of epinephrine containing local anesthetics.
REFERENCES
Thomas P, Rueff F, Pryzbilla B, Severe allergic contact blepharoconjunctivitis from phenylephrine in eye drops, with corresponding T-cell hyperresponsiveness in vitro, Contact. Dermatitis, 1998; 38: 41-3 Rochina A, Burches E, Morales C, Braso J.V, Pelaez A, Adverse reaction to pseudoephedrine, J. Invest. Allergol. Immunol., 1995; 5: 235-6 Tomb R.R, Lepoittevin J.T, Espinassouze F, Heid E, Foussereau J, Systemic contact dermatitis from pseudoephedrine, Contact. Dermatitis., 1991; 24: 86-8 Taylor B.J, Duffill M.B, Recurrent pseudo-scarlatina and allergy to pseudoephedrine hydrochloride, Br. J. Dermatol., 1988; 118: 827-9
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SERA AND VACCINES
XI SERA AND VACCINES
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SERA AND VACCINES
ANTITHYMOCYTE GLOBULINS
Antithymocyte globulins are the preferred treatment for patients with aplastic anemia and in prevention and treatment of renal, cardiac, kidney, and bone marrow graft rejection. Several commercial preparations from different animal serums exist (horse, rabbit, murine).
INCIDENCE
Anaphylaxis < 1% of treatments.
RISK FACTORS
Allergy to horses, rabbits, or murine species.
Anaphylactic shock Bronchospasm, A.R.D.S. Cutaneous eruptions, periorbital edema.
DIAGNOSTIC METHODS
Skin tests must be performed before use of antithymocyte globulins in order to detect at-risk patients. Intradermal skin tests give false positive results. Skin prick-tests with dilutions to 1/1000 to pure have a better predictive value.
MECHANISMS
IgE-mediated hypersensitivity (immediate reactions). Circulating immune complexes (serum sickness).
MANAGEMENT
Skin prick-tests must be performed in all patients treated with heterologous antisera.
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SERA AND VACCINES
For patients with positive skin prick-tests: use a preparation from other mammalian origin (horse < > rabbit). desensitization may be performed: 0.02 ml intradermal 5g/ ml, 50g/ ml, 500 g/ ml, 5 000 g/ ml at ten minutes intervals then 0.5 ml subcutaneous 50 g/ ml, 100 g/ ml, 300 g/ ml, 1 000 g/ ml, 3 000 g/ ml, 5 000 g/ ml at ten minutes intervals then 0.5 mg/ min, 1 mg/ min, 2 mg/ min intravenous for ten minutes each with the therapeutic dose of ATG at 15 mg/kg constantly infused over 24 hours.
REFERENCES
Bielory L, Wright R, Nienhuis A.W, Young N.S, Kaliner M.A, Antilymphocyte globulin hypersensitivity in bone marrow failure patients, JAMA. 1988; 260 (21): 3164-7 Cunningham E, Chi Y, Brentjens J, Venuto R, Acute serum sickness with glomerulonephritis induced by antithymocyte globulins, Transplantation. 1987; 43 (2): 309-12 Gartner J, Earl H, Carrington D, Jiang C.L, Sullivan T, Reactions to antilymphocyte globulins, J. Allergy. Clin. Immunol., 1987; 79 (1): 237
ANTIVENOMS
Antivenoms are prepared from immunized animal sera. They constitute the specific treatment for snake, spider and scorpion envenomation.
INCIDENCE
Snake: 3 to 54%. Spider: 0.5% . Scorpion: 8% with centuroides sculpturatus antivenom. 1.7 to 2.6% with L. quinquestriatus venom.
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SERA AND VACCINES
RISK FACTORS
Allergy to animal serum or dander (horse, goat).
Immediate: anaphylactic shock, urticaria, pruritus, rash, bronchospasm, vomiting, abdominal pain, diarrhea. Delayed: serum sickness, arthralgias, urticaria, polyadenopathy .
DIAGNOSTIC METHODS
Cutaneous testing: its usefulness is controversial. False positive and negative seem to be high. Nevertheless, with centuroides sculpturatus antivenom specificity is 98%, sensitivity 68%.
MECHANISMS
IgE-mediated hypersensitivity. Circulating immune complexes (serum sickness). Complement activation by antivenom or impurities.
MANAGEMENT
In high risk patients, perform intradermal skin tests. If positive, the risk of immediate reaction is high Negative results do not absolutely rule out the possibility of a reaction. Pre-treatment with antihistamine and epinephrine, and slow intravenous injection of the antivenom at a 1/1000 or 1/10000 dilution are good precautions. Rapid desensitization has been recommended.
REFERENCES
Ismail M, The treatment of the scorpion envenoming syndrome: the Saudi experience with serotherapy, Toxicon. 1994; 32 (9): 1019-26 Gateau T, Bloom M, Clark R, Response to specific centuroides sculpturatus antivenom in 151 cases of scorpion stings, J. Clin. Toxicol. 1994; 32 (2): 165-71
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SERA AND VACCINES
Varma T, Rapid desensitization in antivenom hypersensitivity, J. Assoc. Phys. Ind. 1987; 35 (3): 250-1 Malasit P, Warrell DA, Chanthavanich P,Viravan C, Mongkolsapaya J, Singhthong P, Supich C, Prediction, prevention and mechanisms of early (anaphylactic) antivenom reactions in victims of snake bites , Br. Med. J., 1986 . 292: 1720. Otten EJ, Mackimm D, Venomous snakebite in a patient allergic to horse serum, Ann. Emerg. Med., 1983; 12: 6247. Sutherland SK, Lovering KE, Antivenoms, Med. J. Austr., 1979; 6714.
BCG VACCINE
BCG Vaccine is widely used throughout the world to prevent tuberculosis. Other indications are intralesional treatment in superficial bladder cancer.
INCIDENCE
Quite uncommon. Fewer than ten cases in neonates or infants have been reported.
Differentiate from lymphadenitis or generalized granulomatosis. Anaphylaxis. Urticaria. Lupus vulgaris +/- urticarial vasculitis. Acute febrile neutrophilic dermatosis (Sweets syndrome). Pustular vasculitis. Erythema multiforme. Dermatomyositis (conflictual).
DIAGNOSTIC METHODS
Dextran reactive antibodies: in a few cases where high titers of DRA were found in a maternal blood sample or childs blood sample.
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SERA AND VACCINES
MECHANISMS
Concerning the neonatal anaphylactic reactions reported after BCG vaccination, passively acquired maternal dextran antibodies reacted with the 100 KD dextran which is a component of the BCG vaccine.
MANAGEMENT
Use BCG vaccine without dextran (sodium glutamate). Dextran 1 should be used in the vaccines, instead of high molecular weight (100 KD) dextran.
REFERENCES
Rudin C, Gunthard J, Halter C, Staehlin J, Berglund A, Anaphylactod reaction to BCG vaccine containing high molecular weight dextran, Eur. J. Pediatr. 1995;154 (11): 941-2 Barbaud A, Schmutz JL, Mougeolle JM, Reactions immunoallergiques cutanes dues aux vaccins, Ann. Dermatol. Vnrol. 1995;122: 129-38 Sosnowski JT, Complications of bacillus Calmette - Gurin (BCG) immunotherapy in superficial bladder cancer, Compr. Therapy. 1994;20 (12): 695-701 Pnnighaus JM, Fine PEM, Moreno C, Hypersensitivity of dextran in BCG vaccine, Lancet. 1991;337: 1039
BOTULINAL ANTITOXIN
Botulism is a paralyzing illness caused by the action of neurotoxins produced by Clostridium botulinum. One method of management is injection of an equine botulinal antitoxin.
INCIDENCE
9% of injections (immediate manifestations: 5%, delayed manifestations: 4%).
Anaphylactic shock (occurs even with small amounts of serum): 1.9% of cases; Urticaria: 2.6% of cases.
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SERA AND VACCINES
Serum sickness (injections exceeding 40 ml): 3.7% of cases. Generalized erythema, laryngeal edema: 0.7% of cases.
DIAGNOSTIC METHODS
Cutaneous testing Intradermal skin tests may be positive in patients presenting anaphylactic shock. However, the false negative rate is high (50%) and this test does not rule out the possibility of generalized reactions.
MECHANISMS
IgE-mediated hypersensitivity probably underlies anaphylactic manifestations, but IgE antibodies have never been demonstrated. The role of immune complexes is likely in cases involving serum sickness.
MANAGEMENT
No effective prevention for immediate manifestations. Inject less than 40 ml of botulinal antitoxin so as to minimize serum sickness. Using botulinal immune globulin obtained from hyperimmunized human donors will be beneficial.
REFERENCES
Black RE, Gunn RA, Hypersensitivity reactions associated with botulinal antitoxin, Am. J. Med., 1980; 69: 56770.
BOVINE SERUM ALBUMIN

Bovine serum albumin is a powerful immunogen able to produce allergic reactions. It is used during bone marrow transplantation and in vitro fertilization.
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SERA AND VACCINES
INCIDENCE
Serum sickness: 1% to 15% (in 32 patients with in vitro fertilization).
RISK FACTORS
Atopy.
Anaphylactic shock. Urticaria, angioedema. Rhinoconjunctivitis. Bronchospasm. Serum sickness (maculopapular eruption, arthralgias, fever, 8 to 12 days after procedure).
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests: positive with BSA in 1% distilled water. Intradermal skin tests with BSA 0.1 and 1 mg/ ml are positive in immediate and late responses, and positive to fetal calf serum (containing bovine serum albumin). Specific IgE: IgE anti BSA (ELISA / RAST). Specific IgG (ELISA) in serum sickness-like reactions.
MECHANISMS
IgE-mediated hypersensitivity: positive skin tests and specific IgE against BSA. Sensitization to BSA may develop following natural contact (eating meat, drinking cows milk, exposure to animal epithelia, dander or saliva containing serum albumin cross-reactive with BSA) Serum sickness-like reactions: IgG 1 mediated sensitization to BSA
MANAGEMENT
Preoperative skin prick tests or RAST with the insemination medium is recommended.
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SERA AND VACCINES
Concerning bone marrow infusion, autologous plasma or serum is now used instead of BSA.
REFERENCES
Wthrich B, Stern A, Johansson SGO, Severe anaphylactic reaction to bovine serum albumin at the first attempt of artificial insemination, Allergy. 1995;50: 179-83 Morales C, Braso JV, Pellicer A, Ruiz A, Pelaez A, Serum sickness due to bovine serum albumin sensitization during in vitro fertilization, J. Inv. Allergol. Clin. Immunol. 1994;4 (5): 246-9 Moneret-Vautrin DA, Wal JM, Guillet-Rossof F, Gerard H, Boulard P, Bovine serum albumin immunization. A new risk of allergy during protocols for in vivo fertilization, Allergy. 1991; 46: 228-34 Macy E, Bulpitt K, Champlin RE, Saxon A, Anaphylaxis to infusion of autologous bone marrow. An apparent reaction to self mediated by IgE antibodies to bovine serum albumin, J. Allergy Clin. Immunol. 1989; 83: 871-5
EQUINE RABIES IMMUNOGLOBULINS

In developing countries, equine rabies immunoglobulin (ERIG) is more readily available than human rabies immunoglobulin (HRIG). Modern ammonium-sulfate-precipitated ERIG products are safe and effective.
INCIDENCE
Anaphylaxis: 1/35 000. Serum sickness: 1-1,6%.
Anaphylactic shock. Generalized urticaria . Bronchospasm. Serum sickness.
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SERA AND VACCINES
DIAGNOSTIC METHODS AND MANAGEMENT

Intradermal skin test must be performed before administration of ERIG (0.02 ml of 1/100 ERIG). If wheal is > 10 mm in diameter with or without flare, or if wheal is 5-10 mm in diameter with a flare > 20 mm; do not use ERIG. False positives have been reported.
MECHANISMS
Type I hypersensitivity reactions (anaphylaxis). Type III hypersensitivity reactions (serum sickness).
REFERENCES
Tantawichien T, Benjavongkulchai M, Wilde H, Jaijaroensup W, Siakasem A, Chareowai S, Yountong C, Sitprija V, Value of skin testing for predicting reactions to equine rabies immunoglobulin, Clin. Infect. Dis. 1995;21 (3): 660-2
HEPATITIS B VACCINE
Recombinant DNA techniques have permitted the development of vaccines to the hepatitis B virus prepared by cloning and expressing the Hbs antigen in yeast or CHO cells.
INCIDENCE
Less than 1%.
RISK FACTORS
Contact sensitization to formaldehyde or thiomersal. Yeast allergy.
Local reactions: local urticaria or aluminum granuloma. General reactions: arthralgias, myalgias, generalized urticaria, Arthus phenomenon, erythema multiforme (2/200 000), erythema nodosum, pruritus (1/122 500), thrombocytopenic purpura, eczema exacerbation.
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SERA AND VACCINES
DIAGNOSTIC METHODS
Cutaneous testing. Prick tests: full vaccine 1/10, saccharomyces cerevesiae, thiomersal 0.1%, aluminum chloride 0.5%, latex. Intradermal skin tests: full vaccine 1/100. Patch tests: thiomersal 0.1%, aluminum chloride 0.5%, formaldehyde 2%. Few cases with positive tests to thiomersal, aluminum chloride, saccharomyces cerevesiae, latex or formaldehyde. Specific IgE: saccharomyces cerevesiae.
MECHANISMS
Aluminum hydroxide, thiomersal, formalin, yeast or latex are responsible for the few reported allergic reactions to the hepatitis B vaccine.
MANAGEMENT
If revaccination is necessary, use vaccine containing a different preservative . In patients with latex allergy, use a glass syringe and remove the rubber bung.
REFERENCES
Lear JT, English JSC, Anaphylaxis after hepatitis B vaccination, Lancet. 1995;345: 1249 Barbaud A, Schmutz JL, Mougeolle JM, Reactions immunoallergiques cutanes dues aux vaccins, Ann. Dermatol. Venereol. 1995;122: 129-38 Mac Mahon B, Helminiak C, Wainwright R, Bulkow L, Trimble D, Wainwright D, Frequency of adverse reactions to hepatitis B vaccine in 43,618 persons, Am. J. Med, 1992;92: 196-9 Hudson TJ, Newkirk M, Gervais F, Shuster J, Adverse reaction to the recombinant hepatitis B vaccine , J. Allergy. Clin. Immunol. 1991;88 (5): 821-2 Brightman CAJ, Scadding GK, Dumbreck LA, Latchman Y, Brostoff J, Yeast derived hepatitis B vaccine and yeast hypersensitivity, Lancet. 1989; i: 903 Ring J, Exacerbation of eczema by formalin-containing hepatitis B vaccine in formaldehyde allergic patient, Lancet. 1986;i: 522-3
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SERA AND VACCINES
HETEROLOGOUS SERA
Antilymphocyte globulin is a gammaglobulin prepared by injection of human lymphocytes into various animals (e.g. horses) and then purifying the IgG against human lymphocytes from the serum. It is used for prophylactic and curative treatment of kidney graft rejection. Murin monoclonal antibodies are used against tumor antigens in oncology.
INCIDENCE
Anaphylaxis is uncommon. Serum sickness is more frequent.
RISK FACTORS
Detection of IgE antibodies against hair from the animals providing the serum.
General: anaphylactic shock, serum sickness (most common). Respiratory: adult respiratory distress syndrome. Renal: glomerulonephritis. Cutaneous: cutaneous eruptions, periorbital edema.
DIAGNOSTIC METHODS
Skin tests must be performed before injection in order to detect IgE antibodies and ascertain the risk of anaphylactic reaction. A 20-minute intervals, perform: prick test at 1:10 intradermal injection of 0.02 ml at 1:1 000 or 1:100 intravenous injection of 0.5 ml at 1:10. These tests are often positive with fresh antilymphocyte globulin, but negative if the product is left to stand for 4 to 8 hours at room temperature.
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SERA AND VACCINES
MECHANISMS
IgE-mediated hypersensitivity underlies immediate reactions. Circulating immune complexes underlie serum sickness (IgE antibodies).
MANAGEMENT
Use aged antilymphocyte globulins in patients with negative reactions to the aged products. If necessary, desensitization may be performed in patients with positive skin tests, but the risk of fatal anaphylactic shock remains. Start with an intravenous injection of 0.1 ml at 1:1000 and then double the dose every 15 to 20 minutes. If a reaction occurs, resume treatment at half the dose that caused the reaction. When 1 ml of pure serum is reached, the rest can be administered by slow infusion. Serum sickness is probable between the 10 and 14th day following desensitization. Treat with corticosteroids.
REFERENCES
J. Gifford, Serum therapy and immunoprophylaxis. In Altman (ed.) Clinical Allergy and Immunology, Boston G. K. Hall Co., 1984, 359387. E. Cunningham, Y. Chi, J. Brentjens, R. Venuto, Acute serum sickness with glomerulonephritis induced by antithymocyte globulins, Transplantation, 1987, 43, 2, 309312. J. Gartner, H. Earl, D. Carrington, C. L. Jiang, T. Sullivan, Reactions to anti-lymphocyteglobulin (ALG), J. Allergy Clin. Immunol., 1987, 79 (1), 237.
HUMAN SERUM ALBUMIN

Used as a plasma expander, in plasma exchange and for pulmonary perfusion scan (technetium 99 m labeled human albumin microspheres).
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SERA AND VACCINES
INCIDENCE
0.012%. One third of reactions are life-threatening.
Anaphylactic shock.. Bronchospasm. Pruritus, urticaria.
DIAGNOSTIC METHODS
Cutaneous testing Intradermal skin tests with undiluted human serum albumin leads to false positive results. Some authors reported positive skin tests with dialysed, undialyzed and ultracentrifuged HSA 0.5% and 5%. Specific IgE (ELISA).
MECHANISMS
IgE-mediated hypersensitivity is suggested by immediately positive cutaneous tests and evidence of specific IgE. Albumin aggregates (high molecular weight aggregates and some denatured albumin-globulin complexes may form during preparation of albumin solution). IgG anti IgA in IgA-defective patients. Complement activation.
MANAGEMENT
Avoidance.
REFERENCES
Stafford CT, Lobel CA, Fruge BC, Moffitt JE, Hoff RG, Fadel HE, Anaphylaxis to human serum albumin, Ann. Allergy 1988; 61 (2), 858. Edelman BB, Straughn MA, Getz P, Schwartz E, Uneventful plasma exchange with albumin replacement in a patient with a previous anaphylactoid reaction to albumin, Transfusion. 1985; 25: 435-6
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SERA AND VACCINES
Littenberg RL, Anaphylactoid reaction to human albumin microspheres, J. Nucl. Med. 1975; 16 (3): 236-7
INTRAVENOUS IMMUNOGLOBULINS
Polyvalent immunoglobulins are used in the treatment of congenital or acquired immunodeficiencies and in the management of some immune disorders.
INCIDENCE
2 to 6% (rate related).
RISK FACTORS
Selective IgA deficiency. Common variable hypogammaglobulinaemia. Multiple blood or plasma infusions.
Occurring one the first or second infusion. Severe: anaphylactic shock. Moderate: chest tightness, mild wheezing. Mild: headache, flushing, low backache, muscle pain, nausea, chills, abdominal pain.
DIAGNOSTIC METHODS
IgG anti IgA antibodies are detected in a 22% of patients with common variable immunodeficiency, and in 20 to 60% of patients with selective IgA deficiency. Anti IgA antibodies are found more frequently in patients with combined IgA and IgG2 subclass deficiencies. IgA antibodies are class-specific, subclass-specific, antiallotypic, antiisoallotypic, or of limited specificity. IgE anti IgA (ELISA) have been reported in patients with anaphylactic shock and IgA deficiency.
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SERA AND VACCINES
MECHANISMS
Formation of immune complexes between antibodies in intravenous immunoglobulins and microbial antigens in the recipient with subsequent complement activation. Presence of IgG or IgE anti IgA in patients with absolute absence of IgA.
MANAGEMENT
Prophylactic use of hydrocortisone and an antihistamine is advisable (first and second infusion). Use IgA-depleted intravenous immunoglobulins preparations in patients with high titers of anti IgA antibodies.
REFERENCES
Misbah SA, Chapel HM, Adverse effects of intravenous immunoglobulins, Drug. Safety. 1993; 9 (4): 254-62 Burks AW, Sampson HA, Buckley RH, Anaphylactic reactions after gammaglobulin administration in patients with hypogammaglobulinemia, New Eng. J. Med., 1986; 314 (9): 5604. Lederman HM, Roifman CM, Lavi S, Gelfand EW, Corticosteroids for prevention of adverse reactions to intravenous immune serum globulin infusion in hypogammaglobulinemic patients, Am. J. Med., 1986; 81: 4436. Wells JV, King MA, Adverse reactions to human plasma proteins, Anaesth. Intensive. Care., 1980; 8 (2): 139-44
MEASLES VACCINE
Measles vaccine is an attenuated live virus vaccine cultured on chick embryo fibroblasts. Much controversy exists concerning its use in egg-allergic children.
INCIDENCE
< 71.6/million doses (life-threatening anaphylactic reactions).
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SERA AND VACCINES
RISK FACTORS
Allergic reactions to food gelatin. Egg allergy: controversial
Anaphylactic shock, cough, wheezing, urticaria, angioedema. Non-immediate mild skin eruptions (several to 48 hours after vaccination).
DIAGNOSTIC METHODS
Cutaneous testing (controversial): patients with or without allergy may have positive skin test reactions to the vaccine and still be safely immunized. Specific IgE to gelatin (immunoblotting, UniCAP/Pharmacia CAP System, fluorimetric ELISA). Gelatin specific cell mediated immunity: in vitro lymphocyte proliferation assay, antigen specific IL 2 responsiveness (non immediate reactions to gelatin).
MECHANISMS
IgE-mediated hypersensitivity due to the presence of minute quantities of ovalbumin ( 37 to 260 pg). Neomycin: few cases (controversial). Gelatins: numerous papers show a strong relationship between systemic immediate-type allergic reactions to vaccine and the presence of specific IgE to gelatins.
MANAGEMENT (CONTROVERSIAL)
Measles vaccine containing the Edmoston-Zagreb strain (grown in human diploid cells) has lower immunogenicity than the Schwarz strain grown in a chick embryo fibroblast culture. Up to now (1997), 1326 egg-allergic children who received the Schwarz strain measles vaccine suffered no allergic reactions, whereas 43 non egg-allergic children showed immediate reactions after the immunization.
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SERA AND VACCINES
In egg-allergic patients, some doctors perform skin prick-tests with vaccine (1/10). if positive administer subcutaneously 0.05 ml at 1/100, 1/ 10, pure up to a total dose of 0.5 ml (at 15 minute intervals) if negative perform an intradermal tests with measles vaccine 1/100 if positive, proceed in the same way as for a positive prick-test if negative, administer the total dose of vaccine, i.e. 0.5 ml subcutaneously under medical supervision (30 minutes). This protocol is contested by many authors who prefer the following recommendations: 1/ all immunizations should be performed by those capable of managing vaccine-associated anaphylaxis. 2/ egg allergy is not a contraindication to immunization with MMR. In individuals with a history of anaphylaxis to eggs, measles immunization may be routinely administered nner without prior skin testing. Immunization should be performed where adequate facilities are available to manage anaphylaxis. At-risk patients should be observed for 30 minutes. 3/ Measles vaccine or MMR is contraindicated in individuals with a previous anaphylactic reaction to vaccine containing measles . 4/ Observation for post measles-vaccine anaphylaxis should be improved, and prospective studies should be initiated to better define the risk in individuals with egg allergy.
REFERENCES
Bruno G, Grandolfo M, Lucenti P, Novello F, Ridolfi B, Businco L, Measles vaccine in egg-allergic children: poor immunogenicity of the Edmoston-Zagreb strain, Pediatr. Allergy. Immunol. 1997; 8: 17-20 Kumagai T, Yamanaka T, Wataya Y, Umetsu A, Kanamura N, Ikeda K, Furukawa H, Kimura K, Chiba S, Saito S, Sugawara N, Kurimoto F, Sakaguchi M, Inouye S, Gelatin specific humoral and cellular immune responses in children with immediate and non immediate-type reactions to live measles, mumps, rubella, and varicella vaccines , J. Allergy. Clin. Immunol., 1997; 100: 130-4 National advisory committee on immunization (NACI). Supplementary statement MMR vaccine and anaphylactic hypersensitivity to egg or egg related antigens. Can. Commun. Dis. Resp. 1996; 22 (14): 113-5
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SERA AND VACCINES
James J.M, Burks A.W, Roberson P.K, Sampson H.A, Safe administration of the measles vaccine to children allergic to eggs, N. Eng. J. Med., 1995; 332: 1262-6 Fasano M.B, Wood R.A, Cooke S.K, Sampson H.A, Egg hypersensitivity and adverse reactions to measles, mumps, and rubella vaccine, J. Pediatr.1992; 120: 878-81
RABIES VACCINE
Human diploid cell rabies vaccine is an inactivated vaccine prepared from the rabies virus grown in human diploid cell cultures then dissolved in tributyl phosphate and inactivated a second time with b-propiolactone.
INCIDENCE
108/100000-87/100000 type III reactions 9/100000 type I reactions In some reports, type III reactions occurred in 6% of immunized individuals boosted with the current HDC rabies vaccine.
RISK FACTORS
Booster doses for type III reactions.
Type I: within minutes or hours after a dose of HDCV: bronchospasm, laryngeal edema, generalized pruritic rash, urticaria or angioedema. Type III: occurring 2 to 21 days after a dose or doses of HDCV: generalized pruritic rash or urticaria, arthralgias, arthritis, angioedema, nausea, vomiting, fever and malaise.
DIAGNOSTIC METHODS
Cutaneous testing: positive tests to vaccine and mock vaccine. Specific IgE (immunofluorescence): the specificity of this method has been confirmed by solid phase binding of the vaccine to antigens (19 out of 21 cases of urticaria).
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SERA AND VACCINES
MECHANISMS
Type I hypersensitivity. Type III hypersensitivity. The principal antigen implicated in the IgE-mediated response is a modified protein component of the vaccine: a b-propiolactone human serum albumin (BPL-HSA) complex formed during preparation of the vaccine. Some individuals produce a dual reaction (IgG and IgE) against BPL-HSA and fetal calf serum.
MANAGEMENT
The new HDC rabies vaccine, Lyssavac-HDC Berna is safer (no type III hypersensitivity reactions). The vaccine should be prepared without b-propiolactone (inactivation with formalin or tributylphosphate only). Boosters should only be administered to risk-group patients The use of the intradermal route for both primary and booster injections may result in lower rates of reactions.
REFERENCES
Briggs DJ, Dreesen DW, Morgan P, Chin JE, Seedle CD, Cryz L, Glck R, Cryz SJ, Safety and immunogenicity of Lyssavac Berna human diploid cell rabies vaccine in healthy adults, Vaccine. 1996;14 (14): 1361-5 Fishbein DB, Yenne KN, Dreesen DW, Teplis CF, Mehta N, Briggs DJ, Risk factors for systemic hypersensitivity reactions after booster vaccinations with human diploid cell rabies vaccine: a nationwide prospective study, Vaccine. 1993;11 (14): 1390-4 Swanson MC, Rosanoff E, Gurwith M, Deitch M, Schnurrenberger P, Reed CE, IgE and IgG antibodies to beta propiolactone and human serum albumin associated with urticarial reactions to rabies vaccine, J. Infect. Dis., 1987, 155, 5, 909913. Warrington RJ, Martens CJ, Rubin M, Rutherford WJ, Aoki FY, Immunologic studies in subjects with a serum sickness-like illness after immunization with human diploid cell rabies vaccine, J. Allergy. Clin. Immunol. 1987;79: 605-10 Anonymous Systemic allergic reactions following immunization with human diploid cell rabies vaccine MMWR Morb. Mortal. Wkly. Rep. 1984;33 (14): 185-7
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SERA AND VACCINES
TETANUS TOXOID
Tetanus toxoid has been in use for several decades and has proven its effectiveness and safety. However, a few immediate and delayed reactions have been observed.
INCIDENCE
Local reactions after booster injections: pain - tenderness: 50 -85% erythema-edema: 20 - 30% marked swelling: 2% abscess: 6 to 10/million doses. Anaphylaxis: 1/million.
RISK FACTORS
Previous history of reaction to tetanus toxoid.
Anaphylactic shock. Bronchospasm. Nasal and ophthalmic pruritus. Urticaria, angioedema. Vasculitis, rashes. Glomerulonephritis.
DIAGNOSTIC METHODS
Cutaneous testing (controversial). Skin prick tests positive at 1/1000. Intradermal skin tests positive at 1/10000. Positive in a few patients with anaphylaxis. False positive and negative are frequent. Specific IgE (controversial) Positive in patients with anaphylaxis but: 50% of infants develop specific IgE antibodies after vaccination. 25% of subjects receiving tetanus booster injections have substantial IgE antibodies.
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SERA AND VACCINES
IgE response to tetanus toxoid is higher in atopic children. Detection of circulating immune complexes in patients with vasculitis
MECHANISMS
IgE-mediated hypersensitivity: exceedingly rare. Type III reaction (hyperimmunization): there is correlation between circulating tetanus toxoid IgG levels and the degree of local reaction. Do not overlook the role played by thimerosal and aluminum hydroxide in some reactions.
MANAGEMENT
Obtain an antitetanus IgG titer to verify the need for a booster. Use a tetanus toxoid formulation with a different preservative. Use an isolated tetanus toxoid which has less reactogen than associations (diphtheria/ tetanus) Desensitization has been reported to be effective. 1 2 3 4 5 6 7 8

0.02 cc 0.02 cc 0.02 cc 0.10 cc 0.05 cc 0.10 cc 0.15 cc 0.20 cc
1/1 000 1/100 1/10 1/10 Full strength Full strength Full strength Full strength
ID ID SC SC SC SC SC SC
At 30 min intervals
REFERENCES
Piletta PA, Pasche-Koo F, Saurat JH, Hauser C, Immediate local reaction to tetanus toxoid booster, Allergy. 1997; 52 (6): 676-7 Barbaud A, Schmutz JL, Mougeolle JM, Reactions immunoallergiques cutanes dues aux vaccins, Ann. Dermatol. Venereol. 1995; 122: 129-38 Uriel AJ, Boyter AC, Mac Connachie AM, Nathwani D, Immunization against tetanus in a hypersensitive individual using a graded dosing regimen (letter), J. Infect. 1995; 30 (1): 83-4
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SERA AND VACCINES
Sutter RW, Adverse reactions to tetanus toxoid, JAMA. 1994; 271 (20): 1629 Carey AB, Meltzer EO, Diagnosis and desensitization in tetanus vaccine hypersensitivity, Ann. Allergy. 1992; 69 (4): 336-8
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SERA AND VACCINES
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VITAMINS
XII VITAMINS
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VITAMINS
CALCIPOTRIOL
Calcipotriol is a vitamin D3 derivative widely used in the treatment of psoriasis.
INCIDENCE
High: 20% of patients.
Lesional and perilesional irritation. Contact allergy (underestimated).
DIAGNOSTIC METHODS
Patch-tests with the cream (ointment is irritant) or better with calcipotriol 10 g/ml in isopropanol. Patch-tests with propylene-glycol.
MECHANISMS
Irritation. Sometimes delayed contact hypersensitivity.
MANAGEMENT
Cream and solution are less irritant than ointment. Avoidance in cases of contact allergy. Cross-reactivity may exist between calcipotriol, 1-alphahydroxyvitamin D3 and 25-hydroxyvitamin D3.
REFERENCES
Giordano-Labadie F, Laplanche G, Bazex J, Eczma de contact au calcipotriol, Ann. Dermatol. Venereol., 1996; 123: 196-7 de Groot A, Contact allergy to calcipotriol, Contact. Dermatitis, 1994; 30: 242-3
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VITAMINS
CYANOCOBALAMIN/ HYDROXOCOBALAMIN
Vitamin B12 is widely-used as a supplement for patients with ileal malabsorption and those with pernicious anemia.
INCIDENCE
Rare. Deaths reported.
RISK FACTORS
Intravenous administration.
(occurring within weeks or months, but sometimes after several years of treatment) General: anaphylactic shock Cutaneous: generalized urticaria, angioedema, eczematous rash, pruritus, Respiratory: bronchospasm. Recurrence of allergic reactions to vitamin B12 may occur after ingestion of Marmite (yeast derived extract containing at least 15 g of cyanocobalamin/100 g).
DIAGNOSTIC METHODS
Cutaneous testing: usually negative but: skin-prick tests: positive with pure hydroxocobalamin intradermal skin-tests: positive at 1/100 to 1/10 dilution in one patient. No specific IgE found
Specific histamine-release: positive in one patient.
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VITAMINS
MECHANISMS
The vitamin itself, the preservatives (benzyl alcohol) or some contaminants may be involved. Contact dermatitis has been reported, due to the cobalt ring contained in this vitamin. Possible IgE-mediated hypersensitivity (positive cutaneous tests, specific histamine release).
MANAGEMENT
Cross-sensitivity between hydroxocobalamin and cyanocobalamin has been described but is not always found. In patients with hydroxocobalamin allergy; if cutaneous testing shows negative results; cyanocobalamin can be used in increasing intramuscular doses (0.1mg; 0.5mg; 1 mg). Adjunction of corticosteroids or antihistamines may be useful. Desensitization in patients allergic to both hydroxocobalamin and cyanocobalamin may be performed. For example with cyanocobalamin: 0.1 ml (1/100 = 10 g/ ml) to 0.5 ml pure (500 g) Oral route may be an alternative, but reactions have been reported and therapeutic efficacy is lower.
REFERENCES
Tordjman R, Genereau T, Guinnepain M.T, Weyer A, Lortholary O, Royer I, Casassus P, Guillevin L, Reintroduction of vitamin B12 in 2 patients with prior B12-induced anaphylaxis, Eur. J. Haematol., 1998; 60 (4): 269-70 Branco-Ferreira M, Clode M.H, Pereira-Barbosa M.A, Palma-Carlos A.G, Anaphylactic reaction to hydroxycobalamin, Allergy., 1997; 52 (1): 118-9 Denis R, Amin S, Cummins D, Sensitivity reaction to parenteral vitamin B12: recurrence of symptoms after Marmite ingestion, Clin. Lab. Haematol., 1996; 18 (2): 129-31 de Blay F, Sager M.F, Hirth C, Alt M, Chamouard P, Baumann R, Pauli G, IgE-mediated reaction to hydroxocobalamin injection in a patient with pernicious anaemia, Lancet, 1992; 339: 1535-6
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VITAMINS
THIAMINE (VITAMIN B1)

Vitamin B1 or thiamine hydrochloride is used in thiamine deficiency syndromes (cardiovascular beriberi syndrome and central Wernicke-Korsakoff syndrome). Thiamine is the most allergenic vitamin.
INCIDENCE
9 deaths reported between 1965 and 1985, but only 0.1% major reactions and 1% minor local reactions in a large study (1070 consecutive parenteral administrations of thiamine hydrochloride).
RISK FACTORS
Multiple large doses. Parenteral administration (IV, IM, SC). Allergic symptoms upon prior administration.
General: anaphylactic shock Respiratory: bronchospasm. Cutaneous: erythema, itching of palms, urticaria. Digestive: nausea, abdominal cramps.
DIAGNOSTIC METHODS
Cutaneous testing. A few cases of positive skin prick-tests or intradermal tests (0.5 to 5 mg/ ml) Specific IgE and IgG (ELISA). Specific histamine release.
MECHANISMS
Thiamine may act as a hapten (transformation to an azoprotein).
MANAGEMENT
Administration of parenteral thiamine only when required (thiamine defiency).
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VITAMINS
REFERENCES
Fernandez M, Barcelo M, Munoz C, Torrecillas M, Blanca M, Anaphylaxis to thiamine (vitamin B1), Allergy., 1997; 52: 958-60 Proebstle T.M, Gall H, Jugert F.K, Merk H.F, Sterry W, Specific IgE and IgG serum antibodies to thiamine associated with anaphylactic reaction, J. Allergy. Clin. Immunol., 1995; 95: 1059-60 Stephen J.M, Grant R, Yeh C.S, Anaphylaxis from administration of intravenous thiamine, Am. J. Emerg. Med., 1992; 10 (1): 61-3 Wrenn K.D, Murphy F, Slovis C.M, A toxicity study of parenteral thiamine hydrochloride, Ann. Emerg. Med., 1989; 18: 867-70
VITAMIN B6
Pyridoxine, pyridoxal and pyridoxamine are 3 biologically similar interchangeable compounds referred to as vitamin B6. Pyridoxine is widely used in the preparation of medications and cosmetics (hair lotion).
INCIDENCE
Contact dermatitis is infrequent. Photoallergy is exceptional.
Contact dermatitis, photosensitive dermatitis.
DIAGNOSTIC METHODS
Cutaneous testing Patch -tests and photopatch-tests: pyridoxine hydrochloride (1% pet).
MECHANISMS
Delayed hypersensitivity. Photoallergy.
MANAGEMENT
Avoidance.
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VITAMINS
REFERENCES
Tanaka M, Niizeki H, Shimizu S, Miyakawa S, Photoallergic drug eruption due to pyridoxine hydrochloride, J. Dermatol., 1996; 23 (10): 708-9 Camarasa J.G, Serra-Baldrich E, Lluch M, Contact allergy to vitamin B6, Contact. Dermatitis , 1990; 23 (2): 115
VITAMIN K
Vitamin K is mainly used in patients with hypoprothrombinemia.
INCIDENCE
52 cases of cutaneous hypersensitivity reactions to vitamin K from 1964 to 1995 (Europe and North America). 94 cases of cutaneous hypersensitivity reactions to vitamin K up to 1988 (Japan).
General (intravenous vitamin K1): anaphylactic shock, facial flush, abdominal pain, loss of consciousness. Cutaneous: erythematous plaque like dermatitis: after 4 to 21 days, at the injection site (IM or SC) with oil soluble vitamin K1 (phytomenadione) pseudo-sclerodermatous lesion: from 2 months to 1.5 years following administration of vitamin K1 around the injection site contact dermatitis: occupational handling of vitamin K3 (pig feed, pharmaceutical factory, pharmaceutical or veterinary laboratory) urticaria: one patient after IM injection of vitamin K1.
DIAGNOSTIC METHODS
Cutaneous testing. Intradermal skin-tests: 0.02 ml phytomenadione 0.05% in NaCl 0.9%.
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VITAMINS
Patch-tests: phytomenadione 0.03% and 0.1% in pet. Patch-tests are positive in contact dermatitis, intradermal skin-tests are usually positive in erythematous plaque-like dermatitis and pseudo-sclerodermatosis lesions. Skin-biopsy: erythematous plaque like lesions: parakeratosis, spongiosis, intraepidermal vesiculation.
MECHANISMS
Cremophor EL used in some countries as a solvent for intravenous formulation of vitamin K1 is thought to be the culprit in anaphylactoid reactions. Type IV hypersensitivity (positive patch-tests). The phytyl moiety contained in phytomenadione, but not in other forms of vitamin K, could be the antigenic site.
MANAGEMENT
Vitamin K exists in 4 different pharmacological forms: vitamin K1 (phytomenadione): naturally occurring form (oil soluble) vitamin K2 (menaquinone): synthesized by bacteria in intestine vitamin K3 (menadione): synthetic analogue (oil soluble) vitamin K4 (menadiol): synthetic analogue (water soluble). When administered orally, vitamins K1, K3, and K4 do not result in skin disease. Cross-reactivity between vitamin K3 and K4 has been described, but not between vitamin K1 and other vitamin K derivatives. Prefer oral and water-soluble formulations of vitamin K Slow infusion of vitamin K1 diluted in a physiological solution may decrease the rate of anaphylactic reactions.
REFERENCES
Moreau-Cabarrot A, Giordano-Labadie F, Bazex J, Hypersensibilit cutane au point dinjection de vitamine K1", Ann. Dermatol. Venereol., 1996; 123 (3): 177-9
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VITAMINS
Bruynzeel I, Hebeda C.L, Folkers E, Bruynzeel D.P, Cutaneous hypersensitivity reactions to vitamin K: 2 case reports and a review of the literature, Contact. Dermatitis, 1995; 32 (2): 78-82 Lemlich G, Green M, Phelps R, Lebwohl M, Don P, Gordon M, Cutaneous reactions to vitamin K1 injections, J. Am. Acad. Dermatol., 1993; 28 (2.2): 345-7 Martinez-Abad M, Delgado F, Palop V, Morales-Olivas F.J, Vitamin K1 and anaphylactic shock, DICP, 1991; 25 (7-8): 871-2
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VITAMINS
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MISCELLANEOUS
XIII MISCELLANEOUS
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MISCELLANEOUS
ACETYLCYSTEINE
Intravenous acetylcysteine is the treatment of choice for acetaminophen poisoning and more recently for anticonvulsantinduced hypersensitivity syndrome. N-acetylcysteine is a known precursor of glutathione involved in detoxification from several drugs.
INCIDENCE
0.2 to 3% of courses of intravenous acetylcysteine. Deaths reported (overdose is likely).
RISK FACTORS
Overdose. Intravenous use (no report following oral administration).
(occurring 20 minutes after starting of treatment) General: anaphylactic shock, fever (inhalation therapy). Cutaneous: rash, pruritus, urticaria, angioedema. Respiratory: bronchospasm (sometimes in asthmatic patients by intravenous or inhalation route).
DIAGNOSTIC METHODS
None.
MECHANISMS
Hypotension seems to result from a vasodilator action on resistance vasculature (dose-dependent). Direct non immunological histamine release.
MANAGEMENT
Non life-threatening anaphylactoid reactions to intravenous Nacetylcysteine are easily treated: flushing requires no treatment; urticaria should be treated with antihistamines; angioedema and
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MISCELLANEOUS
respiratory symptoms require antihistamines and symptomatic therapy. In cases of angioedema and respiratory symptoms, N-acetylcysteine should be stopped but can be started again one hour after administration of antihistamines. Oral methionine and mercaptamine may be used as alternative antidotes.
REFERENCES
Bailey B, Mc Guigan M.A, Management of anaphylactoid reactions to intravenous N-acetylcysteine, Ann. Emerg. Med., 1998; 31 (6): 710-5 Simonart T, Tugendhaft P, Vereecken P, de Dobbeleer G, Heenen M, Hazards of therapy with high doses of N-acetylcysteine for anticonvulsant-induced hypersensitivity syndrome, Br. J. Dermatol., 1998; 138 (3): 553 Sunman W, Hughes A.D, Sever P.S, Anaphylactoid response to intravenous acetylcysteine, Lancet, 1992; 339 (8803): 1231-2 Bonfiglio M.F, Traeger S.M, Hulisz D.T, Martin B.R, Anaphylactoid reaction to intravenous acetylcysteine associated with electrocardiographic abnormalities, Ann. Pharmacother., 1992; 26 (1): 22-5 Mant T.G, Tempowski J.H, Volans G.N, Talbot J.C, Adverse reactions to acetylcysteine and effects of overdose, Br. Med. J., 1984; 289 (6439): 217-9
ALLOPURINOL
Allopurinol (4 hydroxypyrazolol (3.4-d) pyramidine) is the drug most commonly prescribed for the treatment of hyperuricemia.
INCIDENCE
2% of users develop a mild cutaneous rash. Severe reaction: 1/260. Allopurinol hypersensitivity syndrome: 100 cases described in the literature (1993) Mortality: 27% (allopurinol hypersensitivity syndrome).
RISK FACTORS
Impaired renal excretion. Thiazide diuretics (co-administration).
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MISCELLANEOUS
(developing days or weeks after initiation of treatment) Criteria for diagnosis: 1 Clear exposure to allopurinol. 2 Clinical picture including: a) at least 2 of the major criteria worsening renal function (84%) acute hepatocellular injury (88%) rash (93.1%): toxic epidermal necrolysis (25.7%) erythema multiforme (8.9%), diffuse maculopapular rash (53.5%), exfoliative dermatitis (20.8%) OR b) one of the major criteria + at least one of the minor criteria fever (95%) eosinophilia (60%) leukocytosis (40%) AND 3 Lack of exposure to another drug which may have caused similar clinical manifestations.
DIAGNOSTIC METHODS
Skin-biopsy: granular deposits of IgM at the dermal-epidermal junction. Liver-biopsy: T lymphocyte infiltration, granulomas, focal necrosis of hepatocytes. Renal-biopsy: linear deposits of IgG and complement along the glomerule basement membrane; C3 deposits along tubular basal membrane, mesangium and arterioles. Lymphocyte stimulation test: positive with oxypurinol but not allopurinol in 3 patients with allopurinol hypersensitivity syndrome.
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MISCELLANEOUS
MECHANISMS
1 Allopurinol accumulation. The risk of development of allopurinol hypersensitivity syndrome is related to the level of oxypurinol (metabolite of allopurinol). The accumulation of oxypurinol leads to tissue damage with development of antibodies against tissue components and formation of immune complexes. 2 Type IV hypersensitivity reactions. T cell-mediated immune reaction could be involved in the pathogenesis of allopurinol hypersensitivity syndrome. 3 Type III hypersensitivity reactions. Generalized vasculitis (formation of immune complexes that precipitate in the vascular endothelium and lead to complement activation and development of inflammatory reactions in and around arteriolar walls). Consumption of complement, circulating immune complexes and deposition of antibodies in different organs.
MANAGEMENT
Asymptomatic hyperuricemia is not an indication of allopurinol prescription. Allopurinol dose must be adjusted to renal function. Allopurinol should only be prescribed in good indications: primary gout with tophi or uric acid stones (over production) uric acid stones or calcium oxalate stones without gout combined with increased urinary excretion of urate secondary renal gout with tophi myeloproliferative diseases or other malignancies high frequency of attacks despite colchicine prophylaxis intolerance to uricosuric agents Lesch-Nyhan syndrome Von Gierke disease
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MISCELLANEOUS
Desensitization 1- Fixed drug eruption (50 mg of allopurinol powder dissolved in 500 ml of distilled water with 14/1000 sodium bicarbonate) Day 1: 10 g, 20 g, 30 g Day 2: 40 g, 50 g, 60 g Day 3: 70 g, 80 g, 90 g Day 4: 100 g, 200 g, 400 g Day 5: 600 g, 800 g, 1mg Day 6: 2 mg, 4 mg, 8 mg Day 7: 16 mg, 25 mg, 35 mg Day 8: 50 mg Day 9: 75 mg Day 10: 100 mg Day 11: 125 mg Day 12: 150 mg Day 13: 175 mg Day 14: 200 mg Day 15: 250 mg Day 16: 300 mg 2- Oral desensitization in minor rashes (renal insufficiency, chronic tophaceous gouty arthritis) Day 1 to 3: 50 g Day 4 to 6: 100 g Day 7 to 9: 200 g Day 10 to 12: 500 g Day 13 to 15: 1 mg Day 16 to 18: 5 mg Day 19 to 21: 10 mg Day 22 to 24: 25mg Day 25 to 27: 50 mg Day 28 and nexts: 100 mg 3- Intravenous desensitization (when oral desensitization fails; in less than 12 hours) 0.1 g, 1 g, 10 g, 50 g, 100 g, 500 g at 15 minute intervals 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg at 30 minute intervals Desensitization can give life-threatening reactions.
REFERENCES
Pluim H.J, Van Deuren M, Wetzels J.F, The allopurinol hypersensitivity syndrome, Neth. J. Med., 1998; 52 (3): 107-10 Umpierrez A, Cuesta-Herranz J, de las Heras M, Lluch-Bernal M, Figueredo E, Sastre J, Successful desensitization of a fixed drug eruption caused by allopurinol, J. Allergy. Clin. Immunol., 1998; 101 (2.1): 286-7 Hamanaka H, Mizutani H, Nouchi N, Shimizu Y, Shimizu M, Allopurinol hypersensitivity syndrome: hypersensitivity to oxypurinol but not allopurinol, Clin. Exp. Dermatol., 1998; 23 (1): 32-4
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MISCELLANEOUS
Braden G.L, Warzynski M.J, Golightly M, Ballow M, Cell-mediated immunity in allopurinol-induced hypersensitivity, Clin. Immunol. Immunopathol., 1994; 70 (2): 145-51 Arellano F, Sacristan J.A, Allopurinol hypersensitivity syndrome: a review , Ann. Pharmacother., 1993; 27 (3): 337-43 Kelsey S.M, Struthers G.R, Beswick T, Blake D.R, Desensitisation to allopurinol, Ann. Rheum. Dis., 1987; 46 (1): 84
CARBAMAZEPINE
Carbamazepine is a drug widely used in the treatment of epilepsy, trigeminal neuralgia and affective disorders.
INCIDENCE
Cutaneous reactions: 3 to 16%. Stevens-Johnsons syndrome: 1/5000 to 1/10000.
(occurring one week to 3 months (average 4 weeks) after starting therapy) Carbamazepine hypersensitivity syndrome: fever + lymphadenopathy (pseudolymphoma syndrome) + generalized rash. Other: serum sickness, glandular fever-like syndrome, Kawasakilike syndrome, systemic lupus erythematosus-like syndrome, hypersensitivity vasculitis, necrotizing granulomatous vasculitis. Cutaneous: macular or maculopapular rash, eczematoid dermatitis, edema of the face, hands and feet, purpura, erythroderma, urticaria, exfoliative dermatitis, erythema multiforme, toxic epidermal necrolysis. Respiratory: cough, dyspnea, pneumonitis. Digestive: hepatosplenomegaly, hepatitis Renal: acute tubulointerstitial nephritis, hypersensitivity vasculitis. Hematological: leukocytosis, eosinophilia, leukopenia, lymphopenia, agranulocytosis, aplastic anemia, thrombocytopenia. E.N.T: pharyngitis. Ophthalmic: conjunctivitis.
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MISCELLANEOUS
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests. Hayes patch-tests chambers: carbamazepine 100%, 10%, 1% and 0.1% in pet. jelly and in acetone: positive in patients with carbamazepine hypersensitivity syndrome. Lymphocyte transformation test : positive in patient with carbamazepine hypersensitivity syndrome.
MECHANISMS
Highly reactive arene oxide or epoxide metabolites formed by cytochrome P 450, or other metabolites formed by myeloperoxidase bind to tissue macromolecules causing cell damage or act as haptens and elicit an immune response. The results of the patch-tests and lymphocyte transformation tests indicate the presence of a specific T-cell reactivity. Anticarbamazepine antibodies have been detected. Presence of immunosuppressive cytokines, production of numerous auto-antibodies, deposits of immune complexes in the skin.
MANAGEMENT
Systemic corticosteroids are recommended in the management of carbamazepine hypersensitivity syndrome. Desensitization is possible (isolated skin rash). Cross-reactivity between carbamazepine, phenytoin, and phenobarbital is common.
REFERENCES
Morkunas A.R, Miller M.B, Anticonvulsivant hypersensitivity syndrome, Crit. Care. Clin., 1997; 13 (4): 727-39 de Vriese A.S, Philippe J, Van Renterghem D.M, de Cuyper C.A, Hindryckx P.H, Matthys E.G, Louagie A, Carbamazepine hypersensitivity syndrome: report of 4 cases and review of the literature, Medicine (Baltimore), 1995; 74 (3): 144-51
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MISCELLANEOUS
Pirmohamed M, Graham A, Roberts P, Smith D, Chadwick D, Breckenridge A.M, Park B.K, Carbamazepine-hypersensitivity: assessment of clinical and in vitro chemical cross-reactivity with phenytoin and oxcarbazepine, Br. J. Clin. Pharmacol., 1991; 32 (6): 741-9
CLOZAPINE
Dibenzodiazepine used as an alternative treatment for refractory psychotic patients.
INCIDENCE
0.05%.
Urticarial rash (maculopapular, erythematous and confluent) involving face, neck, trunk Photosensitivity. Parotitis. Agranulocytosis. Myocarditis.
DIAGNOSTIC METHODS
Lymphocyte transformation test: one positive case in a patient with parotitis.
MECHANISMS
Unknown.
MANAGEMENT
Avoidance. Cross-reactivity with chlorpromazine may occur.
REFERENCES
Kuintana J, Shah B, Guze B, Clozapine-chlorpromazine allergic crossreactivity in a psychotic patient with asymptomatic AIDS, Biol. Psychiatry., 1996; 40 (11): 1185-6
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MISCELLANEOUS
Hinze-Selch D, Becker E.W, Stein G, Schreiber W, Pollmacher T, Clozapineinduced parotitis: an immunological cause ?, Am. J. Psychiatry., 1996; 153 (6): 840 Howanitz E, Pardo M, Losonczy M, Photosensitivity to clozapine, J. Clin. Psychiatry., 1995; 56 (12): 589 Goumemiouk A.D, Ancill R.J, Mac Ewan G.W, A case of drug interaction involving clozapine, Can. J. Psychiatry, 1991; 36: 234
CROMOLYN/SODIUM CROMOGLYCATE/DSCG
Disodium cromoglycate or cromolyn, available since 1973 is an antiasthmatic/ antiallergic drug acting as a mast cell stabilizer.
INCIDENCE
About 20 cases reported in the literature. One death (bronchospasm).
Anaphylactic shock: 3 cases published. Bronchospasm: one death reported. Rhinitis, conjunctivitis, urticaria. Differentiate from dermatitis, myositis, gastroenteritis (2% of patients) and cough, dry mouth, pharyngeal irritation, mild transient bronchospasm (attributed to local irritant effects of the powder on hyperreactive airways).
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests (10 mg/ ml): positive in a few patients. Intradermal skin tests (10 mg/ ml): positive with syndromic reaction in one case. Specific IgE (RAST) by spontaneous binding of DSCG to human serum albumin (one case).
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MISCELLANEOUS
Conjunctival challenge test (20 mg/ ml). Bronchial challenge (20 mg/capsule).
MECHANISMS
IgE-mediated hypersensitivity (positive skin tests, passive transfer, specific IgE). DSCG is a weak hapten (only hydrogen bonds can be found between drug and host cells or tissue).
MANAGEMENT
Avoidance.
Allergic sensitization may disappear with the time. REFERENCES

Ibanez M.D, Laso M.T, Martinez-San Irineo M, Alonso E, Anaphylaxis to disodium cromoglycate (see comments), Ann. Allergy. Asthma. Immunol., 1996; 77 (3): 185-6 Shearer W.T, Anaphylaxis to disodium cromoglycate (editorial), Ann. Allergy. Asthma. Immunol., 1996; 77 (3): 165 Mansfield L.E, Disappearance of allergic reaction to cromolyn (cromoglycate) by avoidance and then reintroduction, J. Asthma., 1991; 28 (6): 447-50 Wass U, Plaschke P, Bjorkander J, Belin L, Assay of specific IgE antibodies to disodium cromoglycate in serum from a patient with an immediate hypersensitivity reaction, J. Allergy. Clin. Immunol, 1988; 81 (4): 750-7
DEFEROXAMINE
Specific iron chelating agent used in the treatment of hemochromatosis and acute iron poisoning.
INCIDENCE
High.
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MISCELLANEOUS
General: anaphylactic shock Respiratory: bronchospasm, hypersensitivity pneumonitis, laryngospasm. Cutaneous: pruritus, urticaria.
DIAGNOSTIC METHODS
Cutaneous testing: false positive. No IgE antibodies excepted in lung biopsies.
MECHANISMS
Direct non-immunological activation of the dermal mast cells (subcutaneous route).
MANAGEMENT
Numerous desensitization protocols have been published in adults and children; by intravenous or subcutaneous route. For example in adults: Starting with a dose of 0.015 mg in 50 cc for 30 minutes, gradually increase (6 hours) to 1 500 mg in 50 cc for 30 minutes. Then administer 1 500 mg per day by continuous infusion for 4 days. Then 1 500 mg per 12 hours for 2 weeks. Finally, 1 500 mg every 2 days. High dose intravenous deferoxamine delivery is highly effective, but can lead to severe hypersensitivity pneumonitis. Other iron chelators (oral deferiprone) are under clinical evaluation.
REFERENCES
La Rosa M, Romeo M.A, Di Gregorio F, Russo G, Desensitization treatment for anaphylactoid reactions to desferrioxamine in a pediatric patient with thalassemia, J. Allergy. Clin. Immunol, 1996; 97: 127-8 Lombardo T, Ferro G, Frontini V, Percolla S, High dose intravenous desferrioxamine (DFO) delivery in four thalassemic patients allergic to subcutaneous DFO administration, Am. J. Hematol., 1996; 51 (1): 90-2
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MISCELLANEOUS
Shalit M, Tedeschi A, Miadonna A, Levy-Shaffer A, Desferal (desferrioxamine)-a novel activator of connective tissue-type mast cells, J. Allergy. Clin. Immunol, 1991; 87: 854-60 Bousquet J, Navarro M, Robert G, Aye P, Michel F.B, Rapid desensitization for desferrioxamine anaphylactic reaction, Lancet., 1983; ii: 859-60 Miller K.B, Rosenwasser L.J, Bessette J.M, Rapid desensitization for desferrioxamine anaphylactic reaction, Lancet., 1981; i: 1059
D. PENICILLAMINE
D. Penicillamine is the product of acid hydrolysis of penicillin. It is used in the treatment of rheumatoid polyarthritis, Wilsons disease, scleroderma, cystinuria, and heavy metal poisoning.
INCIDENCE
High. 50 % of patients will have an adverse drug reaction during the first 6 months of therapy (600 mg/day) and about 1/4 to 1/3 will discontinue therapy.
Cutaneous: maculopapular and pruriginous eruptions, urticaria (early), autoimmune bullous syndrome almost of pemphigus type and rare but severe cicatricial pemphigoides (late), contact allergy (eye drops). Renal: glomerulonephritis with membrane proliferation. Hematological: neutropenia, thrombocytopenia, aplastic anemia. Autoimmune: myasthenia, polymyositis, dermatomyositis, lupus, Goodpastures syndrome. Respiratory: obstructive bronchiolitis, pneumonitis, asthma.
DIAGNOSTIC METHODS
No in vivo or in vitro diagnostic methods are currently available, other than the lymphocyte stimulation test which may be positive in some cases of glomerulonephritis and polymyositis.
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MISCELLANEOUS
Patch-tests (penicillamine 0.15 M aq.): positive in contact allergy. D. penicillamine-induced pemphigus generally has a lower prevalence of tissue-fixed or circulating antibodies than spontaneous pemphigus.
MECHANISMS
Unknown.
MANAGEMENT
If severe glomerulonephritis occurs, do not attempt to re-administer unless no other therapeutic option is available. If use is absolutely necessary, first perform the following desensitization to avoid risk of severe delayed reactions: first week: 1/ 100th of the total dose second week: 1/ 10th of the total dose third week: 1/3 rd of the total dose fourth week: total dose. Should kidney dysfunction or other severe manifestations develop, discontinueD.penicillamine and give 40 to 80 mg of prednisone/ day. In Wilsons disease, alternative treatments are trientine and zinc; desensitization can be performed as follows: day 1: prednisone 30 mg day 3-4-5: D. penicillamine 125 mg day 6-7-8: D.penicillamine 250 mg day 9-10-11: D. penicillamine 375 mg day 12-13-14: D.penicillamine 500 mg day 15-16-17: D.penicillamine 750 mg day 18 and subsequently: D.penicillamine 1 g. If a patient allergic to penicillin requires treatment with D.penicillamine, start with 1/ 1000th of the total dose then 3 to 10 times more every 30 minutes (although no cross-reactivity has been clinically demonstrated between penicillin and D. penicillamine).
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MISCELLANEOUS
REFERENCES
Bialy-Golan S, Brenner S, Penicillamine-induced bullous dermatoses, J. Am. Acad. Dermatol., 1996; 35:732-42 Chan C.Y, Baker A.L, Penicillamine hypersensitivity: successful desensitization of a patient with severe hepatic Wilsons disease (see comments), Am. J. Gastroenterol., 1994; 89 (3): 442-3 de Moor A, Van Hecke E, Kestelyn P, Contact allergy to penicillamine in eye drops, Contact Dermatitis, 1993; 29 (3): 155-6 Matsumura T, Yuhara T, Yamane K, Kono I, Kabashima T, Kashiwagi H, D. penicillamine-induced polymyositis occurring in patients with rheumatoid arthritis: a report of 2 cases and demonstration of positive lymphocyte stimulation test to D penicillamine, Henry Ford Hosp. Med. J, 1986; 34: 123-6 Jaffe I.A, Adverse effects profile of sulfhydryl compounds in man, Am. J. Med, 1986; 80: 471-6
FACTOR VIII
Recombinant factor VIII products are used in the treatment of hemophilia.
INCIDENCE
0.1 to 0.75% (rashes).
General: anaphylactic shock. Cutaneous: erythematous or urticarial rashes.
DIAGNOSTIC METHODS
Specific IgE (Intermediate purity factor VIII concentrates).
MECHANISMS
IgG 4 antibodies to bovine factor VIII? IgE-mediated hypersensitivity? Antibodies against human serum albumin? Ethyleneoxide allergy?
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MISCELLANEOUS
MANAGEMENT
Premedication with antihistamines and corticosteroids. Desensitization.
REFERENCES
Shopnick R.I, Kazemi M, Brettler D.B, Buckwalter C, Yang L, Bray G, Gomperts E.D, Anaphylaxis after treatment with recombinant factor VIII , Transfusion., 1996; 36: 358-61 Bove J.R, Anaphylactic reaction to purified anti-hemophilic factor concentrate (letter), Transfusion, 1988; 28: 603 Jamieson D.M, Stafford C.T, Maloney M.J, Lutcher C.L, Desensitization to factor VIII in a patient with classic hemophilia and C2 deficiency, Ann. Allergy., 1987; 58: 215-20 Shakib F, Stanworth D.R, IgG 4: a possible mediator of anaphylaxis in a haemophiliac patient, Clin. Allergy., 1979; 9: 597-603
HYDROXYZINE
Hydroxyzine hydrochloride is a piperazine derivative, structurally based on a dimer of ethylenediamine and possessing antihistaminic and anticholinergic activity.
INCIDENCE
Rare.
RISK FACTORS
Positive patch-tests to ethylenediamine.
Cutaneous: urticaria, eczema, fixed drug eruption (oral or genital mucous membrane, after 6 hours or more), systemic contact dermatitis (baboon syndrome, vesicular hand eczema, toxico derma-like rash).
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MISCELLANEOUS
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests with hydroxyzine 2%, 5%, 10% aq. M.I.F (macrophage migration inhibitory factor): positive in some cases of fixed drug eruption. Drug re-challenge.
MECHANISMS
The drug may act as a hapten and bind to protein components or receptor cells of the lower dermis. This complex is similarly presented to the Langherans cells as in contact dermatitis (fixed drug eruption).
MANAGEMENT
Cross-reactions among ethylenediamine, hydroxyzine, and cetirizine are influenced by sensitivity to diethylenediamine (common piperazinic ring). Generally, patients sensitive to hydroxyzine are also sensitive to ethylenediamine.
REFERENCES
Stingeni L, Caraffini S, Agostinelli D, Ricci F, Lisi P, Maculopapular and urticarial eruption from cetirizine, Contact. Dermatitis, 1997; 37 (5): 24950 Michel M, Dompmartin A, Louvet S, Szczurko C, Castel B, Leroy D, Skin reactions to hydroxyzine, Contact. Dermatitis., 1997; 36 (3): 147-9 Ash S, Scheman A.J, Systemic contact dermatitis to hydroxyzine, Am. J. Contact. Dermat., 1997; 8 (1): 2-5 Cohen H.A, Barzilai A, Matalon A, Harel L, Gross S, Fixed drug eruption of the penis due to hydroxyzine hydrochloride, Ann. Pharmacother., 1997; 31 (3): 327-9
LATEX
Natural latex is extracted from the Hevea brasiliensis tree and is used to produce rubber (latex + low molecular weight chemical
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MISCELLANEOUS
additives). Main products: household and surgical cloves, balloons, cofferdams used in dentistry, caps, face masks, condoms.The first manifestation described in 1927 was the case of a chronic urticaria due to a dental prosthesis made with latex. Cases of anaphylactic shock due to glove wearing were reported from 1987.
INCIDENCE
20% of the anaphylactic shocks occurring during general anesthesia. Contact dermatitis or urticaria due to glove wearing is observed in 6% of the medical and paramedical operating room staff. Latex sensitization (majority without clinical manifestations) is found in 1-6 % of the general population.
RISK FACTORS
Atopy (70% of cases). Occupational contact. Fruit allergy. In children: spina-bifida and multiple surgical procedures.
General: perioperative anaphylactic shock usually occurs more than 15 minutes after induction of anesthesia. The first symptom is rash or urticaria followed 2 or 3 minutes later by severe collapse with or without bronchospasm requiring blood volume expansion and adrenaline. Anaphylactic shock may occur while putting latex gloves on. Anaphylactic shock has been reported during gynecological examinations or after dental work (latex cofferdams). Cutaneous: flush, contact dermatitis or urticaria, angioedema. E.N.T: rhinitis. Respiratory: asthma. Ophthalmologic: conjunctivitis.
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MISCELLANEOUS
DIAGNOSTIC METHODS
Cutaneous testing. Prick, intradermal, patch, and scratch skin tests with the supernatant of the preparation used to make latex gloves, latex or extracts from Hevea brasiliensis leaves. At present, prick-tests can be performed with commercial standardized natural latex extract. Prick and intradermal skin-tests are positive in case of anaphylactic shock due to surgical gloves. In patients who develop contact dermatitis after wearing gloves, rule out sensitivity to rubber additives (patch-tests with rubber mix, naphtyl mix, PPD mix, carba mix, metal salts). Specific latex IgE antibodies (UniCAP/Pharmacia CAP System and other methods). Often detected in patients with anaphylactic shock Nasal or bronchial provocation tests.
MECHANISMS
IgE-mediated hypersensitivity (immediate positive skin-tests, specific IgE, specific histamine release). The role of several identified proteins (Hev1-7) was shown and may explain some cross-reactivity with fruits (banana, avocado, kiwi, chestnut, tomato). Delayed-type allergy in contact dermatitis.
MANAGEMENT
Avoiding thr use of powdered latex gloves reduces the risk of latex sensitization and clinical symptoms. Avoid mentioning hypoallergenic gloves. Use of non latex gloves and latex-free operating room for allergic patients under surgery. Careful medical questionnaire before any surgical procedure. Avoid any systematic preoperative testing in a non at-risk po pulation.
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MISCELLANEOUS
REFERENCES
Posch A, Chen Z, Raulf-Heimsoth M, Baur X, Latex allergens: a review , Clin. Exp. Allergy, 1998; 28: 134-40 Levy D.A, Leynadier F, Latex and food allergy, Rev. fr. Allergol., 1997; 37: 1188-94 Porri F, Pradal M, Lemiere C, Birnbaum J, Mege J.L, Lanteaume A, Charpin D, Vervloet D, Camboulives J, Association between latex sensitization and repeated latex exposure in children, Anesthesiology, 1997; 86 (3): 597-602 Porri F, Lemiere C, Birnbaum J, Guilloux L, Lantaume A, Didelot R, Vervloet D, Charpin D, Prevalence of latex sensitization in subjects attending health screening: implications for a perioperative screening, Clin. Exp. Allergy., 1997; 27: 413-17 Turjanmaa K, Alenius H, Mkinen-Kiljunen S, Reunala T, Palomo T, Natural rubber latex allergy, Allergy, 1996; 51: 593-602 Laxenaire M.C et le groupe dtude des ractions anaphylactodes peranesthesiques, Substances responsables des chocs anaphylactiques peranesthesiques. Troisime enqute multicentrique franaise (1992-1994), Ann. Fr. Anesth. Reanim., 1996; 15: 1211-8 Levy D.A, Charpin D, Pecquet C, Leynadier F, Vervloet D, Allergy to latex, Allergy, 1992; 47: 579-87
LDL APHERESIS
Low density lipoprotein apheresis is used in the treatment of severe familial hypercholesterolemia and advanced coronary heart disease.
INCIDENCE
Uncommon. Temporary hypotension: 1%.
RISK FACTORS
Concomitant use of ACE inhibitors.
General: hypotension, bradycardia. Cutaneous: flushing, facial edema.
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MISCELLANEOUS
Respiratory: dyspnea. Digestive: nausea, abdominal pain.
MECHANISMS
Because of its strong negative charges, dextran sulphate is a potent activator of the contact activation system (Hageman factor, high molecular weight kininogen, prekallikrein, coagulation factor XI). Kallikrein generates bradykinin from high molecular weight kininogen. LDL apheresis with dextran sulphate is associated with increased bradykinin generation. Bradykinin catabolism is decreased by ACE inhibitors. Bradykinin is a potent vasodilator and smooth muscle constrictor in bronchi and intestine.
MANAGEMENT
Withdraw captopril 24 hours before treatment. No reaction is observed when futhan is used instead of heparin (protease inhibitory activity of futhan).
REFERENCES
Schwarzbeck A, Hilgenfeldt U, Riester U, Rambausek M, Kiral A, Anaphylacotid reactions during dextran apheresis may occur even in the absence of ACE-inhibitor administration, Nephrol. Dial. Transplant., 1997; 12 (5): 1083-4 Koga N, Nagano T, Sato T, Kagasawa K, Anaphylactoid reactions and bradykinin generation in patients treated with LDL-apheresis and an ACE inhibitor, ASAIO J, 1993; 39 (3): M288-91 Keller C, Grutzmacher P, Bahr F, Schwarzbeck A, Kroon A.A, Kiral A, LDLapheresis with dextran sulphate and anaphylactoid reactions to ACE inhibitors, Lancet, 1993; 341 (8836): 60-1 Kroon A.A, Mol M.J, Stalenhoef A.F, ACE inhibitors and LDL-apheresis with dextran sulphate adsorption, Lancet., 1992; 340 (8833): 1476 Olbricht C.J, Schaumann D, Fischer D, Anaphylactoid reactions, LDL apheresis with dextran sulphate, and ACE inhibitors, Lancet, 1992; 340 (8824): 908-9
- 293 -
MISCELLANEOUS
NIZATIDINE
Specific H2 receptor antagonist, belonging to the group of imidazole derivatives. Used in the treatment of gastric and duodenal ulcers, gastroesophageal reflux and hypersecretory states.
INCIDENCE
One case reported.
General: anaphylactic shock Respiratory: dyspnea, laryngeal stridor. Cutaneous: urticaria, angioedema of lips and tongue.
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests: 10 mg/ ml: negative. Intradermal skin tests: positive at 1/10000 to 1/1000. Oral challenge test.
MECHANISMS
IgE-mediated hypersensitivity (positive skin tests, positive oral challenge).
MANAGEMENT
No cross-reactivity found with other anti H2 drugs (oral challenge).
REFERENCES
Mira-Perceval J.L, Ortiz J.L, Sarrio F, Miralles J.C, Hernandez J, NegroAlvarez J.M, Lopez-Sanchez J.D, Garcia-Selles F.J, Pagan J.A, Nizatidine anaphylaxis, J. Allergy. Clin. Immunol., 1996; 97: 855 - 6
- 294 -
MISCELLANEOUS
OMEPRAZOLE
Omeprazole reduces acid gastric secretion by specific binding to the parietal cell proton pump H+/ K+- adenosine triphosphatase.
INCIDENCE
Uncommon (skin inflammation, urticaria, pruritus, alopecia and dry skin have been reported in 0.5 - 1.5% of patients).
General: anaphylactic shock (one case). Cutaneous: rashes, urticaria, angioedema (2 cases), epidermal necrolysis, contact dermatitis. Hematological: thrombocytopenia.
DIAGNOSTIC METHODS
Cutaneous testing. Prick-tests (4 mg/ ml) positive in one patient who experienced anaphylactic shock. Drug re-challenge
MECHANISMS
Unknown.
MANAGEMENT
Eviction.
REFERENCES
Ottervanger J.P, Phaff R.A, Vermeulen E.G, Stricker B.H, Anaphylaxis to omeprazole, J. Allergy. Clin. Immunol., 1996; 97: 1413-4 Bowlby H.A, Dickens G.R, Angioedema and urticaria associated with omeprazole confirmed by drug re-challenge, Pharmacotherapy., 1994; 14 (1): 119-22 Haeney M.R, Angioedema and urticaria associated with omeprazole , B.M.J., 1992; 305: 870 Meding B. Contact allergy to omeprazole, Contact Dermatitis., 1986; 15: 36
- 295 -
MISCELLANEOUS
PHENYTOIN
Widely used antiepileptic drug.
INCIDENCE
22 patients with local cutaneous reactions to intravenous phenytoin (1991). 1/1000 to 1/10000 exposures (phenytoin hypersensitivity syndrome). Cutaneous reactions to phenytoin up to 19% (maculopapular rash). More than 100 cases of the complete syndrome have been reported.
RISK FACTORS
Elderly black men (more severe reactions). Siblings of patients with an history of anticonvulsant hypersensitivity syndrome. Autosomal pattern of inheritance. Patients who experienced prior reactions to phenytoin, phenobarbital, carbamazepine.
Phenytoin hypersensitivity syndrome. 1 to 4 weeks after starting the therapy (when re-challenge within hours). fever (90 to 100%) rash (90%): exanthema +/- pruritus involving upper trunk, extremities, face lymphadenopathy liver abnormalities (30 to 60%): hepatosplenomegaly, severe hepatitis hematological abnormalities: lymphocytosis (65%), leukocyt osis, eosinophilia (30%), anemia, leukopenia, thrombocytopenia, aplastic anemia. renal dysfunction (11%), pneumonitis (9 to 12%) arthralgias, myalgias, rhabdomyolysis Mortality 18 to 40% when liver is involved.
- 296 -
MISCELLANEOUS
Isolated cutaneous manifestations. Morbilliform eruption, erythema multiforme, scarlatiniform dermatitis, periarteris nodosa, lupus erythematosus, cutaneous pseudolymphoma, angioedema, exfoliative dermatitis, Stevens Johnsons syndrome, toxic epidermal necrolysis, vasculitis.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests: phenytoin 1, 5, 20% in pet. and aq. positive in some cases of phenytoin hypersensitivity syndrome. Lymphocyte toxicity testing. Skin-biopsies. Epidermal necrosis, occasional dyskeratosis, frequent multinucleated keratinocytes, mild edema, superficial perivascular chronic inflammation.
MECHANISMS
The 3 major anticonvulsants have a common aromatic benzene ring that is metabolized via cytochrome P450 to an arene oxide. The arene oxide metabolites derived from the 3 anticonvulsants are highly electrophilic compounds that covalently bind to macromolecules and disrupt cellular function (cytotoxicity) or to form neoantigens that trigger an immunological response. This metabolites are highly unstable an can be detoxified by conversion to a dihydrodiol by epoxide hydrolase reduction by binding to glutathione spontaneous rearrangement to form a phenol. Deficient enzymatic reduction by epoxide hydrolase leads to toxic intermediate metabolite with resultant cytotoxicity (hepatitis) and hypersensitivity reactions. The lymphocyte toxicity studies suggest a genetic basis (autosomal co-dominant pattern). Immune mechanisms. Positive patch-tests, circulating antibody drug complexes, positive lymphocyte stimulation tests.
- 297 -
MISCELLANEOUS
MANAGEMENT
Phenytoin should not be administered intravenously into dorsal hand veins. Phenytoin given intravenously must be administered only in larger veins at a rate < 50 mg/ min. 75% of a series of patients with anticonvulsant hypersensitivity syndrome to one of the oxide metabolites producing anticonvulsants showed in vitro cross-sensitivity to the other two. Substitute for benzodiazepines, valproic acid, lamotrigine Cross-reactivity with amitriptyline may occur.
REFERENCES
Galindo Bonilla P.A, Romero Aguilera G, Feo Brito F, Gomez Torrijos E, Garcia Rodriguez R, Cortina de la Calle P, Encinas Barrios C, Phenytoin hypersensitivity syndrome with positive patch-tests. A possible cross-reactivity with amitriptyline, J. Investig. Allergol. Clin. Immunol., 1998; 8 (3): 18690 Morkunas A.R, Miller M.B, Anticonvulsant hypersensitivity syndrome, Crit. Care. Clin., 1997; 13 (4): 727-39 Hyson C, Sadler M, Cross-sensitivity of skin rashes with antiepileptic drugs, Can. J. Neurol. Sci., 1997; 24 (3): 245-9 Conger L.A Jr, Grabski W.J, Dilantin* hypersensitivity reaction, Cutis., 1996; 57 (4): 223-6 Sanders D.Y, Thompson J.R, Carlton F.B, Phenytoin hypersensitivity syndrome, J. Miss. State Med. Assoc., 1996; 37 (2): 471-5 Creamer J.D, Whittaker S.J, Kerr-Muir M, Smith N.P, Phenytoin-induced toxic epidermal necrolysis: a case report, Clin. Exp. Dermatol., 1996; 21 (2): 116-20 Vittorio C.C, Muglia J.J, Anticonvulsant hypersensitivity syndrome, Arch. Intern. Med, 1995; 155 (21): 2285-90
RANITIDINE
Histamine H2 receptor antagonist used in the treatment of gastric and duodenal ulcers, gastroesophageal reflux and hypersecretory states.
- 298 -
MISCELLANEOUS
INCIDENCE
Uncommon. 3 cases described in obstetric patients.
Differentiate from other side-effects: headaches, tiredness, dizziness, mild gastrointestinal disturbance. General: anaphylactic shock Respiratory: dyspnea, bronchospasm, laryngeal edema. Cutaneous: pruritus, urticaria, edema of the face, tongue, arms, maculopapular rash, toxic epidermal necrolysis, cutaneous delayed reactions (papular eruptions). Digestive: acute cholestatic hepatitis with rash and hypereosinophilia (one case).
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests: 10 mg/ ml positive with ranitidine, negative with famotidine, nizatidine, nitrofurantoin. Intradermal skin tests: one case positive 1/1000. No specific IgE found. Oral challenge.
MECHANISMS
IgE-mediated hypersensitivity (positive skin tests, positive oral challenge).
Direct histamine release. MANAGEMENT

Cross-reactivity with other H2 receptor antagonists is exceptional (one case published) Omeprazole can be used in obstetric patients to reduce gastric acid production.
- 299 -
MISCELLANEOUS
REFERENCES
Gonzalo-Garijo M.A, Revenga-Arranz F, Rovira-Farre I, Cutaneous delayed reaction to ranitidine, Allergy., 1996; 51 (9): 659-60 Lazaro M, Compaired J.A, de la Hoz B, Igea J.M, Marcos C, Davila I, Losada E, Anaphylactic reaction to ranitidine , Allergy, 1993; 48 (5): 385-7 Powell J.A, Maycock E.J, Anaphylactoid reaction to ranitidine in an obstetric patient, Anaesth. Intensive. Care., 1993; 21 (5): 702-3 Picardo M, Santucci B, Urticaria from ranitidine, Contact. Dermatitis., 1983; 9: 327
RECOMBINANT HUMAN TYPE I IL-1 RECEPTOR (rhu IL-1R)

Recombinant human type I IL-1 receptor is used to suppress inflammatory disorders.
INCIDENCE
One report.
Cutaneous: erythema, pruritus at the injection site within 15 minutes.
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests: negative. Intradermal skin-tests: 0.05 ml 500 g/ml (25 g): negative 0.05 ml 2500 g/ml (125 g): positive. Specific IgE (ELISA): positive in one patient. The specificity of antibodies is confirmed by inhibition ELISA studies.
MANAGEMENT
Avoidance.
- 300 -
MISCELLANEOUS
REFERENCES
Grammer L.C, Roberts M, Cutaneous allergy to recombinant human type I IL-1 receptor (rhu IL-1R), J. Allergy. Clin. Immunol., 1997; 99 (5): 714-5
SULFASALAZINE
Sulfasalazine is used chiefly in the treatment of hemorrhagic ulcerative colitis and Crohns disease. It consists of a sulfonamide moiety linked by a nitrogen bond to aminosalicylate.
INCIDENCE
5 to 55% of patients present side-effects. Hypersensitivity is involved only in 2% of these manifestations.
Manifestations may be divided in two categories: I/ Dose-dependent manifestations linked to the rate of acetylation of sulfapyridine are frequent (30%) under the following conditions: doses > 4 g/ day serum levels of sulfasalazine > 50g/ ml patients presenting slow acetylation rate. These manifestations are: General: headache, discomfort Digestive: nausea, vomiting, anorexia, epigastralgia Hematological: hemolytic anemia, hemolysis without anemia, methemoglobinemia Cutaneous: bluish skin. II/ Hypersensitivity manifestations occurring early, independently of the dose or rate of acetylation, are uncommon (2%). General: prolonged fever, arthralgia, vasculitis, lupus Cutaneous: rash (1% of treatments), urticaria, erythrodermia, erythema multiforme, Lyells syndrome, Stevens-Johnsons syndrome.
- 301 -
MISCELLANEOUS
Hematological: autoimmune anemia, agranulocytosis, leukopenia, thrombocytopenia, aplastic anemia Respiratory: bronchospasm, pulmonary infiltrates and eosinophilia, diffuse interstitial fibrosis, obliterans bronchiolitis, subacute hypersensitivity pneumonitis Digestive: hepatitis (12 cases, 2 deaths), pancreatitis, bloody diarrhea.
DIAGNOSTIC METHODS
No in vivo or in vitro method is currently available, other than stopping and then restarting sulfasalazine.
MECHANISMS
Unknown, but the following hypotheses have been proposed: Cytotoxicity in hematological manifestations. Immune complexes in cutaneous vasculitis. Delayed cell-mediated hypersensitivity in some cutaneous manifestations.
MANAGEMENT
91% of sulfasalazine intolerant patients are able to tolerate at least one of the three 5 ASA preparations (mesalazine, olsalazine, balsalazide), but adverse effects may occur: colitis, diarrhea and sometimes hypersensitivity reactions. Desensitization is a safe approach in mild hypersensitivity reactions (rash, fever). Absolute contra-indications: toxic epidermal necrolysis, fibrosing pulmonary alveolitis, eosinophilic pneumonia, granulomatous hepatitis, massive hemolytic anemia, agranulocytosis, bone marrow aplasia, neurotoxicity. Many protocols have been published. For example: starting with 1 mg and doubling the dose each week: 1 mg, 2 mg, 4 mg, 8 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1000 mg, 2000 mg. If a reaction occurs, slow the progression.
- 302 -
MISCELLANEOUS
REFERENCES
Lachaux A, Legall C, Loras-Duclaux I, Aboufadel A, Hermier M, Hypersensibilit lacide 5-aminosalicylique. Intert de la dsensibilisation par voie orale, Arch. Pediatr., 1997; 4 (2): 144-6 Akahoshi K, Chijiiwa Y, Kabemura T, Okabe H, Akamine Y, Nawata H, Desensitization for sulfasalazine-induced skin-rash in a patient with ulcerative colitis, J. Gastroenterol., 1994; 29 (6): 772-5 Koski J.M, Desensitization to sulphasalazine in patients with arthritis , Clin. Exp. Rheumatol., 1993; 11 (2): 169-70 Tolia V, Sulfasalazine desensitization in children and adolescents with chronic inflammatory bowel disease, Am. J. Gastroenterol., 1992; 87 (8): 1029-32 Giaffer M.H, OBrien C.J, Holdsworth C.D, Clinical tolerance to three 5aminosalicylic acid releasing preparations in patients with inflammatory bowel disease intolerant or allergic to sulphasalazine, Aliment. Pharmacol. Ther., 1992; 6 (1): 51-9
TETRAZEPAM
Tetrazepam is a benzodiazepine with the general properties of diazepam, used as muscle relaxants (50 to 200 mg daily).
INCIDENCE
2/4767 recipients of benzodiazepine drugs.
Cutaneous: pruritus, urticaria, angioedema, general papular, maculopapular or purpuric rash, hand and face contact dermatitis (handling of the drug), erythema multiforme. Respiratory: tightness of the chest.
DIAGNOSTIC METHODS
Cutaneous testing. Patch-tests with tetrazepam 1% aq or 1% and 5% pet.: positive in all cases. Oral drug challenge.
- 303 -
MISCELLANEOUS
MECHANISMS
Type IV hypersensitivity.
MANAGEMENT
Avoidance of all benzodiazepines is not mandatory, since crossreactivity is not always found in oral challenge tests.
REFERENCES
Blanco R, Diez-Gomez M.L, Gala G, Quirce S, Delayed hypersensitivity to tetrazepam, Allergy, 1997; 52 (11): 1146-7 Ortega N.R, Barranco P, Lopez-Serrano C, Romualdo L, Mora C, Delayed cell-mediated hypersensitivity to tetrazepam, Contact. Dermatitis, 1996; 34 (2): 139 Kmpgen E, Burger T, Brocker E.B, Klein E, Cross-reactive type IV hypersensitivity reactions to benzodiazepines revealed by patch testing, Contact. Dermatitis, 1995; 33 (5): 356-7 Camarasa J.G, Serra-Baldrich E, Tetrazepam allergy detected by patch-test, Contact. Dermatitis, 1990; 22 (4): 246
UBIQUINONE
Ubiquinone (coenzyme Q): 2-3 dimethoxy 5 methyl-6-decaphenyl benzoquinone is used in the treatment of mitochondrial myopathies and encephalomyopathies.
INCIDENCE
3/2664 (rashes).
Urticaria.
DIAGNOSTIC METHODS
Cutaneous testing. Skin prick-tests: ubiquinone (5 mg/ ml): negative. Patch-tests (15% in vaseline): negative.
- 304 -
MISCELLANEOUS
Oral challenge tests: 5 mg, 10 mg, 15 mg, 20 mg: positive in one patient.
MECHANISMS
Unknown.
MANAGEMENT
Desensitization (every 30 minutes). Day 1: 0.25 mg, 050 mg, 1 mg, 2 mg Day 2: 3.5 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg Day 3: 10 mg, 12.5 mg, 15 mg, Day 4: 15 mg, 17.5 mg, 17.5 mg.
REFERENCES:
Schiavino D, Nucera E, Zoppi A, Misuraca C, Patriarca G, Rush desensitization with ubiquinone, Allergy, 1997; 52 (7): 783-4
- 305 -
INDEX
INDEX
2 -mercaptoethane sulphonate .............................................. 5 hydroxytryptamine 3 receptors antagonists ....................... 5-fluorouracil ........................................................................ 6-mercaptopurine .................................................................. A ACE inhibitors ............................................................. 193, 292 Acetaminophen ....................................................................... 46 Acetazolamide ........................................................................ 93 Acetylcysteine ...................................................................... 274 ACTH ................................................................................... 218 Actinomycin ......................................................................... 139 Acyclovir ................................................................................ 54 Adenocorticotrophic hormone .............................................. 218 Alkylating agents .................................................................. 106 Allergoids ............................................................................. 189 Allopurinol .................................................................. 136, 275 Allylamines............................................................................. 55 Alminoprofen ......................................................................... 50 Alphacaine ................................................................................ 8 Alphaxalone.......................................................................... 168 Alphazurin 2 G ..................................................................... 206 Althesin................................................................................. 168 Aluminum hydroxide............................................................ 249 Amidophenazone .................................................................... 48 Amikacin ................................................................................ 56 Aminoglutethimide ................................................................ 111 Aminoglycosides ........................................................... 55, 178 Aminophylline ...................................................................... 170 Amitriptyline ................................................................ 180, 298 150 148 130 117
- 306 -
INDEX
Amphotericin b ....................................................................... 59 Ampicillin ............................................................................... 77 Amylopectin ........................................................................... 34 An 69 membrane .................................................................. 193 Analgesics............................................................................... 37 Ancillary drugs ..................................................................... 148 Ancrod ......................................................................... 229, 236 Anesthetics ............................................................................... 8 Angiotensin Converting Enzyme Inhibitors (ACE) ............. 152 Aniline .................................................................................. 206 Antazoline phosphate ........................................................... 172 Anthracycline antibiotics ...................................................... 113 Anthralinic acid derivatives.................................................... 40 Anti-inflammatory drugs ........................................................ 37 Antibiotic additive ................................................................ 189 Antibiotics .................................................................. 9, 53, 180 Anticonvulsant...................................................................... 296 Antidepressants..................................................................... 180 Antifibrinolytics ................................................................... 236 Antifungal creams ................................................................ 178 Antifungal drugs ..................................................................... 53 Antihepatitis B ...................................................................... 173 Antihepatitis B vaccine......................................................... 189 Antihistamines ....................................................... 10, 180, 192 Antilymphocyte globulin ...................................................... 250 Antiseptics ............................................................................ 163 Antithymocyte globulins ...................................................... 240 Antitoxin ............................................................................... 244 Antituberculosis.................................................................... 173 Antivenoms........................................................................... 241 Antiviral .................................................................................. 53 Antrafenine ............................................................................. 40 Aprotinin....................................................................... 210, 236 Argatroban ............................................................................ 229 Articaine ................................................................................... 8 Arylpropionic derivatives ....................................................... 49
- 307 -
INDEX
Aspirin ............................................................................ 41, 221 Atovaquone............................................................................. 95 Atracurium ....................................................................... 17, 23 Atropine ................................................................................ 155 Azapropazone ......................................................................... 42 Azathioprine ......................................................................... 117 Azithromycin .......................................................................... 95 Azole derivatives .................................................................... 60 B B-propiolactone .................................................................... 258 Bacitracin................................................................................ 64 Balsalazide............................................................................ 303 Barbiturates............................................................................. 11 Barium enema ....................................................................... 164 Barium sulfate ...................................................................... 198 Basic tetracycline.................................................................... 96 Bcg vaccine .......................................................................... 243 Benoxaprofen ......................................................................... 42 Benzocaine ........................................................................... 174 Benzocaine ............................................................................... 8 Benzodiazepine....................................................... 26, 298, 304 Benzophenones ....................................................................... 50 Benzothiazepines .................................................................. 159 Benzylpenicillin...................................................................... 76 Benzylpenicilloate salt............................................................ 76 Benzylpenicilloic acid ............................................................ 76 Benzylpenicilloylamine .......................................................... 76 Benzylpenilloate ..................................................................... 76 Beta-blockers ........................................................................ 156 Beta-lactams ........................................................................... 74 Betadine ................................................................................ 177 Betamethasone...................................................................... 223 Betamethasone-dipropionate ................................................ 223 Betamethasone-valerate........................................................ 223 Betaxolol............................................................................... 158
- 308 -
INDEX
Bleomycin............................................................ 119, 134, 139 Botulinal antitoxin ................................................................ 244 Bronchodilators .................................................................... 180 Budesonide .................................................................. 222, 223 Bumetanide ........................................................................... 161 Bupivacaine .............................................................................. 8 Buserelin ............................................................................... 225 Busulfan................................................................................ 120 Butylparaben......................................................................... 174 C Calcipotriol ........................................................................... 264 Calcitonin ............................................................................. 219 Calcium channel blockers..................................................... 159 Captopril ...................................................................... 153, 293 Carbamazepine .................................................... 279, 280, 296 Carbinoxamine ..................................................................... 171 Carboplatin ........................................................................... 137 Carboxymethylcellulose ............................................... 164, 222 Cephalosporins ....................................................................... 74 Cetirizine .............................................................................. 289 Chemotherapy drugs and immunosuppressors ..................... 105 Chlorambucil ............................................................... 106, 108 Chloramphenicol .................................................................... 65 Chlorhexidine ....................................................................... 165 Chloroquine ............................................................................ 85 Chlorothiazide ........................................................................ 93 Chlorprocaine ........................................................................... 8 Chlorpromazine .................................................................... 281 Chlorpropanol ......................................................................... 93 Chlortetracycline .................................................................... 96 Choline salicylate ................................................................... 45 Chymopapain........................................................................ 212 Ciprofloxacin .......................................................................... 85 Cisatracurium ......................................................................... 23 Cisplatin................................................................................ 139
- 309 -
INDEX
Clarithromycin ........................................................................ 95 Clemastine ............................................................................ 171 Clindamycin ..................................................................... 67, 95 Clonixin .................................................................................. 44 Clozapine .............................................................................. 281 Cocaine ..................................................................................... 8 Codeine ................................................................................... 18 Coenzyme Q ......................................................................... 305 Collagen.................................................................................. 31 Contrast agents ..................................................................... 204 Contrast media ............................................................. 197, 199 Corticosteroids............................................ 164, 178, 192, 221 Corticotrophin....................................................................... 218 Cortivazol ............................................................................. 164 Cotrimoxazole ........................................................................ 91 Cremophor e.l.. ..................................................................... 168 Cromolyn .............................................................................. 282 Cuprammonium cellulose dialyzers ..................................... 187 Cuprammonium cellulose hemodialyzers ............................ 186 Cyanocobalamin/hydroxocobalamin .................................... 265 Cyclophosphamide .............................................. 107, 111, 139 Cyclosporine ................................................................. 121, 168 Cytarabine............................................................................. 123 D D. Penicillamine ................................................................... 285 Dacarbazine .......................................................................... 125 Daktarin ................................................................................ 168 Dapsone .................................................................................. 69 Daunorubicin ........................................................................ 113 Deferoxamine ....................................................................... 283 Desipramine.......................................................................... 180 Desonide ............................................................................... 223 Desoxymethasone ................................................................. 223 Dexamethasone..................................................................... 221 Dextran .................................................................. 29, 191, 244
- 310 -
INDEX
Dextran sulphate ................................................................... 293 Diagnostic agents.................................................................. 195 Dialyzers ............................................................. 186, 187, 189 Diaminodiphenylsulfone ........................................................ 69 Diatrizoate ............................................................................ 200 Diazepam ....................................................................... 26, 168 Diaziquone............................................................................ 126 Diazoxide................................................................................ 93 Dibenzodiazepine ................................................................. 281 Dibucaine.................................................................................. 8 Diclofenac................................................................. 42, 44, 45 Didemnin B .......................................................................... 168 Diethylenediamine................................................................ 289 Diethylglycine ........................................................................ 46 Diflunisal ................................................................................ 44 Dihydropyridines .................................................................. 159 Dihydrostreptomycin .............................................................. 56 Diltiazem .............................................................................. 159 Diphenhydramine ........................................................... 10, 171 Diprivan ................................................................................ 168 Disinfectant........................................................................... 165 Disodium cromoglycate........................................................ 282 Docetaxel .............................................................................. 142 Doxorubicin ................................................................. 114, 134 Doxycycline................................................................... 97, 178 Droperidol............................................................................... 28 Dyes ...................................................................................... 163 E Enoxacin ................................................................................. 85 Enzymes ............................................................................... 209 Ephedrine..................................................................... 192, 238 Epidophyllotoxins................................................................. 127 Epinephrine............................................................. 9, 178, 238 Epontol ................................................................................. 168 Equine rabies immunoglobulins ........................................... 247
- 311 -
INDEX
Erythromycin .......................................................................... 73 Erythrosine ........................................................................... 169 Ethambutol ............................................................................. 70 Ethylene oxide ...................................................... 186, 187, 287 Ethylenediamine ........................................................... 170, 289 Ethylmercurychloride ........................................................... 182 Ethylparaben ......................................................................... 174 Etidocaine ................................................................................. 8 Etofenamic.............................................................................. 40 Etomidate................................................................................ 14 Etoposide .............................................................................. 127 Examethasone ....................................................................... 223 F Factor VIII ............................................................................ 287 Famotidine ............................................................................ 299 Fenbrufen ................................................................................ 42 Fenofibrate .............................................................................. 50 Fenoprofen ....................................................................... 44, 50 Fentanyl .................................................................................. 20 Floctafenine ............................................................................ 40 Fluconazole............................................................................. 60 Flufenamic .............................................................................. 40 Flumequin ............................................................................... 85 Flunitrazepam ......................................................................... 26 Fluocortolone ........................................................................ 223 Fluorescein ........................................................................... 196 Flurbiprofen ..................................................................... 45, 50 Formaldehyde ....................................................................... 189 Formalin ............................................................................... 249 Framycetin .............................................................................. 57 Furosemide ..................................................................... 93, 160 Futhan ................................................................................... 293 G Gadolinium chelates ............................................................. 204
- 312 -
INDEX
Gadopentetate dimeglumine ................................................. 204 Gadoterate meglumine.......................................................... 204 Gadoteridol ........................................................................... 204 Gastrografin .......................................................................... 198 Gastrointestinal contrast media ............................................ 197 Gelatin ............................................................................ 31, 255 Gentamicin .................................................................... 56, 178 Glafenine ......................................................................... 40, 85 Glucose polymers ................................................................... 29 Glycosaminoglycans............................................................. 228 GnRH analogues ................................................................... 225 Gonadorelin .......................................................................... 225 Goserelin............................................................................... 225 Granisetron ........................................................................... 148 Guanosine ............................................................................... 54 H Hemodialyzer ....................................................................... 186 Heparin ......................................................................... 227, 293 Hepatitis b vaccine ............................................................... 248 Hetastarch ............................................................................... 34 Heterologous sera ................................................................. 250 Hexadimethrine .................................................................... 236 Hirudin ......................................................................... 229, 236 Hormones ............................................................................. 217 Human serum albumin ......................................................... 251 Hydrocortisone ............................................................ 221, 223 Hydrocortisone-17-butyrate ................................................. 223 Hydroxyethylstarch (HES) ..................................................... 34 Hydroxystreptomycin ............................................................. 56 Hydroxyurea ......................................................................... 131 Hydroxyzine ................................................................. 172, 288 Hypnotics................................................................................ 11 I Ibuprofen .................................................................. 42, 44, 50
- 313 -
INDEX
Ifosfamide .................................................................... 107, 108 IL-1 receptor ......................................................................... 300 Imidazobenzodiazepine .......................................................... 27 Imidazole salicylate ................................................................ 45 Imipramine ........................................................................... 180 Immunoglobulin ........................................................... 247, 253 Indocyanine green ................................................................ 198 Indomethacin ................................................................... 42, 44 Insulin ................................................................................... 230 Interleukin 2.......................................................................... 201 Intravenous immunoglobulins .............................................. 253 Iodamide ............................................................................... 200 Iodinated contrast media....................................................... 199 Iodixanol ............................................................................... 200 Iohexol .................................................................................. 200 Iomeprol ............................................................................... 200 Iopamidol .............................................................................. 200 Iopentol ................................................................................. 200 Iopromide ............................................................................. 200 Iothalamate ........................................................................... 200 Iotrolan ................................................................................. 200 Ioversol ................................................................................. 200 Ioxaglate ............................................................................... 200 Ioxitol ................................................................................... 200 Ioxythalamate ....................................................................... 200 Iron dextran .......................................................................... 191 Isoniazid ................................................................................. 72 Isonixin ................................................................................... 44 Itraconazole ............................................................................ 61 K Kanamycin.............................................................................. Ketalar .................................................................................... Ketamine................................................................................. Ketoconazole .......................................................................... Ketoprofen ....................................................................... 44, 56 15 15 62 49
- 314 -
INDEX
Ketorolac ................................................................................ 45 Konakion .............................................................................. 168 L L-asparaginase ...................................................................... 115 Lamotrigine .......................................................................... 298 Latex .................................................................... 198, 249, 289 Ldl apheresis ......................................................................... 292 Leuprolide............................................................................. 225 Leuprorelin ........................................................................... 225 Lidocaine ......................................................................... 8, 178 Lincomycin ............................................................................. 67 Local anethetics .......................................................................... 8 Lomefloxacin.......................................................................... 85 Low density lipoprotein apheresis ........................................ 292 Lozartan ................................................................................ 154 Lyssavac-HDC Berna ........................................................... 258 M Macrolides .............................................................................. 73 Mannitol ................................................................................. 35 Manosidostreptomycin ........................................................... 56 Marmite ................................................................................ 265 Measles vaccine .................................................................... 254 Mechlorethamine .................................................................. 109 Meclofenamic acids ................................................................ 40 Mefenamic acid ............................................................... 40, 44 Melphalan .................................................................... 108, 110 Meperidine.............................................................................. 21 Mepivacaine ............................................................................. 8 Mercurochrome ........................................................... 172, 173 Mercury nitrate ..................................................................... 173 Mercury antiseptics .............................................................. 172 Mercury chloride .................................................................. 173 Merthiolate ........................................................................... 181 Mesalazine ............................................................................ 303
- 315 -
INDEX
Mesna ................................................................................... 150 Metamizol ............................................................................... 48 Methadone .............................................................................. 19 Methohexital ........................................................................... 11 Methotrexate ......................................................................... 132 Methylmorphine ..................................................................... 18 Methylparaben ...................................................................... 174 Methylprednisolone .............................................................. 221 Metoclopramide.................................................................... 178 Metrizamide.......................................................................... 200 Metrizoate ............................................................................. 200 Metronidazole ......................................................................... 63 Miconazole ........................................................................... 168 Midazolam .............................................................................. 27 Minocycline ............................................................................ 97 Mitomycin .................................................................... 134, 147 Mitoxantrone ........................................................................ 135 Mivacurium ............................................................................ 23 Morphine ................................................................................ 22 Morphine monomethyl ether .................................................. 18 Morphinomimetics ................................................................. 18 Muscle relaxants ..................................................................... 23 N Nafarelin ............................................................................... 225 Nalidixic acid.......................................................................... 85 Naproxen .................................................................. 42, 44, 50 Neomycin ...................................................................... 56, 255 Neoral ................................................................................... 122 Neosynephrine ...................................................................... 238 Netilmicin ............................................................................... 56 Neuroleptics............................................................................ 28 Nicotinamide .......................................................................... 82 Nifedipine ............................................................................. 159 Nimesulide.............................................................................. 45 Nitrofurantoin ....................................................................... 299
- 316 -
INDEX
Nitroxolin ............................................................................... 85 Nizatidine ..................................................................... 294, 299 Non Steroid Anti-Inflammatory Drugs (NSAIDs) ................. 41 Non-barbiturates ..................................................................... 14 Norephedrine ........................................................................ 238 Norfloxacin ............................................................................. 85 Novocaine ............................................................................. 178 O Ofloxacin ................................................................................ 85 Olsalazine ............................................................................. 303 Omeprazole........................................................................... 295 Ondansetron.......................................................................... 148 Opiod ...................................................................................... 18 Oxolinic acid .......................................................................... 85 Oxyphenylbutazone ................................................................ 42 Oxypolygelatins...................................................................... 32 Oxytetracycline....................................................................... 96 Ozagrel ................................................................................. 154 P Paclitaxel ..................................................................... 144, 168 Pancuronium ........................................................................... 23 Papain ................................................................................... 212 Para-phenylendiamine .......................................................... 175 Paraben ..................................................................... 9, 173, 222 Paracetamol ..................................................................... 39, 44 Paramagnetic contrast agents ............................................... 204 Paramomycin .......................................................................... 56 Patent blue dye ..................................................................... 206 Pefloxacin ............................................................................... 85 Penicillin ................................................................................. 74 Pentamidine ............................................................................ 79 Pentastarch.............................................................................. 34 Pentostatin ............................................................................ 136 Pethidine ................................................................................. 21
- 317 -
INDEX
Phenazone ............................................................................... 48 Phenobarbital ...................................................... 141, 280, 296 Phenothiazine ......................................................................... 28 Phenylalkylamines................................................................ 159 Phenylbutazone................................................................ 42, 44 Phenylephrine ....................................................................... 238 Phenylmercuric acetate ......................................................... 172 Phenylpiperidine .............................................................. 19, 20 Phenytoin ..................................................................... 280, 296 Pipemidic acid ........................................................................ 85 Piperazine ............................................................................. 171 Piperocaine ............................................................................... 8 Piroxicam ......................................................................... 42, 44 Plasma substitutes ................................................................... 29 Platinum compounds ............................................................ 137 Polyacrylonitrile an 69 membrane........................................ 193 Polyvinyl pyrrolidone ........................................................... 175 Potassium metabisulfite ........................................................ 177 Povidone ............................................................................... 175 Povidone iodine .................................................................... 176 Praziquantel ............................................................................ 81 Prazosin ................................................................................ 162 Prednisolone ................................................................ 221, 223 Prednisolone acetate ............................................................. 164 Prednisone ............................................................................ 221 Preservatives ......................................................................... 163 Prilocaine .................................................................................. 8 Procaine .................................................................................... 8 Procarbazine ......................................................................... 141 Propacetamol .......................................................................... 46 Propacetamol hydrochloride ................................................... 39 Propanidid...................................................................... 15, 168 Propranolol ........................................................................... 156 Propofol ......................................................................... 16, 168 Propoxycaine ............................................................................ 8 Propoxyphene ......................................................................... 45
- 318 -
INDEX
Propylparaben ....................................................................... 174 Propylphenazone .................................................................... 48 Protamine ...................................................................... 232, 235 Pseudoephedrine ................................................................... 237 Pyrazinamide .......................................................................... 82 Pyrazoline drugs ..................................................................... 48 Pyrazolones............................................................................. 48 Pyridoxal............................................................................... 268 Pyridoxamine ........................................................................ 268 Pyridoxine............................................................................. 268 Pyrimethamine ................................................................. 67, 95 Q Quarternary ammonium.......................................................... Quinidine ................................................................................ Quinine ................................................................................... Quinolones.............................................................................. R Rabies immunoglobulin........................................................ 247 Rabies vaccine ...................................................................... 257 Ranitidine ............................................................................. 298 Recombinant human type 1 il-1 receptor ............................. 300 Rifabutine ............................................................................... 89 Rifampicin .............................................................................. 86 Rifampicine ............................................................................ 89 Rifamycin B............................................................................ 88 Rifamycin sv ........................................................................... 88 Rocuronium ............................................................................ 23 S Salicylate ......................................................................... 42, 45 Salsalate .................................................................................. 44 Sandimmune ................................................................. 122, 168 Sera ....................................................................................... 239 Sisomicin ................................................................................ 56 24 84 83 85
- 319 -
INDEX
Sodium bisulfite.................................................................... 177 Sodium cromoglycate ................................................... 154, 282 Sodium fusidate ...................................................................... 90 Sodium glutamate ................................................................. 244 Sodium metabisulfite ............................................................ 177 Sodium salicylate.................................................................... 45 Sodium sulfite ....................................................................... 177 Sparfloxacin ............................................................................ 85 Steroids ................................................................................. 180 Stesolid mr ............................................................................ 168 Streptokinase ........................................................................ 214 Streptomycin.................................................................... 56, 57 Sulfadiazine ............................................................................ 93 Sulfamethoxazole-Trimethoprim (SMX-TMP) ...................... 91 Sulfapyridine .......................................................................... 70 Sulfasalazine ......................................................................... 301 Sulfites ..................................................................... 9, 177, 222 Sulfonamides ................................................ 91, 102, 161, 175 Sulfurous anhydride.............................................................. 177 Sulindac .................................................................................. 42 Sulphadiazine ......................................................................... 95 Suprofen ................................................................................. 45 Suxamethonium ...................................................................... 23 T Tartrazine .............................................................................. 180 Taxanes ................................................................................. 142 Taxol ..................................................................................... 168 Teicoplanin ........................................................................... 101 Teniposide.................................................................... 128, 168 Terbinafine .............................................................................. 55 Tetanus toxoid ...................................................................... 259 Tetracaine ................................................................................. 8 Tetracosactrin ....................................................................... 218 Tetracycline group .................................................................. 96 Tetrazepam ........................................................................... 304
- 320 -
INDEX
Theophylline ......................................................................... 170 Thiamine (vitamin b1) .......................................................... 267 Thiazide ................................................................................ 275 Thimerosal ............................................................................ 181 Thiomersal .......................................................... 172, 181, 249 Thiopental ............................................................................... 12 Thiopentone ............................................................................ 13 Thiosalicylic acid......................................................... 173, 182 Thiotepa ................................................................................ 146 Thymidine............................................................................. 102 Tiaprofenic acid ................................................................ 42, 50 Tiliquinol ................................................................................ 85 Timolol maleate .................................................................... 156 Tinidazole ............................................................................... 64 Tixocortol pivalate ....................................................... 222, 223 Tobramycin ............................................................................. 56 Tolbutanol ............................................................................... 93 Tolmetine ................................................................................ 42 Topical corticosteroids.......................................................... 223 Topical non-steroidal antiinflammatory drugs (NSAIDs) ...... 49 Triamcinolone ....................................................................... 223 Triamcinolone acetonide ...................................................... 164 Trientine ................................................................................ 286 Trimethoprim .......................................................................... 98 Tripelennamine hydrochloride ............................................. 172 Tripterolin ............................................................................. 225 Tropisetron ............................................................................ 148 Tryphenylmethane dyes ........................................................ 206 U Ubiquinone ........................................................................... 305 V Vaccines ................................................................................ 239 Valacyclovir ............................................................................ 54 Valproic acid ......................................................................... 298
- 321 -
INDEX
Vancomycin .......................................................................... 100 Vecuronium ............................................................................. 23 Verapamil .............................................................................. 159 Vinblastine ................................................................... 139, 147 Vinca alkaloids ..................................................................... 147 Vincristine ..................................................................... 134, 147 Vindesine .............................................................................. 147 Vitamin B.............................................................................. 178 Vitamin B1............................................................................ 267 Vitamin B6............................................................................ 268 Vitamin D3 ........................................................................... 264 Vitamin K ............................................................................. 269 Vitamin K1 ........................................................................... 168 Vitamins ................................................................................ 263 Vumon .................................................................................. 168 Z Zidovudine............................................................................ 102 Zomepirac ........................................................................ 42, 44
- 322 -
INDEX
- 323 -
Pharmacia & Upjohn Diagnostics AB, SE-751 82 Uppsala, Sweden. +46 18 16 30 00, e-mail: marketing.diagnostics@eu.pnu.com
ISBN 91-973440-0-1 52-5103-59/02

Drug Allergy Book

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DRUG ALLERGY

Daniel Vervloet Michel Pradal Michel Castelain

Daniel Vervloet/Michel Pradal/Michel Castelain ISBN 91-973440-0-1

XII. VITAMINS................................................................... 263 XIII. MISCELLANEOUS .................................................... 273 INDEX................................................................................... 306

I DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

CLINICAL MANIFESTATIONS Reactions unrelated to drugs:

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

0.2% in dentistry. No deaths have been reported. CLINICAL MANIFESTATIONS

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

Severe reactions: 0.007% to 0.13%.

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

GENERAL: ANAPHYLACTIC SHOCK, FEVER.

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

DRUGS USED FOR ANESTHESIA AND INTENSIVE CARE

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

II ANALGESICS AND ANTIINFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANTHRALINIC ACID DERIVATIVES

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ASPIRIN AND NON STEROID ANTI-INFLAMMATORY DRUGS (NSAIDs)

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

PYRAZOLINE DRUGS OR PYRAZOLONES

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

TOPICAL NON STEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDs)

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANALGESICS AND ANTI-INFLAMMATORY DRUGS

ANTIBIOTICS, ANTIVIRAL, ANTIFUNGAL DRUGS

III ANTIBIOTICS, ANTIVIRAL, ANTIFUNGAL DRUGS

ANTIBIOTICS, ANTIVIRAL, ANTIFUNGAL DRUGS

ANTIBIOTICS, ANTIVIRAL, ANTIFUNGAL DRUGS

ANTIBIOTICS, ANTIVIRAL, ANTIFUNGAL DRUGS