Allergic and Allergic-Like Reactions to Drugs and Other Therapeutic Agents
Drug reactions can be produced by a number of different mechanisms, including true allergic, immunoglobulin E-mediated events, events due to other immunological reactions, intolerance, idiosyncrasies, overdoses, and a particular sensitivity to well-recognized side effects of a drug. Predictable reactions include, for example, an overdose, and unpredictable reactions include allergic reactions and idiosyncratic responses. Probably the most common class of drugs to produce reactions is antibiotics, and β-lactams are possibly the most frequent offenders in this regard. An immunological reaction such as those resulting from β-lactams diagnosis can be assisted by allergy testing, but in nonimmunological events such testing is not helpful. When a drug or diagnostic agent to which a patient has previously experienced a reaction is required, measures such as desensitization and pretreatment can be used according to the nature of the previous reaction and the drug or diagnostic agent in question.
Table Definition of Terms Used to Describe Adverse Reactions to Drugs and Therapeutics
| Drug allergy: drug reactions resulting from an immunological mechanism |
| Drug intolerance: adverse reaction to drugs resulting from nonimmunological or unknown mechanisms |
| Drug overdose: toxic reaction owing to excess drug dose or impaired excretion |
| Side effect to a drug: unavoidable secondary pharmacological action of a drug |
| Drug interactions: actions of two or more drugs on the toxicity or effects of each individual agent |
| Idiosyncratic drug reaction: a measurable, abnormal response to a drug that differs from its pharmaceutical effect |
| Other terms used to describe allergic/intolerant reactions |
| Allergic-like or pseudo-allergic reactions to drugs: drug reactions that clinically resemble those of drug allergy; the mechanism usually involves clinical mediators or activators, enzyme inhibition, or may be unknown |
| Anaphylaxis and anaphylactoid reactions to drugs: generalized drug reactions owing to chemical mediator release/activation either involving immunoglobulin E (anaphylaxis) or direct action of the drug on the mast cell (anaphylactoid) |
Definitions
Drug allergy is a common term often used to depict any unexpected and unwanted event or effect that occurs when an individual is taking a specific drug or therapeutic agent. A better, overall term to describe these circumstances would be an adverse reaction to a drug (Table Definition of Terms Used to Describe Adverse Reactions to Drugs and Therapeutics).
These reactions can be further classified into either drug allergy (reactions resulting from an immunological mechanism) or drug intolerance (reactions resulting from nonimmunological or unknown mechanisms). Some reactions closely resemble allergic reactions and are termed allergic-like or pseudo-allergic. This includes anaphylactoid reactions that clinically resemble anaphylaxis, since in both situations chemical mediator release or activation is responsible for these symptoms. Some idiosyncratic reactions to drugs can be confused with drug allergy.
Classifications
Because of the different mechanisms involved in adverse reactions, it is impossible to classify all reactions to drugs and therapeutic agents under one heading. Table 2 classifies adverse reactions to these agents under four categories: generalized, immunological, organ specific, and allergic-like reactions. A specific drug reaction may be classified under more than one category.
In addition to the different definitions and classifications involving adverse reactions to drug, some experts, have simply referred to these events under two categories: predictable reactions (including drug overdose, side effects and interactions) or unpredictable reactions (including drug intolerance, idiosyncratic reactions, and allergic-like/ pseudoallergic reactions. Important in this general division is that unpredictable adverse drug reactions (those that allergy specialists usually are concerned with) are (1) unrelated to the drug’s pharmacological action, (2) are generally independent of drug dose, and (3) often related to either an immune response in the patient or the patient’s genetic susceptibility.
Table Classifiation of Different Manifestations of Adverse Reactions to Drugs or Therapeutic
| Generalized reactions |
| Mast cell-derived mediator reactions |
| Systemic anaphylaxis and anaphylactoid reactions |
| Generalized urticaria and angioedema |
| Serum sickness-like reactions |
| Drug fever |
| Drug-induced vasculitis |
| Drug related lupus |
| Stevens-Johnson/toxic epidermal necrolyis |
| Anticonvulsant drug hypersensitivity syndrome |
| Immunological reactions |
| Type I: immunoglobulin E-antibody-mediated (e.g., P-lactam antibiotics, insulin urticaria or anaphylaxis) |
| Type II: antitissue cytotoxic antibodies (e.g., drug-induced hemolytic anemia or thromocytopenia) |
| Type III: antigen-antibody immune complex involving complement reactions (e.g., serum sickness-like drug reactions) |
| Type IV: cell-mediated hypersensitivity (e.g., neomycin contact dermatitis) |
| Organ-specific drug reactions |
| Skin (e.g., pruritus, maculopapular, morbilliform and erythemic rashes, urticaria/ |
| angioedema, erthema multiforme, fi xed drug eruptions, phototoxic and photoallergic |
| reactions) |
| Blood (e.g., drug-induced hemolytic anemia, thrombocytopenia) |
| Liver (e.g., hepatitis) |
| Lung (e.g., fibrosis) |
| Kidney (e.g., nephritis) |
| Pseudo-allergic (allergic-like) reactions |
| Ampicillin/amoxicillin rash |
| radiocontrast media reactions |
| Reactions to aspirin and nonsteroidal anti-inflammatory agents |
| Reactions to enzyme inhibitors (e.g., angiotensin-converting enzyme inhibitor-induced angioedema) |
| Reactions involving histamine release (e.g., vancomycin red man syndrome) |
Incidence
It has been estimated that more than 80% of all drug reactions are predictable, and the rest are unpredictable with allergic or allergic-like reactions accounting for less than 5-10% of all adverse events.
The exact incidence of all types of adverse reactions to drugs and therapeutic agents is unknown. However, it is estimated that 1-2 million individuals in the United States experience a drug reaction each year. The most frequent manifestation of a drug reaction is a skin rash. Reports indicate that 2% of adult medical admissions each year to a community hospital are the result of drug reactions. Most of these cutaneous reactions were morbilliform eruptions (94%), but 5% were urticarial.
Studies involving adults admitted to either medical or surgical wards in tertiary care hospitals demonstrate a yearly serious adverse reaction rate of 6.7%. The overall proportion of both serious and nonserious adverse reactions was 23.8%. Most drug reactions involve nonimmune or unknown mechanism and are thus defined as drug intolerances, not drug allergies.
In the case of two types of drug reactions, penicillin and other p-lactams as well as conventional radiocontrast media (radiocontrast media), the incidence of allergic and allergic-like reactions has been calculated. The risk of developing an allergic reactions, usually a rash, to a single course of penicillin has been estimated to be 2%, and to cephalosporin it is 2-3%. The risk of developing anaphylaxis to penicillin is no more than 0.04% (1/2500 courses of the drug), but it is rare to have such a reaction with a third-generation cephalosporin. Fatalities to penicillin are unusual. The risk ranges between 0.0015 and 0.002% (1 death/50,000-75,000 courses of the drug). These previous estimates were based on small series of inpatients. Recently, studies of a very large outpatients population in England who received a prescription for penicillin (usually amoxicillin) demonstrated an allergic reaction rate of 0.18%. This increased to 1.89% with the second prescription of antibiotics.
The overall reaction rate to conventional radiocontrast media (hypermolarity) has been reported in a review of 10,000 consecutive intravenous pyelogram (I VP) procedures to be 2-3 %. The frequency of fatalities has been reported to be 1/50,000 IVP procedures. Overall reaction rated to lower-molarity radiocontrast media have been less than conventional high-molarity material and have been reported to be approx 0.5%. Serious reactions to radiocontrast media that require subsequent hospitalizations are estimated to be 1/2900 conventional radiocontrast media infusions and 1/ 8400 infusions with the low-molarity radiocontrast media. Death from conventional radiocontrast media is reported to be 1/10,900 but is rare with low-molarity radiocontrast media use (1/165,000-500,000 procedures).
In 2001 it was estimated that 75 % of previous reported fatal drug-induced anaphylactic reactions in the United States were due to p-lactam antibiotics. It was reported in Denmark that between 1968 and 1990, the most common cause of drug-induced anaphylaxis or anaphylactoid reactions was radiocontrast media, antibiotics, or allergenic extract. In the United Kingdom, these same types of fatal drug reactions between 1992 and 1998 were most likely to occur to anesthetics (53%), antibiotics (31%), or radiocontrast media (16%).
Factors That Influence Incidence
Table 3 lists important factors that may influence the likelihood of an adverse reaction during the use of a drug or therapeutic agent. Some drugs are more likely to be involved in reactions than others. Antibiotics, especially p -lactams and sulfonamides, followed by aspirin and nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs) and central nervous system (central nervous system) depressants, are most commonly involved in these serious reactions. The p -lactam antibiotics, trimethoprim sulfamethoxazole (TMP-SMX), and whole blood are most likely to be involved in skin rashes, the most common manifestation of adverse reactions. Minor drug reactions (e.g., nausea) are more often involve with narcotic use, antibiotics, and cardiovascular drugs.
Allergic sensitization to drugs is more likely to occur after multiple, intermittent courses of a drug than with continuous administration of that drug. All types of reactions to medicine occur more often when patients are treated with multiple agents than with single agents. Allergic drug sensitization is least likely to occur with oral administration. Topical application of drugs/chemicals favors contact sensitization. Once sensitization has occurred, however, elicitation of a drug reaction upon re-exposure to that drug may occur by any route, but the oral route is the safest, and the intramuscular route is more risky than the intravenous route.
Table Factors Influencing the Frequency of Adverse Reactions to Drugs and Therapeutic Agents
| Drug type | Familial history of reactions |
| Degree of drug exposure | Atopy |
| Routes of administration | Viral infections |
| Age and sex | Concomitant drug use |
There are probably less adverse drug reactions in children and the elderly. Drug-induced skin rashes are reported to be one-third higher in females. Individuals who have a severe reaction to one drug (e.g., p-lactam antibiotics) may be at increased risk for reactions to other antibiotics. Children of parents with a confirmed reaction to a p-lactam antibiotic have more risk that the general population to develop reaction to p-lactam antibiotics. Although being “allergic” or atopic does not increase the risk of development of an allergy to p-lactam antibiotics, it may increase the risk of having an anaphylactoid reaction to radiocontrast media exposure.
A maculopapular (toxic) rash due to amoxicillin/ampicillin is more likely to occur when the patient treated with this drug has an Epstein-Barr virus infection (acute infectious mononucleosis). Both drug allergies (e.g., to p-lactam antibiotics) and drug intolerance reactions (e.g., systemic or skin reactions to may types of therapeutic agents) are more likely to occur in patients afflicted with HIV than HIV-seronegative individuals. The risk of drug reactions increases with the degree of immunosuppression. The presence of other viral infections and altered drug metabolism because of chronic disease may also be an important factor effect in risk. Concurrent administration of p -adrenergic blocking agents with other drugs increases the risk of anaphylaxis, in the case of p-lactam antibiotic use, and of serious anaphylactoid reactions in the case of radiocontrast media use. Concurrent use of angiotensin-converting enzyme inhibiting agents with other drugs may also increase the risk of a serious anaphylactic or anaphylactoid reaction.
Mechanisms of allergic and allergic-like reactions to drugs and therapeutics
Signs and symptoms
General approach to the diagnosis and management of allergic and allergic-like reactions to drugs and therapeutics
Diagnosis and management of selected allergic and allergic-like drug reactions
β-Lactam Antibiotics
In patients with a history of an allergic reaction to penicillin or other β-lactam antibiotics, penicillin skin testing should be done electively. Only 20% of adults and 10% of children with this diagnosis turn out to be actually allergic based on allergy skin testing (the positive penicillin allergy skin test rate is higher in the first year after labeled allergic to penicillin).
1. In many cases, the original reaction, usually a rash, is a result of an infection (usually viral) rather than the antibiotic used to treat that infection.
2. In cases of true penicillin allergy, the reaction rate dissipates about 10%/yr.
3. In children, toxic (nonallergic) maculopapular rash to ampicillin/amoxicillin and to some cephalosporins like Ceclor are common (5% of antibiotic therapies).
In most cases it is advisable to refer the suspected penicillin-allergic patient to an allergist-immunologist specialist for evaluation of the condition. Table 6 lists the peni cillin skin tests bases on commonly available agents.
Penicillin Allergy Skin Tests
• p-lactams are the only type of antimicrobial agents in which a suspected reaction (allergic) can be verified by skin tests.
• Of those patients with a history of a prior reaction, only 20% of adults and 10% of children have been found to be skin test positive.
• Positive skin test to penicolloyl-polylysine (Pre-Pen) correlates best with rash(usually urticarial reactions); positive skin test to penicillin “minor determinant mix” correlates with anaphylaxis.
• Skin testing with penicillin G metabolites is usually a measure of potential clinical reactions to the β-lactam ring in amoxicillin and cephalosporins.
Table Penicillin Skin Testing
| Reagent | Type of test | Dose |
| Penicilloyl-polylsine (Pre-Pen) test strength | Prick/scratch/puncture (intradermal) | 1 drop 0.02 mL |
| Penicillin G, 10,000 U/mL | Prick/scratch/puncture (intradermal) | 1 drop 0.02 mL |
| Penicillin — minor determinant mixture | Not commercially available in the US |
Penicolloyl polylysine is an example of the major breakdown product of penicillin drug metabolism coupled to a carrier protein. This test reagent is responsible for positive skin tests in patients with an isolated skin rash (especially urticaria, or urticaria and angioedema). Penicillin G (Pen G) is the parent drug. A positive skin test to Pen G correlates with all types of allergic reactions. A positive minor determinant mixture skin test (minor or secondary penicillin metabolites) correlates best with more serious life-threatening, systemic anaphylaxis penicillin reactions. Unfortunately, this latter skin test reagent is not available commercially, but is available in some academic centers and large clinics.
In addition, in 2000-2001 and again in 2004 — 2005, Penicolloyl polylysine commercial manufacture was suspended. Because of the uncertainty of future supplies, allergists may have to consider preparation of β-lactum antibiotics allergy skin test reagents in their own local laboratories.
In studies of penicillin allergic individuals, skin testing with Penicolloyl polylysine, Pen G, and minor determinant mixture is safe, can be done electively, and is predictive of the risk of subsequent challenge with penicillin. If all tests are negative, there is only a small risk of a minor skin rash upon challenge. The positive predictive value of skin testing to assess the future risk for allergic reactions to β-lactam antibiotics using only Pre-Pen and Pen G is unclear but has been estimated to be 70-97% reliable.
Penicillin skin testing also tests to reactions directed to the p-lactam ring in cephalosporins and other penicillins. In some cases, individuals may develop sensitivity to the side chain rather than to the β-lactam ring. Usually this occurs in reaction to either ampicillin/amoxicillin or a specific cephalosporin. Fortunately, this is uncommon in β-lactam-allergic individuals in North America. Allergy skin testing can be done to other penicillins and cephalosporins and if positive, may be helpful information. However, these types of skin tests have not been validated in controlled studies.
In cases in which the skin test results are equivocal or the history of the prior reaction is severe but the skin tests are negative, a graded challenge with a single usual oral dose of the β-lactam antibiotic in question under controlled conditions. In most situations, when minor determinant mixture skin testing reagent is not available, an oral β-lactam challenge is advised following negative Penicolloyl polylysine and Pen G allergy skin testing.
In cases in which the individual is found to be allergic (positive history of reaction, confirmed by skin test and/or challenge), all β-lactam antibiotics should be avoided. Usually substitute medications are used to treat subsequent infections.
The overall cross-reactivity rate between penicillin allergy and cephalosporin allergy is estimated to be 4% or less (third and fourth generation) to 10% or more (first generation). Some authorities have recommended the use of third- or fourth-generation cephalosporin in suspected penicillin-allergic individuals. However, most experts feel that all β-lactam antibiotics should be avoided in proven penicillin-allergic individuals.
In select cases, in which individuals who are proven β-lactam antibiotic-allergic and need a β-lactam antibiotic (life-threatening or other serious infections without suitable substitutes available), then penicillin or the appropriate β-lactam antibiotic desensitization may be indicated. In these cases it is advisable to consult an allergist-immunologist specialist.
This procedure should be done only in the hospital under controlled conditions, such as an intensive care unit with a doctor present during the entire procedure. Each individual case is different, and published protocols are only guides to the procedure.
The oral route is felt to be safest, but the intravenous route may be preferable in some cases. Studies have shown that reactions during the procedure should be expected approx 30% of the time. When these occur, the patient should be treated appropriately and stabilized before restarting the desensitization procedure. The next desensitizing dose should be less than the one producing the reaction.
Once the procedure is complete, the patient is usually maintained at a full treatment dose of the medication until the therapy is complete. Once the drug has been stopped for 12-24 h, the patient should be considered to have reverted to his or her previous sensitized (allergic) state.
Sulfonamides and Other Antibiotics
Reactions to sulfonamides (particularly rashes) are common in the general US population. There is marked accentuation of these rates in the patient with HIV infection. In particular, with TMP-SMX, which is frequently used for the treatment and prophylaxis Pneumocystis carinii pneumonitis, the reaction rates are as follows: general population 3%, immunodeficient patients (HIV-seronegative) 12%, AIDS patients (HIV-seroposi tive) 29-70%. Sulfa drugs are also likely to be associated with Erythema multiform minor, Stevens-Johnson syndrome, and Toxic epidermal necrolysis types of reactions.
Table Oral Penicillin Desensitization Protocol
| Desensitization
dose” |
Stock drug,
250 mg/5 mL concentration |
Oral dose | |
| mL | mg | ||
| 1 | 0.5 mg/mL | 0.05 | 0.0025 |
| 2 | 0.10 | 0.05 | |
| 3 | 0.20 | 0.10 | |
| 4 | 0.40 | 0.20 | |
| 5 | 0.80 | 0.40 | |
| 6 | 5.0 mg/mL | 0.15 | 0.75 |
| 7 | 0.30 | 1.50 | |
| 8 | 0.60 | 3. | |
| 9 | 1.20 | 6. | |
| 10 | 2.40 | 12. | |
| 11 | 50 mg/mL | 0.50 | 25 |
| 12 | 1.20 | 60 | |
| 13 | 2.50 | 125 | |
| 14 | 5.0 | 250 | |
aDose increased approximately every 20 min unless reaction occurs; then adjust accordingly.
The allergic-like reaction to sulfonamides is not felt to be immunoglobulin E mediated or, for that matter, an immune event. Unfortunately, there is no skin test or in vitro blood test to confirm a suspected reaction. In almost all cases, strict avoidance of the drug is recommended once a presumptive diagnosis has been made.
The exception is life-threatening situations, such as in patients with AIDS with P. carinii infection. In some cases the infection can be successfully treated with antimicrobial agents other than the TMP-SMX, such as inhaled pentamidine. In other cases, this is not possible, and TMP-SMX is the optimal drug for treatment of active infection and/or use in P.carinii prophylaxis.
In some cases adults with a documented history of a prior rash to TMP-SMX have later been given full doses of TMP-SMX without subsequent reaction. In other cases, serious reactions have resulted from this “full-dose” challenge.
Extended oral TMP-SMX desensitization procedures have proved successful in a limited series of patients: 10-23 d (19/21 patients); 10 d (23/28 patients); 2 d (6/7 patients). Use of full-dose challenge or desensitization is not advised for any patient who has a prior history of drug-associated erythema multiform, Stevens-Johnson syndrome, or Toxic epidermal necrolysis. The management of these situations is best left to the allergist/immunologist or an infectious disease specialist. Recent evidence would indicate that individuals who develop a rash to sulfonamide antibiotics are not at risk for a reaction to sulfonamide containing nonantibiotic drugs because of cross-reactivity, but may be a risk because of having multiple drugs sensitivity.
Documented allergic-like reactions to other antibiotics are uncommon. Usually they are not life threatening in nature. Most reactions to intravenous vancomycin result in a red flush (“red man syndrome”) resulting from direct histamine release and can be controlled symptomatically and with adjustment of the intravenous drug administration rate. Occasionally serious allergic reactions can occur to ciprofloxin, and if this occurs quinolone-type antibiotics should be avoided.
In the case of reactions to other antibiotics, in almost all situations long-term avoidance is usually recommended, and the event is documented in the patient’s records. Since there are usually substitute antibiotics available, it is not a problem for most individuals.
In a few individuals, however, multiple antibiotic sensitivities of different types occur. This type of patient presents a problem when the primary care physician tries to treat common infections. In most cases, β-lactam antibiotics are involved, so penicillin skin testing can be done. (Often the tests are negative.) There are no convenient tests for reactions involving other antibiotics. Reproducible reactions of any kind, especially those that are systemic in nature, are unusual. If the history of reaction is minor and the drug is necessary for therapy, a graded oral challenge can usually be done without difficulty to prove the safety of this alternative antibiotic.
Insulin
Approximately 50% of humans given insulin regularly as a replacement therapy, especially the animal-derived forms, develop some immunoglobulin E antibody to the insulin molecule that can be validated by a positive immediate-reacting immunoglobulin E skin test. Most of these individuals do not have clinical reactions to insulin. A few, however, do have bothersome local swelling at the insulin injection site.
Management of this local reaction problem consists of the following:
1. Division of the insulin dose in half and administering these doses at different sites
2. Trial of an added oral antihistamine
3. If steps 1 and 2 fail, switching to another commercial type of insulin
Generalized urticaria or systemic anaphylaxis to insulin is very uncommon. Usually the systemic reaction is the direct result of a diabetic discontinuing insulin replacement therapy regularly, for a time, and then resuming regular therapy. About 12 d after restarting of the insulin, systemic anaphylaxis occurs.
Patients who have a systemic reaction to insulin should be hospitalized after treatment of the acute symptoms. If the reaction is mild and the patient is seen within 24-48 h, the total insulin daily replacement can be decreased by one-third and subsequently the dose can usually be safely increased 5 U/dose until therapeutic levels have been achieved.
In the situation in which the reaction is more severe or the interval between reaction time and examination is more than 48 hours, the patient will require specific insulin allergy skin testing by an allergist/immunologist specialist to identify the least reactive insulin type (usually human insulin). The patient then requires desensitization over the course of a week with this new insulin.
Anesthetic Agents
Some patients given local anesthetics complain of allergic-like symptoms. Few if any of these reactions have been shown to be immunoglobulin E mediated. When a patient is confronted with such a problem, the goal is to find one local anesthetic the patient can tolerate. The allergist-immunologist will usually skin test the individual complaining of symptoms with more than one type of local anesthetic, including the one that the surgeon-dentist wants to use.
Drug Challenge and Desensitization
• Graded drug challenges, or drug desensitization, should be done only when necessary, with informed consent, and under controlled conditions by specialists familiar with these techniques
• Any serious (anaphylaxis or anaphylactoid) reactions following drug challenge usually start within 2 h of drug exposure
• Reactions during drug desensitization procedures, such as with β-lactam antibiotics, should be expected to occur in one third of patients.
The specialist will select one of the nonreacting agents and then administer a graded sc injection challenge using dilutions of the local anesthetic at 1:100 (dose: 0.1 mL), 1:10 (dose: 0.1 mL), and full-strength local anesthetic (dose: 0.1,0.5,1.0, and possibly 2.0 mL) at 20-min intervals under controlled conditions.
Most patients successfully complete the local anesthetic challenge without difficulty. The referring physician is then informed regarding the safety of the drug used in the challenge.
It is common for an allergic-like reaction to occur during the induction of general anesthesia (1:5000 to 1: 15,000 inductions). The symptoms include urticaria, wheezing, rapid heart rate, low blood pressure, and shock. Two types of allergic reactions should be considered should these symptoms occur: (1) reactions to natural rubber latex and (2) allergic reactions to one of the neuromuscular blocking agents used in the induction period (e.g., tubocurarine chloride, alcuronium, gallamine triethiodide, pancuronium bromide, succinylcholine chloride, fluphenazine hydrochloride, thiopental, amytal sodium, and methohexital).
Certain individuals (e.g., health care workers, children with spina bifida or multiple operations, highly allergic individuals, and individuals with atopic dermatitis) are at increased risk for systemic reactions to natural rubber latex. Usually there is a history of prior contact dermatitis or contact urticaria to latex products before the patient has a systemic reaction. Latex proteins can be transferred via aerosol coupled to glove powder, so that severe reactions may occur in very sensitized individuals just by being in a room where latex is being used.
In situations in which systemic anaphylaxis has occurred in an operating room, it is advisable to draw blood from the patient as soon as possible after the event so that in vitro testing can be subsequently be performed for mast cell tryptase (as a sign of mast cell release; see General Approaches to Diagnosis and Management) and immunoglobulin E latex-specific antibodies. If the latex in vitro test is positive, it supports the possibility of a clinical reaction to latex.
No commercial latex allergen is available to allergy skin testing. However, some allergist-immunologists may be able to skin test or challenge selective patients using commonly available natural rubber sources. Although the allergist-immunologist specialist may attempt direct skin testing with various neuromuscular-blocking agents, such a type of testing procedure is not standardized. Positive allergy skin testing to neuromuscular agents would provide helpful information, but a negative skin test result to these agents does not rule out an association between these agents and clinical reactions.
ASA and NSAIDs
There is no skin test or in vitro test available to confirm the presumptive diagnosis of ASA/nonsteroidal anti-inflammatory drug intolerance in patients who have a history of allergic-like reactions (e.g., urticaria or asthma). The usual management is to advise the individual to avoid these drugs strictly. A graded drug challenge (beginning with no more than 3 or 30 mg of ASA, depending upon the history of sensitivity, and advancing to 60,100, 150, and 300 mg at 3-h intervals) can be done under controlled conditions, but such a challenge is usually not advocated in most clinical situations. ASA desensitization has proven successful in patients with AS A-sensitive asthma, but not with most individuals with AS A/NSAID-induced urticaria, angioedema, or anaphylactoid reactions.
Most allergic-like reaction to ASA or nonsteroidal anti-inflammatory drug are a result of the cyclooxygenase-1 inhibitor portion of these drugs. cyclooxygenase-2 inhibitor drugs have been shown to be safe in ASA-induced asthma. However, some individuals who have had urticaria/angioedema or anaphylactoid reactions to AS A/NSAIDs may also react to these new drugs. A graded oral challenge of a cyclooxygenase-2 inhibitor can be helpful to assure the safety of this type of drug in patients known to be sensitive to ASA/nonsteroidal anti-inflammatory drugs.
Adverse Effects of ASA/nonsteroidal anti-inflammatory drug
• gastrointestinal bleeding
• Exacerbation of urticaria/angioedema from any cause
• Asthma; especially in nonatopic adults with chronic rhinitis and nasal polyps
• Anaphylaxis/urticaria-angioedema
Radiocontrast media
Radiocontrast media is used in imaging diagnostic procedures, and adverse reactions to radiocontrast media are fairly common. Therefore, one allergic-like problem that a primary care physician is likely to face is the patient with a prior history of radiocontrast media reaction who needs another diagnostic imaging procedure.
There is no skin test or in vitro diagnostic test that can be done to predict whether or not the patient with a history of prior reaction to radiocontrast media will have another reaction. Studies have shown that the chance a patient with a previous reaction to conventional radiocontrast media will have another reaction to the same material is approx 30%. This risk can be reduced to 10% by using a preprocedure treatment of prednisone and diphenhydramine (Benadryl). It may be reduced to a risk of 0.5% by using a low-molarity radiocontrast media material plus a preprocedure treatment of medications as outline in Table 8.
In spite of these procedure treatments and the use of a low-ionic radiocontrast media during the procedure, the individual with a prior radiocontrast media reaction is at some risk, and the radiologist should be prepared to treat anaphylaxis should it occur. In addition to the usual treatments, the radiologist should be prepared to treat an unusual but occasionally severe radiocontrast media reaction that mimics excess vagal stimulation, inducing bradycardia and resistant shock. Under these special circumstances, the addition of atropine to the anaphylactoid treatment regimen may be lifesaving.
Table Pre-radiocontrast media Treatment Protocol for Prevention of Repeat radiocontrast media Anaphylactoid Reactions
| Time | Agent/Dose |
| 18, 12 and 6 h before procedure | Prednisone 50 mg every 6 h for 3 doses (total 150 mg) |
| Immediately before procedure | Diphenhydrammine hydrochloride (Benadryl) |
| 50 mg po, intramuscular, 1 h or intravenous 5 min before radiocontrast media | |
| Cimetidine (Tagamet) 300 mg or ranitidine | |
| (Zantac) 300 mg po, 1-3 h before, or 5 min before radiocontrast media | |
| During procedure | Low-ionic radiocontrast media |
Angiotensin-converting enzyme-IN and AII-RAS
As described under mechanisms of action, angiotensin-converting enzyme-INs can be associated with either a cough or angioedema of the throat, which can be severe and life threatening. The most important aspect of acute management is to recognize the possible relationship between the clinical symptoms and signs of these conditions and the drugs. Long-term angiotensin-converting enzyme-INs should be avoided. Switching to another angiotensin-converting enzyme-IN or to an A-IIRAS is not advised since both drug types has been shown to cause the same symptoms in some patients.
The cough associated with angiotensin-converting enzyme-INs (occurs in up to 25% of patients) generally resolves over a few weeks, after the drug is discontinued. Angioedema is more serious but occurs in fewer patients (0.1-0.7%). The symptoms tend to resolve with 24 — 48 h after discontinuing the drug.
In an emergency situation, life-threatening angioedema usually responds to epinephrine, antihistamines, antileukotrienes, corticosteroids, and possibly anticholinergic drugs. Recently it has been shown that when these conventional medications failed to control angiotensin-converting enzyme-IN-induced angioedema. The patient responded to the infusion of fresh frozen plasma. This therapy may be considered in resistant cases.
Management of Other Drugs Involved in Allergic-Like Reactions
In situations in which a serious, usually systemic allergic-like reaction has occurred to a drug which is critical to the health or survival of the patient, it is not unusual that a subsequent graded drug challenge or desensitization procedure has been attempted. Usually the mechanism of the drug reaction is not clear and often successful results of challenges are only reported in case reports or small members or patients. Excellent management advice in these situations can be obtain by reading the monograph of Grammer and Grenberger.
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