Drug Allergy

Drug AllergyDrug Allergy

Adverse Reactions to DrugsAdverse Reactions to Drugs

Can be categorized as follows:Can be categorized as follows:(1) Drug intolerance --- predictable (1) Drug intolerance --- predictable

side effect at low to therapeutic doses side effect at low to therapeutic doses due to altered drug metabolism or end due to altered drug metabolism or end organ hyperacorgan hyperactivitytivity

(2) Idiosyncratic drug reactions(2) Idiosyncratic drug reactions(3) Immunologic drug reactions (drug (3) Immunologic drug reactions (drug

allergy)allergy)

Adverse Drug ReactionsAdverse Drug Reactions

Type Example Drug intolerance Tinnitus after a single

ASA tablet Idiosyncrasy Glucose 6-phosphate

deficiency: anemia after antioxidant drugs

Immunologic drug reactions

Anaphylaxis from betalactam antibiotics

Types of Allergic ReactionsTypes of Allergic Reactions

Type I (immediate)Type I (immediate)Type II (cytolytic)Type II (cytolytic)Type III (immune-complex Type III (immune-complex

associated)associated)Type IV (delayed)Type IV (delayed)

Types of Allergic ReactionsTypes of Allergic Reactions

Type Mechanism Examples

I Anaphylactic (IgE-mediated) Acute anaphylaxis, urticaria

II Complement dependent cytolysis (IgG/IgM)

Hemolytic anemias, thrombocytopenias, interstitial nephritis

III Immune complex damage Serum sickness, drug fever, some cutaneous eruptions, vasculitis

IV “Delayed” or Cellular Hypersensitivity

Contact dermatitis, ?morbilliform dermatitis

Symptoms of allergic drug Symptoms of allergic drug reactionsreactions

Skin reactions Skin reactions (80%)(80%)

Anaphylaxis (9 - Anaphylaxis (9 - 15%)15%)

Respiratory Respiratory symptoms (6 - 9%)symptoms (6 - 9%)

Drug fever (2 - 6%)Drug fever (2 - 6%)

Anaphylaxis versus Anaphylaxis versus Anaphylactoid ReactionsAnaphylactoid Reactions

Anaphylaxis refers to a systemic, Anaphylaxis refers to a systemic, immediate hypersensitivity reaction due immediate hypersensitivity reaction due to the IgE-mediated release of mediators to the IgE-mediated release of mediators from mast cells and basophils.from mast cells and basophils.

Anaphylactoid reactions refer to clinically Anaphylactoid reactions refer to clinically similar events as anaphylaxis but are similar events as anaphylaxis but are notnot mediated by IgE. They cause, via an mediated by IgE. They cause, via an unknown mechanism, the degranulation unknown mechanism, the degranulation of mast cells and/or basophils.of mast cells and/or basophils.

MultivalencyMultivalency

Generally, an antigen must be presented Generally, an antigen must be presented to the immune system in a multivalent to the immune system in a multivalent form to elicit a specific immune response.form to elicit a specific immune response.

Valency refers to the number of binding Valency refers to the number of binding sites available to bind antibody.sites available to bind antibody.

Multivalency is necessary to ensure cross-Multivalency is necessary to ensure cross-linking of receptors on the surface of cells, linking of receptors on the surface of cells, which then causes transduction of the which then causes transduction of the signal within the cell and the initiation of signal within the cell and the initiation of an immune response.an immune response.

Multivalency Multivalency

Drugs alone are poor stimulators of Drugs alone are poor stimulators of immune responses due to their simple immune responses due to their simple structure and low molecular weight.structure and low molecular weight.

Drugs can fulfill the requirement for Drugs can fulfill the requirement for multivalency and elicit an immune multivalency and elicit an immune response in two ways: (1) form hapten-response in two ways: (1) form hapten-carrier complexes and (2) be converted carrier complexes and (2) be converted into reactive intermediates.into reactive intermediates.

HaptenizationHaptenization

A hapten in this case A hapten in this case would be a particular would be a particular drug, which would be drug, which would be immunogenic in immunogenic in protein-conjugated protein-conjugated but not free form.but not free form.

An example would An example would be penicillins and be penicillins and other betalactams other betalactams that bind covalently that bind covalently to proteins.to proteins.

Conversion into reactive Conversion into reactive intermediatesintermediates

This may occur via drug metabolism This may occur via drug metabolism in the liver or elsewhere.in the liver or elsewhere.

This is the case with sulfonamides, This is the case with sulfonamides, which are acetylated and oxidated to which are acetylated and oxidated to yield the predominant N4-yield the predominant N4-sulfonamidoyl hapten.sulfonamidoyl hapten.

Factors that Increase the Risk of Allergic Factors that Increase the Risk of Allergic ReactionsReactions

Chronic diseases that require continuous or Chronic diseases that require continuous or frequent courses of therapy with the same or cross-frequent courses of therapy with the same or cross-reactive drugsreactive drugs

Some allergic reactions are more likely to occur Some allergic reactions are more likely to occur with certain infectionswith certain infections e.g. Aminopenicillins with EBV infection, e.g. Aminopenicillins with EBV infection, Sulfonamides with AIDS patientsSulfonamides with AIDS patients

Atopy, a genetically determined state of Atopy, a genetically determined state of hypersensitivity, manifested as asthma, hay fever, hypersensitivity, manifested as asthma, hay fever, and atopic dermatitisand atopic dermatitis

History of other drug allergyHistory of other drug allergy Family history of allergic drug reactionsFamily history of allergic drug reactions

Evaluation of Drug AllergyEvaluation of Drug Allergy

First, obtain a complete drug First, obtain a complete drug reaction history, atopic history, reaction history, atopic history, complete medication list, and complete medication list, and chronology of all symptoms and chronology of all symptoms and signs.signs.

Second, narrow the list of Second, narrow the list of medications suspected based on the medications suspected based on the temporal association between starts temporal association between starts and stops and changes in dose.and stops and changes in dose.

Evaluation of Drug AllergyEvaluation of Drug Allergy

Third, stop and/or substitute all drugs Third, stop and/or substitute all drugs with known allergic potential begun on with known allergic potential begun on the day of or several days prior to the the day of or several days prior to the reaction. If the suspected drug cannot be reaction. If the suspected drug cannot be substituted, skin testing can be used to substituted, skin testing can be used to assess IgE response. assess IgE response. Currently skin Currently skin testing is accepted to test only for testing is accepted to test only for penicillin allergy. penicillin allergy. Radioallergosorbent Radioallergosorbent testing can also be used to evaluate for testing can also be used to evaluate for drug allergy.drug allergy.

RAST TestingRAST Testing

In RAST testing, a given In RAST testing, a given allergen is bound to allergen is bound to polydextran bead. polydextran bead. Serum is then added and Serum is then added and antigen-specific IgE will antigen-specific IgE will bind to the immobilized bind to the immobilized antigen. Radiolabeled antigen. Radiolabeled anti IgE is then added. anti IgE is then added. The amount of bead-The amount of bead-bound radioactivity is bound radioactivity is proportional to the proportional to the concentration of antigen-concentration of antigen-specific IgE in the serum.specific IgE in the serum.

Disadvantages of RAST Disadvantages of RAST testingtesting

Skin testing is preferred since it Skin testing is preferred since it correlates better with clinical correlates better with clinical symptoms. A positive RAST test may symptoms. A positive RAST test may occur in asymptomatic individuals.occur in asymptomatic individuals.

ExpensiveExpensiveLimited range of antigens availableLimited range of antigens available

Evaluation of drug allergyEvaluation of drug allergy

Finally, in skin test negative patients, readminister Finally, in skin test negative patients, readminister the suspected drug if necessary with gradual the suspected drug if necessary with gradual escalation of the dose or desensitize. Another option, escalation of the dose or desensitize. Another option, of course, would be choose another drug.of course, would be choose another drug.

Rechallenge should generally begin at 1% of the Rechallenge should generally begin at 1% of the desired therapeutic dose and increased incrementally desired therapeutic dose and increased incrementally (3-fold) at intervals determined by the half life of the (3-fold) at intervals determined by the half life of the drug and the patient’s prior experiences with itdrug and the patient’s prior experiences with it

No rechallenge of drug should be done in patients No rechallenge of drug should be done in patients with Stevens-Johnson syndrome, toxic epidermal with Stevens-Johnson syndrome, toxic epidermal necrolysis, or with any mucous membrane necrolysis, or with any mucous membrane involvement.involvement.

Drug DesensitizationDrug Desensitization

Effective in the treatment of type I Effective in the treatment of type I allergic reactions and may be effective allergic reactions and may be effective for other reactions that are delayed in for other reactions that are delayed in onset but are not IgE-mediatedonset but are not IgE-mediated

Antigen-specific mast cell Antigen-specific mast cell desensitization appears to be desensitization appears to be responsible for the tolerant stateresponsible for the tolerant state

Specific mast cell desensitization is Specific mast cell desensitization is poorly understoodpoorly understood

Drug DesensitizationDrug Desensitization

Successful Successful antibiotic antibiotic desensitizationsdesensitizations

PenicillinsPenicillins SulfonamidesSulfonamides AminoglycosidesAminoglycosides ClindamycinClindamycin CephalosporinsCephalosporins VancomycinVancomycin PentamidinePentamidine Anti-tubercular agentsAnti-tubercular agents

Successful Successful desensitizations to desensitizations to other agentsother agents

Chemotherapeutics Chemotherapeutics AntivenomsAntivenoms

Heterologous seraHeterologous sera InsulinInsulin DeferoxamineDeferoxamine LHRHLHRH Measles vaccineMeasles vaccine HeparinHeparin Tetanus toxoidTetanus toxoid D-penicillamineD-penicillamine CorticotropinCorticotropin CarbamazepineCarbamazepine

DesensitizationDesensitizationThe starting dose for the drug can be The starting dose for the drug can be

determined by performing intradermal skin determined by performing intradermal skin tests with the native drug at a dose that does tests with the native drug at a dose that does not cause a non-specific irritant reaction.not cause a non-specific irritant reaction.

For example, if a 0.02 ml intradermal For example, if a 0.02 ml intradermal injection of a drug at 1 mg/ml concentration injection of a drug at 1 mg/ml concentration does not cause a local or systemic reaction, does not cause a local or systemic reaction, oral desensitization may be started at the oral desensitization may be started at the dose injected (i.e. the tolerated dose, 20 µg).dose injected (i.e. the tolerated dose, 20 µg).

DesensitizationDesensitization

Parenteral desensitization should be Parenteral desensitization should be using 1/10 or 1/100 of the dose that using 1/10 or 1/100 of the dose that was administered intradermally.was administered intradermally.

Desensitization is a REVERSIBLE Desensitization is a REVERSIBLE process that is dependent on the process that is dependent on the continued presence of the drug.continued presence of the drug.

It is also drug-dose dependent in that It is also drug-dose dependent in that a substantial dose increase may result a substantial dose increase may result in breakthrough allergic symptoms.in breakthrough allergic symptoms.

DesensitizationDesensitization-example-example

Sullivan et alSullivan et al4848

30 patients with histories of allergic reactions to PCN, 30 patients with histories of allergic reactions to PCN, positive skin tests, and life threatening infections positive skin tests, and life threatening infections (bacterial endocarditis, (bacterial endocarditis, PseudomonasPseudomonas sepsis or sepsis or pneumonia) were desensitized. Skin test reactions pneumonia) were desensitized. Skin test reactions disappeared or diminished in all 23 subjects who were disappeared or diminished in all 23 subjects who were retested after desensitization. Full courses of antibiotic retested after desensitization. Full courses of antibiotic therapy and cure of the infections were accomplished therapy and cure of the infections were accomplished in 30 of 30 patients.No deaths, anaphylaxis, or severe in 30 of 30 patients.No deaths, anaphylaxis, or severe acute allergic reactions occurred. Pruritic cutaneous acute allergic reactions occurred. Pruritic cutaneous eruptions appeared in 9 patients (30%) 6 to 48 hrs eruptions appeared in 9 patients (30%) 6 to 48 hrs after the onset of therapy. One patient developed after the onset of therapy. One patient developed reversible nephritis 3 weeks into therapy with PCN G.reversible nephritis 3 weeks into therapy with PCN G.

PenicillinsPenicillins

The reported history of penicillin The reported history of penicillin allergy ranges from 0.7% to 10%.allergy ranges from 0.7% to 10%.

There are four classes of betalactam There are four classes of betalactam antibiotics: penicillins, cephalosporins, antibiotics: penicillins, cephalosporins, carbapenems, and monobactams.carbapenems, and monobactams.

The first three all have bicyclic nuclei The first three all have bicyclic nuclei in contrast to monobactams in contrast to monobactams (aztreonam), which lacks a second ring (aztreonam), which lacks a second ring adjacent to the betalactam nucleus.adjacent to the betalactam nucleus.

Major and minor Major and minor determinantsdeterminants The betalactam ring The betalactam ring

is unstable and is unstable and readily acylates readily acylates lysine residues in lysine residues in proteins. The proteins. The penicilloyl epitope is penicilloyl epitope is produced, which is produced, which is called the “major called the “major determinant” since determinant” since over 75% of all IgE over 75% of all IgE mediated reactions mediated reactions are directed against are directed against this epitope.this epitope.

Minor DeterminantsMinor Determinants

Beta lactams can also haptenize Beta lactams can also haptenize covalently through carboxyl and thiol covalently through carboxyl and thiol groups, which results in a variety of groups, which results in a variety of less dominant or “minor” determinants.less dominant or “minor” determinants.

Minor determinant IgE responses have Minor determinant IgE responses have been associated with anaphylaxis, been associated with anaphylaxis, while penicilloyl IgE responses are while penicilloyl IgE responses are usually associated with urticarial usually associated with urticarial reactions.reactions.

Signs and symptoms Signs and symptoms

Allergic symptoms Allergic symptoms commonly include:commonly include:

an erythematous, an erythematous, maculopapular and maculopapular and usually pruritic usually pruritic rashrash

urticariaurticaria

Less common Less common symptoms include symptoms include angioedema, angioedema, serum sickness, serum sickness, arthralgias, arthralgias, bronchospasm, bronchospasm, laryngeal edema, laryngeal edema, and anaphylaxisand anaphylaxis

Signs and SymptomsSigns and SymptomsAn example of a delayed reaction would be An example of a delayed reaction would be

maculopapular or morbilliform rashes maculopapular or morbilliform rashes associated with treatment with associated with treatment with aminopenicillins, particularly ampicillin.aminopenicillins, particularly ampicillin.

The incidence of rash associated with The incidence of rash associated with ampicillin has been estimated at 9.5%.ampicillin has been estimated at 9.5%.

Since the rash typically appears 2-3 days or Since the rash typically appears 2-3 days or more after drug administration, it is more after drug administration, it is thought to represent type IV (delayed) thought to represent type IV (delayed) hypersensitivity.hypersensitivity.

Allergic Reactions to PenicillinsAllergic Reactions to Penicillins

• Allergization often occult (food containing pen. or the pen. mould itself)• Anti-pen abs are detectable in almost everyone• Patients reports of previous ‘allergy’ are frequently inaccurate• A class problem manifesting as -

Rash (MP > urticarial)FeverBronchospasmVasculitisSerum sickness/Stevens-JohnsonAnaphylaxis

• Rashes most frequent with ampicillin (10%); essentially 100% in IM infection.• Rashes more likely if allopurinol co-administered• Cross-sensitisation with cephalosporins now thought to be <1% and reactions usually mild• If pen drug-of-choice consider either ‘controlled’ challenge or desensitisation

* VERY uncommon <1/10,000 prescriptions; 2/3 have previously received it and of these only 1/3 report previous reaction.

Frequency

Skin testingSkin testing

More than 80% of history-positive More than 80% of history-positive patients will have negative skin tests.patients will have negative skin tests.

Allergic reactions observed in the Allergic reactions observed in the retreatment of history-positive, skin retreatment of history-positive, skin test-negative patients have virtually test-negative patients have virtually all been mild and self-limited; no life-all been mild and self-limited; no life-threatening false-negative reactions threatening false-negative reactions have been reported.have been reported.

Sogn et alSogn et al

A prospective study using patients with A prospective study using patients with infectious diseases for which penicillin or infectious diseases for which penicillin or related compounds was the drug of choice. related compounds was the drug of choice. Patients were skin tested with major and minor Patients were skin tested with major and minor determinant antigens. determinant antigens. Only if skin tests were Only if skin tests were negativenegative, patients were given penicillin or a , patients were given penicillin or a semisynthetic penicillin. 9 skin test semisynthetic penicillin. 9 skin test positivepositive patients were patients were accidentallyaccidentally given penicillin and given penicillin and 2 had allergic reactions. The allergic reactions 2 had allergic reactions. The allergic reactions noted in the table that follows were urticaria, noted in the table that follows were urticaria, generalized erythema, and pruritis.generalized erythema, and pruritis.

Sogn et alSogn et al

Skin test positive

Skin test negative

Allergic reactions

Patients with a history of penicillin allergy

139 566 7/566 (1.2%)

Patients without a history of penicillin allergy

25 568 0/568 (0.0%)

Skin testingSkin testing

Up to 67% of patients with positive Up to 67% of patients with positive skin tests have experienced clinical skin tests have experienced clinical allergic reactions when given allergic reactions when given therapeutic doses of penicillin.therapeutic doses of penicillin.

For patients with a history of rash For patients with a history of rash with the aminopenicillins, skin testing with the aminopenicillins, skin testing with extended observation for late with extended observation for late reactions and also patch testing is reactions and also patch testing is recommended.recommended.

Skin TestingSkin Testing

Since recurrent rather than Since recurrent rather than continuous therapy can resensitize continuous therapy can resensitize patients to penicillin, skin tests patients to penicillin, skin tests should be repeated before should be repeated before subsequent courses of therapy.subsequent courses of therapy.

CephalosporinsCephalosporins

It has been reported that there is an It has been reported that there is an 8.1% incidence of allergic reactions 8.1% incidence of allergic reactions to various cephalosporins in patients to various cephalosporins in patients with histories of penicillin allergy with histories of penicillin allergy compared to a reaction rate of 1.9% compared to a reaction rate of 1.9% in patients without such histories.in patients without such histories.

CephalosporinsCephalosporins

The overall incidence of cephalosporin The overall incidence of cephalosporin allergy in the general population is allergy in the general population is about 4%, so the 8% incidence of about 4%, so the 8% incidence of reactions in the PCN-allergic group is reactions in the PCN-allergic group is only a 2-fold increase.only a 2-fold increase.

When PCN-allergic patients receive When PCN-allergic patients receive ANYANY drug, the incidence of adverse drug drug, the incidence of adverse drug reactions is 3 times higher compared to reactions is 3 times higher compared to those with no history of PCN allergy.those with no history of PCN allergy.

Skin testing with Skin testing with CephalosporinsCephalosporins

Currently there are no reliable Currently there are no reliable cephalosporin allergens available for cephalosporin allergens available for skin testing.skin testing.

Allergic reactions to cephalosporins Allergic reactions to cephalosporins do not appear to correlate with do not appear to correlate with positive penicillin test reactions.positive penicillin test reactions.

Summary of Studies of Cephalosporin to Patients with Summary of Studies of Cephalosporin to Patients with Histories of Penicillin Allergy and Penicillin Skin Test Histories of Penicillin Allergy and Penicillin Skin Test

EvaluationsEvaluations

Sulfa DrugsSulfa Drugs

Co-trimazole, or sulfamethoxazole-Co-trimazole, or sulfamethoxazole-trimethoprim, is used extensively in the trimethoprim, is used extensively in the HIV population as prophylaxis against HIV population as prophylaxis against Pneumocystis cariniiPneumocystis carinii pneumonia. pneumonia.

It is estimated that the overall It is estimated that the overall prevalence of sulfa hypersensitivity in prevalence of sulfa hypersensitivity in the general population is approximately the general population is approximately 3.3%, while in the HIV population it is in 3.3%, while in the HIV population it is in the range of 17-20%.the range of 17-20%.

Sulfa DrugsSulfa Drugs

Up to 80% of these reactions has Up to 80% of these reactions has been reported in HIV-positive been reported in HIV-positive patients compared to less than 5% in patients compared to less than 5% in HIV-negative patients.HIV-negative patients.

The incidence of adverse events to The incidence of adverse events to cotrimazole is greater than 50% in cotrimazole is greater than 50% in patients receiving the medication for patients receiving the medication for treatment for active PCP.treatment for active PCP.

Sulfa Drugs and HIVSulfa Drugs and HIV

A recent retrospective case-control A recent retrospective case-control study found an association between study found an association between the number of opportunistic the number of opportunistic infections and the occurrence of infections and the occurrence of TMP/SMX hypersensitivity reactionsTMP/SMX hypersensitivity reactions

Hennessy et al, however, found no Hennessy et al, however, found no correlation between low CD4 counts correlation between low CD4 counts and an increased risk of and an increased risk of hypersensitivity reactions to sulfahypersensitivity reactions to sulfa

Hennessy et alHennessy et al

A retrospective A retrospective cohort study cohort study involving patients in involving patients in an outpatient HIV an outpatient HIV clinic and clinic and university-affiliated university-affiliated IM and ID practices IM and ID practices receiving receiving cotrimazole for cotrimazole for primary primary prophylaxis.prophylaxis.

The outcome The outcome measured was the measured was the occurrence of a occurrence of a cutaneous cutaneous hypersensitivity hypersensitivity reaction (rash, reaction (rash, fever, or pruritis) fever, or pruritis) per chart review per chart review that resulted in that resulted in discontinuation of discontinuation of cotrimazole.cotrimazole.

Signs and SymptomsSigns and Symptoms

The most common adverse reactions to The most common adverse reactions to sulfa drugs in AIDS patients include rash, sulfa drugs in AIDS patients include rash, nausea and vomiting.nausea and vomiting.

The rash is usually a generalized The rash is usually a generalized exanthema, which may or may not be exanthema, which may or may not be pruritic and often is accompanied by fever.pruritic and often is accompanied by fever.

The majority of patients can be treated with The majority of patients can be treated with antihistamines and the rash in over 65% of antihistamines and the rash in over 65% of cases will resolve without further sequelae cases will resolve without further sequelae despite continuation of cotrimazole.despite continuation of cotrimazole.

History of Rash and History of Rash and RechallengeRechallenge

A history of rash is not necessarily a A history of rash is not necessarily a contraindication to retreatment as less than contraindication to retreatment as less than 20% may have a recurrence on rechallenge.20% may have a recurrence on rechallenge.

Shafer et alShafer et al 34 homosexual men given IV cotrimazole for PCP 34 homosexual men given IV cotrimazole for PCP

with development of hypersensitivity reactions in with development of hypersensitivity reactions in 21 of these patients (erythematous macular or 21 of these patients (erythematous macular or maculopapular rashes, fever). All 31 survivors were maculopapular rashes, fever). All 31 survivors were started on oral cotrimazole for PCP prophylaxis but started on oral cotrimazole for PCP prophylaxis but only 4 developed reactions which necessitated only 4 developed reactions which necessitated discontinuation of the drug (desquamative rash, discontinuation of the drug (desquamative rash, fever, etc..)fever, etc..)

Sulfonamide Hypersensitivity Sulfonamide Hypersensitivity ReactionReaction

Multiorgan, systemic disease Multiorgan, systemic disease characterized by fever, skin rash, characterized by fever, skin rash, and toxicity in one or more internal and toxicity in one or more internal organs starting 7 to 14 days after organs starting 7 to 14 days after initiation of therapy.initiation of therapy.Incidence of life-threatening reactions is Incidence of life-threatening reactions is

less than 1/1000less than 1/1000skin reactions occur in 1.5 - 3% given skin reactions occur in 1.5 - 3% given

sulfa drugssulfa drugs

Sulfonamide Hypersensitivity Sulfonamide Hypersensitivity ReactionReaction

Maculopapular eruptions and urticarial Maculopapular eruptions and urticarial rash occur most frequently within the first rash occur most frequently within the first 1-3 days after administration, are usually 1-3 days after administration, are usually not accompanied by fever, and resolve not accompanied by fever, and resolve spontaneously on withdrawal.spontaneously on withdrawal.

Other disease states associated with the Other disease states associated with the hypersensitivity reaction include: hypersensitivity reaction include: hepatotoxicity, eosinophilic pneumonitis, hepatotoxicity, eosinophilic pneumonitis, aseptic meningitis, AIN, serum sickness,aseptic meningitis, AIN, serum sickness, polyarthritis, and blood dyscrasias.polyarthritis, and blood dyscrasias.

Stevens Johnson syndrome with Stevens Johnson syndrome with sulfa drugssulfa drugs

Non-urticarial drug Non-urticarial drug eruptions (Stevens-eruptions (Stevens-Johnson syndrome) Johnson syndrome) typically occur 7-14 typically occur 7-14 days after initiation of days after initiation of treatmenttreatment

Incidence is between Incidence is between 1/1000 and 1/30001/1000 and 1/3000

Any patients with either Any patients with either disease should be disease should be removed from the drug removed from the drug and rechallenge avoidedand rechallenge avoided

MechanismMechanism

The mechanism of hypersensitivity to The mechanism of hypersensitivity to cotrimazole is poorly understood. Several cotrimazole is poorly understood. Several hypotheses have been put forward to explain hypotheses have been put forward to explain the predominance of reactions in HIV patients:the predominance of reactions in HIV patients:(1) slow acetylation in HIV patients(1) slow acetylation in HIV patients(2) polypharmacy with drugs such as INH (2) polypharmacy with drugs such as INH

and rifampin that compete for metabolism and rifampin that compete for metabolism in the liverin the liver

(3) reduced availability of cellular (3) reduced availability of cellular glutathioneglutathione

Sulfa Drug MetabolismSulfa Drug Metabolism

Sulfa drugs are metabolized in the liver Sulfa drugs are metabolized in the liver by two pathways: oxidative metabolism by two pathways: oxidative metabolism by the cytochrome p450 system and by the cytochrome p450 system and acetylation by N-acetyltransferase.acetylation by N-acetyltransferase.

Sulfa drug MetabolismSulfa drug Metabolism

Sulfamethoxazole is predominantly Sulfamethoxazole is predominantly cleared by acetylation and excreted by cleared by acetylation and excreted by active tubular excretion. The alternative active tubular excretion. The alternative pathway yields a reactive metabolite, pathway yields a reactive metabolite, sulfamethoxazole hydroxylamine, which sulfamethoxazole hydroxylamine, which can generate an immune response.can generate an immune response.Generally, slow acetylators develop more Generally, slow acetylators develop more

adverse reactions, whereas rapid adverse reactions, whereas rapid acetylators are more prone to show an acetylators are more prone to show an inadequate response to a standard dose.inadequate response to a standard dose.

Slow acetylationSlow acetylation

The ratio of rapid versus slow The ratio of rapid versus slow acetylators varies widely among acetylators varies widely among ethnic groups throughout the world.ethnic groups throughout the world.For example, approximately 50% of For example, approximately 50% of

Caucasians and African-Americans are Caucasians and African-Americans are “slow” acetylators while this is rare “slow” acetylators while this is rare among Asians.among Asians.

Slow Acetylation in AIDS patientsSlow Acetylation in AIDS patients

Lee et al investigated the prevalence of Lee et al investigated the prevalence of slow acetylation in AIDS patientsslow acetylation in AIDS patientsGroup Prevalence of Slow

Acetylation AIDS-ill 27/29 (93%)

AIDS-stable 19/29 (66%)

HIV positive 10/18 (56%)

Control (HIV negative) 18/29 (62%)

Slow acetylation in AIDS patientsSlow acetylation in AIDS patients

The cause of the increased prevalence of The cause of the increased prevalence of slow acetylation in acutely ill AIDS slow acetylation in acutely ill AIDS patients is not known.patients is not known.

Due to slow acetylation, more of the drug Due to slow acetylation, more of the drug is shunted to alternative oxidative is shunted to alternative oxidative pathways.pathways.These pathways form toxic metabolites which These pathways form toxic metabolites which

are normally detoxified by scavengers, such are normally detoxified by scavengers, such as glutathione. A few studies have reported as glutathione. A few studies have reported decreased levels of GSH in HIV patients but decreased levels of GSH in HIV patients but this has not been confirmed in other studies.this has not been confirmed in other studies.

Slow acetylation in AIDS patientsSlow acetylation in AIDS patients

The accumulated metabolites can The accumulated metabolites can then cause cellular injury which may then cause cellular injury which may be expressed clinically as an adverse be expressed clinically as an adverse reaction.reaction.

Skin TestingSkin Testing

Some investigators have reported Some investigators have reported positive skin tests in approximately positive skin tests in approximately 25% of patients with immediate 25% of patients with immediate hypersensitivity reactions to SMX, hypersensitivity reactions to SMX, but others have not found it useful in but others have not found it useful in predicting the recurrence of SMX predicting the recurrence of SMX related adverse events.related adverse events.

Currently, skin testing cannot be Currently, skin testing cannot be recommended.recommended.


The earlier reports of desensitization The earlier reports of desensitization to sulfonamides had limited success to sulfonamides had limited success rates, ranging from 45 to 82%. rates, ranging from 45 to 82%.

The success rates of desensitization The success rates of desensitization have improved significantly over the have improved significantly over the years.years.


Kalanadhabhatta et alKalanadhabhatta et al3939

A prospective study with 13 patients with AIDS A prospective study with 13 patients with AIDS (CD4<200) with PCP and allergy to sulfonamides (CD4<200) with PCP and allergy to sulfonamides who failed alternative therapy (dapsone, who failed alternative therapy (dapsone, pentamidine). The allergic reactions noted were a pentamidine). The allergic reactions noted were a generalized, pruritic maculopapular rash, generalized, pruritic maculopapular rash, urticaria, angioedema, and pruritis. All patients urticaria, angioedema, and pruritis. All patients had tolerated oral desensitization to cotrimazole had tolerated oral desensitization to cotrimazole without any adverse reaction including three without any adverse reaction including three patients who were critically ill and on mechanical patients who were critically ill and on mechanical ventilation. Total follow up ranged from 4 to 84 ventilation. Total follow up ranged from 4 to 84 weeks.weeks.

NSAIDSNSAIDS

In 1922, the association of ASA sensitivity, In 1922, the association of ASA sensitivity, asthma, and nasal polyposis was asthma, and nasal polyposis was described by Widal et al and was described by Widal et al and was subsequently coined as the “aspirin triad.”subsequently coined as the “aspirin triad.”

Aspirin-induced asthma (AIA) affects 10% Aspirin-induced asthma (AIA) affects 10% of adults with asthma.of adults with asthma.After ingestion of ASA or an NSAID, an acute After ingestion of ASA or an NSAID, an acute

asthma attack occurs within 3 hrs, usually asthma attack occurs within 3 hrs, usually accompanied by profuse rhinorrhea, accompanied by profuse rhinorrhea, conjunctival injection, and periorbital edema.conjunctival injection, and periorbital edema.

NSAID Intolerance (NI)NSAID Intolerance (NI)

NI prevalence in asthma NI prevalence in asthma andand nasal nasal polyposis or rhinosinusitis is 30-40%.polyposis or rhinosinusitis is 30-40%.

In chronic urticaria, the prevalence of In chronic urticaria, the prevalence of NSAID intolerance is 20-30%.NSAID intolerance is 20-30%.

MechanismsMechanisms

The search for an underlying antigen The search for an underlying antigen - antibody mechanism has not been - antibody mechanism has not been successful.successful.

Skin tests with ASA-lysine have been Skin tests with ASA-lysine have been negative, and numerous attempts to negative, and numerous attempts to demonstrate specific antibodies demonstrate specific antibodies against ASA or its derivatives have against ASA or its derivatives have been unsuccessful.been unsuccessful.


In patients with AIA, asthmatic attacks In patients with AIA, asthmatic attacks can be caused by ASA can be caused by ASA andand other NSAIDS. other NSAIDS. After desensitization, cross After desensitization, cross desensitization to other NSAIDS that desensitization to other NSAIDS that inhibit cyclooxygenase (COX) also occurs.inhibit cyclooxygenase (COX) also occurs.Szczeklik et al reported in 1975 that drug Szczeklik et al reported in 1975 that drug

cross-reactivity could be predicted on the cross-reactivity could be predicted on the basis of each NSAID’s in vitro inhibition of basis of each NSAID’s in vitro inhibition of COX. This has been consistently reaffirmed COX. This has been consistently reaffirmed over the years.over the years.


During inflammatory During inflammatory respiratory disease, respiratory disease, leukotrienes, leukotrienes, histamine, and histamine, and eosinophilic cationic eosinophilic cationic protein are formed protein are formed and released with and released with subsequent increase in subsequent increase in vascular permeability, vascular permeability, mucus secretion, and mucus secretion, and bronchial bronchial hyperreactivity.hyperreactivity.


Three hypothesis have been Three hypothesis have been proposed to explain AIA:proposed to explain AIA:(1) cyclooxygenase inhibition(1) cyclooxygenase inhibition(2) overproduction of leukotrienes(2) overproduction of leukotrienes(3) chronic inflammation of the airways(3) chronic inflammation of the airways

COX InhibitionCOX Inhibition

5-lipoxygenase and COX catalyze the 5-lipoxygenase and COX catalyze the production of leukotrienes and production of leukotrienes and prostaglandins, respectively.prostaglandins, respectively.

Prostaglandin E2 has several Prostaglandin E2 has several immunoregulatory effects, including immunoregulatory effects, including inhibition of 5-lipoxygenase and inhibition of 5-lipoxygenase and preventing the release of mediators preventing the release of mediators from mast cells.from mast cells.

COX InhibitionCOX Inhibition

When ASA is given, COX-1 and COX-2 are When ASA is given, COX-1 and COX-2 are disabled, PGE2 synthesis stops and its modulating disabled, PGE2 synthesis stops and its modulating effects on mast cells and 5-LO are removed, and effects on mast cells and 5-LO are removed, and mediators are released or synthesized.mediators are released or synthesized.

Leukotrienes are continuously and aggressively Leukotrienes are continuously and aggressively synthesized in patients with AIA before any synthesized in patients with AIA before any exposure to NSAIDS/ASA, and during ASA-induced exposure to NSAIDS/ASA, and during ASA-induced reactions, marked acceleration of synthesis reactions, marked acceleration of synthesis occurs.occurs.

It is not known why interruption of PGE2 synthesis It is not known why interruption of PGE2 synthesis does not induce respiratory reactions in all does not induce respiratory reactions in all humanshumans..

Chronic inflammation of the Chronic inflammation of the airwaysairways

Eosinophil infiltration of the airways Eosinophil infiltration of the airways appears to be a central feature of appears to be a central feature of AIA. AIA.

The large numbers of eosinophils, The large numbers of eosinophils, loaded with leukotriene enzymes, loaded with leukotriene enzymes, may be responsible for the may be responsible for the overproduction of leukotrienes.overproduction of leukotrienes.

Delayed reactions to NSAIDSDelayed reactions to NSAIDS

Appear to have an immunologic basis Appear to have an immunologic basis since they recur on re-exposure with since they recur on re-exposure with a shorter latency after re-exposure. a shorter latency after re-exposure.

Signs and SymptomsSigns and Symptoms

Urticaria, angioedema, rhinoconjunctivitis, Urticaria, angioedema, rhinoconjunctivitis, bronchial asthma, and occasionally bronchial asthma, and occasionally anaphylactoid reactions.anaphylactoid reactions.

Stevens Johnson syndrome have been Stevens Johnson syndrome have been associated with NSAIDS in 14% and 19% of associated with NSAIDS in 14% and 19% of cases, respectively.cases, respectively.

The most frequent delayed cutaneous The most frequent delayed cutaneous reaction is a morbilliform exanthem, which reaction is a morbilliform exanthem, which usually occurs 1 week after therapy is usually occurs 1 week after therapy is begun and can last 2 weeks.begun and can last 2 weeks.

TestingTesting

Numerous attempts to demonstrate specific Numerous attempts to demonstrate specific antibodies against ASA or its derivatives antibodies against ASA or its derivatives have been unsuccessful. Skin test responses have been unsuccessful. Skin test responses with ASA-lysine have been negative.with ASA-lysine have been negative.

Currently, the only way to test for NSAID Currently, the only way to test for NSAID intolerance is with provocation tests.intolerance is with provocation tests.There are three types of provocation tests: oral There are three types of provocation tests: oral

(most common), inhaled, and nasal.(most common), inhaled, and nasal.Only oral ASA challenges are available in the US.Only oral ASA challenges are available in the US.

Oral ASA ChallengeOral ASA Challenge

Patients with a history of severe or very rapid ASA Patients with a history of severe or very rapid ASA or NSAID-induced reactions may be started with a or NSAID-induced reactions may be started with a dose lower than 30 mg.dose lower than 30 mg.

As soon as signs and symptoms of reactions occur As soon as signs and symptoms of reactions occur (20% decrease in FEV1, rhinorrhea, ocular (20% decrease in FEV1, rhinorrhea, ocular injection, periorbital edema, stridor, and rarely injection, periorbital edema, stridor, and rarely flushing, urticaria, cramps, or explosive diarrhea), flushing, urticaria, cramps, or explosive diarrhea), the ASA challenge is stopped.the ASA challenge is stopped.

Oral challenges to detect anaphylaxis should not Oral challenges to detect anaphylaxis should not be done; history of anaphylaxis should be relied be done; history of anaphylaxis should be relied upon instead.upon instead.

Prevention and TreatmentPrevention and Treatment Patients should avoid ASA and other Patients should avoid ASA and other

analgesics that inhibit COX.analgesics that inhibit COX. NSAIDS that cross react with ASA in NSAIDS that cross react with ASA in

respiratory and cutaneous reactions:respiratory and cutaneous reactions: piroxicampiroxicam mefenamic acidmefenamic acid flurbiprofenflurbiprofen ketoprofenketoprofen meclofenematemeclofenemate diclofenacdiclofenac ketorolacketorolac etodolacetodolac nabutemonenabutemone indomethacinindomethacin oxaprozinoxaprozin sulindacsulindac tolmetintolmetin zomepiraczomepirac ibuprofenibuprofen naproxennaproxen naproxen sodiumnaproxen sodium fenoprofenfenoprofen diflunisaldiflunisal

Prevention and TreatmentPrevention and Treatment

Acetaminophen is usually safe for Acetaminophen is usually safe for these patients to take. However, high these patients to take. However, high dose acetaminophen (1000 mg dose acetaminophen (1000 mg followed by 1500 mg) has been followed by 1500 mg) has been shown to have a cross-reaction shown to have a cross-reaction prevalence of 34%.prevalence of 34%.Animal models have demonstrated that Animal models have demonstrated that

acetaminophen may have COX acetaminophen may have COX inhibitory activity.inhibitory activity.

Prevention and TreatmentPrevention and Treatment

Patients can also take the following Patients can also take the following drugs, which are all without anti-drugs, which are all without anti-COX activity or are weak anti-COX COX activity or are weak anti-COX 2 inhibitors:2 inhibitors:sodium salicylate, salicylamide, sodium salicylate, salicylamide,

choline magnesium trisalicylate, choline magnesium trisalicylate, benzydamine, chloroquine, benzydamine, chloroquine, azapropazone, and azapropazone, and dextropropoxyphenedextropropoxyphene

COX-2 InhibitorsCOX-2 Inhibitors

Selective inhibitors of COX-2, in Selective inhibitors of COX-2, in theory, should be safe in patients theory, should be safe in patients with AIA due to continued synthesis with AIA due to continued synthesis of the protective prostanoid, PGE2, of the protective prostanoid, PGE2, by COX-1.by COX-1.

However, COX-2 inhibitors have not However, COX-2 inhibitors have not yet been studied in patients with AIA yet been studied in patients with AIA and are currently contraindicated.and are currently contraindicated.


NSAID allergic patients can also be NSAID allergic patients can also be desensitized. desensitized.

Small incremental doses of ASA are taken over Small incremental doses of ASA are taken over 2 to 3 days until 400 to 650 mg of ASA is 2 to 3 days until 400 to 650 mg of ASA is tolerated. ASA should then be given daily, with tolerated. ASA should then be given daily, with doses ranging from 80 to 325 mg to maintain doses ranging from 80 to 325 mg to maintain desensitization.desensitization.

After each dose of ASA, there is a refractory After each dose of ASA, there is a refractory period of 2 to 5 days, during which ASA and period of 2 to 5 days, during which ASA and other COX inhibitors can be given without any other COX inhibitors can be given without any risk of an allergic reaction.risk of an allergic reaction.

DesensitizationDesensitizationThe patient most likely to benefit from The patient most likely to benefit from

desensitization is one with AIA who has desensitization is one with AIA who has just had sinus/polyp surgery.just had sinus/polyp surgery.ASA desensitization has been shown to delay ASA desensitization has been shown to delay

recurrence of nasal polyp formation by an recurrence of nasal polyp formation by an average of 6 years.average of 6 years.

The mechanism behind desensitization is The mechanism behind desensitization is poorly understood but may be associated poorly understood but may be associated with downregulation of leukotriene with downregulation of leukotriene receptors.receptors.

Stevenson et alStevenson et al Between 1988 and 1994, 78 patients with asthma and Between 1988 and 1994, 78 patients with asthma and

documented ASA sensitivity per oral challenge documented ASA sensitivity per oral challenge (decrease of 20% or more in FEV1 and/or naso-ocular (decrease of 20% or more in FEV1 and/or naso-ocular reactions within 3 hours of incremental oral reactions within 3 hours of incremental oral challenges) were enrolled in a prospective study challenges) were enrolled in a prospective study investigating ASA desensitization. 10 patients investigating ASA desensitization. 10 patients discontinued ASA desensitization treatment due to discontinued ASA desensitization treatment due to gastritis. 3 patients were lost to follow up. After gastritis. 3 patients were lost to follow up. After desensitization, all patients began a treatment desensitization, all patients began a treatment program of 650 mg of ASA twice daily, which was program of 650 mg of ASA twice daily, which was continued from 1 to 6 years (mean 3.1 years). Data continued from 1 to 6 years (mean 3.1 years). Data was compared for 65 patients from the year prior to was compared for 65 patients from the year prior to ASA desensitization and one year before re-evaluation ASA desensitization and one year before re-evaluation (January to March 1995)(January to March 1995)

ConclusionConclusion

Patients with a history of penicillin allergy Patients with a history of penicillin allergy should be skin tested. More than 80% of should be skin tested. More than 80% of patients with a history of penicillin allergy patients with a history of penicillin allergy will have negative skin tests. will have negative skin tests.

Allergic reactions observed in the re-Allergic reactions observed in the re-treatment of history-positive, skin-test treatment of history-positive, skin-test negative patients have virtually all been negative patients have virtually all been mild and self-limited; no life threatening mild and self-limited; no life threatening false-negative reactions have been false-negative reactions have been reported.reported.

ConclusionConclusion

Up to 67% of patients with positive skin Up to 67% of patients with positive skin tests have had allergic reactions when tests have had allergic reactions when given therapeutic doses of penicillin. There given therapeutic doses of penicillin. There are no skin tests available to evaluate for are no skin tests available to evaluate for cephalosporins. Positive penicillin skin cephalosporins. Positive penicillin skin tests do not predict allergic reactions to tests do not predict allergic reactions to cephalosporins. If no other alternatives are cephalosporins. If no other alternatives are available, cephalosporins can be available, cephalosporins can be administered cautiously to patients with a administered cautiously to patients with a history of penicillin allergy.history of penicillin allergy.

ConclusionConclusionThere is an increased frequency of There is an increased frequency of

adverse reactions to sulfa drugs in HIV adverse reactions to sulfa drugs in HIV patients; the reason for which is not known patients; the reason for which is not known at this time. A history of rash is not at this time. A history of rash is not necessarily a contraindication to necessarily a contraindication to retreatment since less than 20% may have retreatment since less than 20% may have a recurrence on rechallenge. Skin testing a recurrence on rechallenge. Skin testing cannot be recommended to evaluate sulfa cannot be recommended to evaluate sulfa allergy. Desensitization to sulfa drugs has allergy. Desensitization to sulfa drugs has had variable success.had variable success.

ConclusionConclusion NSAID intolerance prevalence in asthma and NSAID intolerance prevalence in asthma and

nasal polyposis or rhinosinusitis is 30-40%. nasal polyposis or rhinosinusitis is 30-40%. Aspirin-induced asthma affects 10% of adults Aspirin-induced asthma affects 10% of adults with asthma. The only way to test for NSAID with asthma. The only way to test for NSAID intolerance in the US is with an oral provocation intolerance in the US is with an oral provocation test. High dose acetaminophen has been shown test. High dose acetaminophen has been shown to have a cross-reaction prevalence of 34%. After to have a cross-reaction prevalence of 34%. After ASA desensitization, cross desensitization to ASA desensitization, cross desensitization to other NSAIDS than inhibit cyclooxygenase also other NSAIDS than inhibit cyclooxygenase also occurs. The patient most likely to benefit from occurs. The patient most likely to benefit from desensitization is one with AIA who has just had desensitization is one with AIA who has just had sinus/polyp surgery.sinus/polyp surgery.

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