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Diagnosis of drug reactions: methods and limitations
REVUE FRANCAISE D'ALLERGOLbGIE ETD'IMMUNOLOGIECLINIQUE
52
Diagnosis of drug reactions: methods and limitations B. PRZYBILLA, F. RU#FF
Drug reactions are elicited by the pharmacological action of a compound, i.e. toxicity, or they occur due to hypersensitivity of the individual patient. Only the latter will be considered here. The following types of hypersensitivity can be discerned: • Intolerance: Symptoms of the pharmacological action develop after a low dose which is tolerated by other individuals; no immunologic (allergic) mechanism can be demonstrated. • Idiosyncrasy: Symptoms differ from those of the pharmacological action; an immunologic (allergic) pathomechanism cannot be found. • Allergy: The hypersensitivity reaction occurs due to an i m m u n o l o g i c mechanism. If the symptoms of intolerance or idiosyncrasy are similiar to those of allergic diseases, they may be called "pseudo-allergic". Many drug reactions are caused by such pseudo-allergy. Drug reactions can involve all organ systems, skin symptoms are particularly frequent. Severity ranges from very mild reactions (e.g. exclusive itching, single lesions of fixed drug eruption) to life-threatening disorders (e.g. anaphylactic shock, toxic epidermal necrolysis, agranulocytosis). In o r d e r to identify the eliciting agent, an allergological work-up has to be p e r f o r m e d in any
Klinik und Poliklinik ffir Dermatologie und Allergologie, LudwigMaximilians-Universitfit, FrauenlobstraBe 9-11, D-80337 MUNCHEN.
patient with a hypersensitivity reaction related to the administration of a drug. Otherwise the patient is at risk to develop severe reactions on re-exposure or, on the other hand, necessary therapeutic modalities may be withheld for possibly unjustified "safety" reasons. To identify the elicitor of a drug hypersensitivity reaction, history, skin tests and challenge tests are used; in some cases also in vitro tests are useful. Diagnostics are to be p e r f o r m e d promptly after remission of the symptoms of a drug reaction as test reactivity may decline with time. Not only the active c o m p o u n d of a drug, but also all other components, i.e. also vehicles and additives, have to be considered as possible elicitors. To assess the reaction of a patient, an individual approach is necessary in order to get reliable results and also not to put the patient at an unacceptable risk from test procedures. History taking is the most important diagnostic step. All drugs (brand names!) administered in connection with the suspected drug reaction have to be identified definitely. It has to be considered that also topically applied compounds can cause systemic reactions (i.e. anaphylaxis due to topical bacitracin). No exposure should be regarded as irrelevant. The clinical presentation of the
PRZYBILLA B., RUEFF F. - Diagnosis of drug reactions: methods and limitations. Rev. fr. Allergol., 1999, (Num6ro sp6cial), 52-54.
© Expansion Scientifique Publications, 1999
/ DIAGNOSIS OF DRUG REACTIONS °
hypersensitivity reaction should be characterized as accurately as possible in order to get clues to the possible mechanism (e.g. anaphylactoid/ anaphylactic symptoms? t h r o m b o c y t o p e n i a ? vasculitis? exanthema?). The time course of symptoms has to be put into relation to the administration of drugs. Other possibly concurrent elicitors of hypersensitiviw reactions, such as natural rubber latex eposure or food ingestion, have to be taken into account. Skin tests are p e r f o r m e d with the active compound(s) and other components of the drug, if not possible at least with the drug itself. Only for the diagnosis of penicillin allergy standardized test substances are available. Thus, all other c o m p o u n d s have to be individually prepared for skin testing, irritancy and pharmacological effects (e.g. whealing due to morphine derivatives or chinolones) have to be taken into account. The choice of a test m e t h o d has to consider the p r e s u m e d p a t h o m e c h a n i s m of the reaction. C o m m o n procedures are the skin prick or scratch test, the interdermal test, and the patch test; if photo-induced reactions are suspected, additional irradiation has to be performed. The general rules of skin testing are to be followed. Particularly, as skin tests may elicit systemic symptoms, adequate precautions have to be taken to ensure immediate treatment. Also, a risk of sensitization by skin testing exists, especially when performing intradermal or patch tests. If a skin test reaction occurs to a non-standardized test compound, specifity has to be proven by tests in control persons. However, if active sensitization by skin testing is a possibility, such control tests must not be performed. In most cases, the results of skin tests do not allow to establish a definite diagnosis. With regard to in vitro tests, the only standardized procedure is the measurement of specific IgE antibodies in the serum, which is available for only a few compounds. In case other immunological methods (e.g. determination of other specific antibodies, histamine or leukotriene release from peripheral b l o o d leukocytes, lymphocyte transformation tests) are used, the results have to be assessed critically. Particularly the specifity of positive results has to be confirmed by adequate control tests performed with material from individuals who have been not exposed and from persons who have been exposed without reaction to the respective drug. Neither "positive" nor "negative" in vitro test results allow to exclude or to diagnose with certainity a clinically relevant drug hypersensitivity. Rev.f~ AllergoL, 1999, Numtro sp6cial
53
Challenge tests are p e r f o r m e d when the elicitor of a hypersensitivity reaction cannot be identified by history, skin tests, and in vitro tests. They can also be used to select tolerated substances in case of reactions to c o m p o u n d s from groups of indispensable drugs such as analgesics or local anesthetics. In the diagnosis of reactions due to pseudo-allergic mechanisms skin tests and in vitro tests usually are not helpflal, therefore in this situation challenge tests are the only diagnostic means beyond history. Before challenge tests are performed, the risk-benefit-ratio for the individual patient is to be assesed. Attention must be payed to the general contraindications of challenge tests; especially, such tests must not be p e r f o r m e d if reactions may occur which cannot be definitely managed without any hazard for the patient. The test material is applied in incremental doses (e.g. 1 % / 1 0 % / 5 0 % / 100% of the usual single dose) at intervals c o r r e s p o n d i n g to the suspected reaction mechanism (e.g. two hours in anaphylactic reactions), taking into consideration the pharmacologic action of the drug given. All precautions have to be taken to assure adequate treatment of test reactions, which may occur within minutes or not before days, depending on the reaction type. Additional irradiations have to be administered in cases of probably photoinduced drug reactions. Double blind placebocontrolled challenges are the gold standard, but for routine purposes critical evaluation of results of open or single-blind, placebo-controlled tests is sufficient in most cases. Often challenges are p e r f o r m e d orally, b u t o t h e r routes of drug administration may be used to simulate the eliciting situation. Falsely negative challenge tests (e.g. due to missed cofactors, too low challenge doses) are not infrequent. The risk of de novo sensitization or of boosting hypersensitivity by challenge testing has to be considered. For patients with reactions to mild analgesics or to local anesthetics it is a time-tested procedure to select alternative, tolerated drugs by oral challenges with a standard series of analgesics or by subcutaneous testing with a standard series of local anesthetics. To make a final diagnosis, all information obtained by history and by testing is interpreted critically. The information given to the patient has to include: • what has to be avoided, • what presumably is tolerated, and • what special precautions are r e c o m m e n d e d if the elicitor(s) of hypersensitivity reactions could not be identified with certainty.
• B. PRZYBILLA, E R U f F /
54 REFERENCES 1. Arbeitsgruppe "Arzneimittelunvertrfiglichkeiten" der Deutschen Gesellschaft ffir Allergie und Immunitfitsforschung: Empfehlungen ffir die Autkl~irung yon Uberempfindlichkeitsreakfionen aufArzneimittet. Allergologie, 1991, 14, 58-60. 2. Bleck O., Vieluf D. - Pseudo-allergische Reaktionen auf nichtsteroidale Anfiphlogistika und Analgefika, Allergologie, 1997, 20, 375-384. 3. Brockow K., Ring J. - Anaphylaktoide Reaktionen nach Infusion yon R6ntgenkontrastmitteln. Grundlagen, Klinik, Pathomechanismus und Prophylaxe. Allergologie, 1997, 20, 400-406. 4. Przybilla B., RufiffE - Oraler Provokafionstest. In: Korting H.C., Sterry W. (Hrsg) Diagnosfische Verfahren in der Dermatologie. pp. 123-131, Blackwell, Berlin, 1997. 5. Ru~ff E, Przybilla B. - Lokalanfisthetika-Unvertrfiglichkeit. Allergologie, 1997, 20, 385-392.
mmll
Rev.fr. AllergoL, 1999, Num6ro special
52
Diagnosis of drug reactions: methods and limitations B. PRZYBILLA, F. RU#FF
Drug reactions are elicited by the pharmacological action of a compound, i.e. toxicity, or they occur due to hypersensitivity of the individual patient. Only the latter will be considered here. The following types of hypersensitivity can be discerned: • Intolerance: Symptoms of the pharmacological action develop after a low dose which is tolerated by other individuals; no immunologic (allergic) mechanism can be demonstrated. • Idiosyncrasy: Symptoms differ from those of the pharmacological action; an immunologic (allergic) pathomechanism cannot be found. • Allergy: The hypersensitivity reaction occurs due to an i m m u n o l o g i c mechanism. If the symptoms of intolerance or idiosyncrasy are similiar to those of allergic diseases, they may be called "pseudo-allergic". Many drug reactions are caused by such pseudo-allergy. Drug reactions can involve all organ systems, skin symptoms are particularly frequent. Severity ranges from very mild reactions (e.g. exclusive itching, single lesions of fixed drug eruption) to life-threatening disorders (e.g. anaphylactic shock, toxic epidermal necrolysis, agranulocytosis). In o r d e r to identify the eliciting agent, an allergological work-up has to be p e r f o r m e d in any
Klinik und Poliklinik ffir Dermatologie und Allergologie, LudwigMaximilians-Universitfit, FrauenlobstraBe 9-11, D-80337 MUNCHEN.
patient with a hypersensitivity reaction related to the administration of a drug. Otherwise the patient is at risk to develop severe reactions on re-exposure or, on the other hand, necessary therapeutic modalities may be withheld for possibly unjustified "safety" reasons. To identify the elicitor of a drug hypersensitivity reaction, history, skin tests and challenge tests are used; in some cases also in vitro tests are useful. Diagnostics are to be p e r f o r m e d promptly after remission of the symptoms of a drug reaction as test reactivity may decline with time. Not only the active c o m p o u n d of a drug, but also all other components, i.e. also vehicles and additives, have to be considered as possible elicitors. To assess the reaction of a patient, an individual approach is necessary in order to get reliable results and also not to put the patient at an unacceptable risk from test procedures. History taking is the most important diagnostic step. All drugs (brand names!) administered in connection with the suspected drug reaction have to be identified definitely. It has to be considered that also topically applied compounds can cause systemic reactions (i.e. anaphylaxis due to topical bacitracin). No exposure should be regarded as irrelevant. The clinical presentation of the
PRZYBILLA B., RUEFF F. - Diagnosis of drug reactions: methods and limitations. Rev. fr. Allergol., 1999, (Num6ro sp6cial), 52-54.
© Expansion Scientifique Publications, 1999
/ DIAGNOSIS OF DRUG REACTIONS °
hypersensitivity reaction should be characterized as accurately as possible in order to get clues to the possible mechanism (e.g. anaphylactoid/ anaphylactic symptoms? t h r o m b o c y t o p e n i a ? vasculitis? exanthema?). The time course of symptoms has to be put into relation to the administration of drugs. Other possibly concurrent elicitors of hypersensitiviw reactions, such as natural rubber latex eposure or food ingestion, have to be taken into account. Skin tests are p e r f o r m e d with the active compound(s) and other components of the drug, if not possible at least with the drug itself. Only for the diagnosis of penicillin allergy standardized test substances are available. Thus, all other c o m p o u n d s have to be individually prepared for skin testing, irritancy and pharmacological effects (e.g. whealing due to morphine derivatives or chinolones) have to be taken into account. The choice of a test m e t h o d has to consider the p r e s u m e d p a t h o m e c h a n i s m of the reaction. C o m m o n procedures are the skin prick or scratch test, the interdermal test, and the patch test; if photo-induced reactions are suspected, additional irradiation has to be performed. The general rules of skin testing are to be followed. Particularly, as skin tests may elicit systemic symptoms, adequate precautions have to be taken to ensure immediate treatment. Also, a risk of sensitization by skin testing exists, especially when performing intradermal or patch tests. If a skin test reaction occurs to a non-standardized test compound, specifity has to be proven by tests in control persons. However, if active sensitization by skin testing is a possibility, such control tests must not be performed. In most cases, the results of skin tests do not allow to establish a definite diagnosis. With regard to in vitro tests, the only standardized procedure is the measurement of specific IgE antibodies in the serum, which is available for only a few compounds. In case other immunological methods (e.g. determination of other specific antibodies, histamine or leukotriene release from peripheral b l o o d leukocytes, lymphocyte transformation tests) are used, the results have to be assessed critically. Particularly the specifity of positive results has to be confirmed by adequate control tests performed with material from individuals who have been not exposed and from persons who have been exposed without reaction to the respective drug. Neither "positive" nor "negative" in vitro test results allow to exclude or to diagnose with certainity a clinically relevant drug hypersensitivity. Rev.f~ AllergoL, 1999, Numtro sp6cial
53
Challenge tests are p e r f o r m e d when the elicitor of a hypersensitivity reaction cannot be identified by history, skin tests, and in vitro tests. They can also be used to select tolerated substances in case of reactions to c o m p o u n d s from groups of indispensable drugs such as analgesics or local anesthetics. In the diagnosis of reactions due to pseudo-allergic mechanisms skin tests and in vitro tests usually are not helpflal, therefore in this situation challenge tests are the only diagnostic means beyond history. Before challenge tests are performed, the risk-benefit-ratio for the individual patient is to be assesed. Attention must be payed to the general contraindications of challenge tests; especially, such tests must not be p e r f o r m e d if reactions may occur which cannot be definitely managed without any hazard for the patient. The test material is applied in incremental doses (e.g. 1 % / 1 0 % / 5 0 % / 100% of the usual single dose) at intervals c o r r e s p o n d i n g to the suspected reaction mechanism (e.g. two hours in anaphylactic reactions), taking into consideration the pharmacologic action of the drug given. All precautions have to be taken to assure adequate treatment of test reactions, which may occur within minutes or not before days, depending on the reaction type. Additional irradiations have to be administered in cases of probably photoinduced drug reactions. Double blind placebocontrolled challenges are the gold standard, but for routine purposes critical evaluation of results of open or single-blind, placebo-controlled tests is sufficient in most cases. Often challenges are p e r f o r m e d orally, b u t o t h e r routes of drug administration may be used to simulate the eliciting situation. Falsely negative challenge tests (e.g. due to missed cofactors, too low challenge doses) are not infrequent. The risk of de novo sensitization or of boosting hypersensitivity by challenge testing has to be considered. For patients with reactions to mild analgesics or to local anesthetics it is a time-tested procedure to select alternative, tolerated drugs by oral challenges with a standard series of analgesics or by subcutaneous testing with a standard series of local anesthetics. To make a final diagnosis, all information obtained by history and by testing is interpreted critically. The information given to the patient has to include: • what has to be avoided, • what presumably is tolerated, and • what special precautions are r e c o m m e n d e d if the elicitor(s) of hypersensitivity reactions could not be identified with certainty.
• B. PRZYBILLA, E R U f F /
54 REFERENCES 1. Arbeitsgruppe "Arzneimittelunvertrfiglichkeiten" der Deutschen Gesellschaft ffir Allergie und Immunitfitsforschung: Empfehlungen ffir die Autkl~irung yon Uberempfindlichkeitsreakfionen aufArzneimittet. Allergologie, 1991, 14, 58-60. 2. Bleck O., Vieluf D. - Pseudo-allergische Reaktionen auf nichtsteroidale Anfiphlogistika und Analgefika, Allergologie, 1997, 20, 375-384. 3. Brockow K., Ring J. - Anaphylaktoide Reaktionen nach Infusion yon R6ntgenkontrastmitteln. Grundlagen, Klinik, Pathomechanismus und Prophylaxe. Allergologie, 1997, 20, 400-406. 4. Przybilla B., RufiffE - Oraler Provokafionstest. In: Korting H.C., Sterry W. (Hrsg) Diagnosfische Verfahren in der Dermatologie. pp. 123-131, Blackwell, Berlin, 1997. 5. Ru~ff E, Przybilla B. - Lokalanfisthetika-Unvertrfiglichkeit. Allergologie, 1997, 20, 385-392.
mmll
Rev.fr. AllergoL, 1999, Num6ro special