3. Drug hypersensitivity

Francis C K Thien
Med J Aust 2006; 185 (6): 333-338. || doi: 10.5694/j.1326-5377.2006.tb00591.x
Published online: 18 September 2006

Doctors are frequently faced with patients who report that they are “allergic” to a drug or a range of drugs. In some cases, further questioning reveals only scant information about a possible reaction in early childhood, with no recollection of the circumstances or reaction, and no documentation available; in other cases, detailed history taking reveals that the reaction was a side effect, intolerance or some other adverse drug reaction (ADR) rather than a true drug allergy. A common problem faced by doctors is trying to determine the specific cause of a possibly drug-related skin rash in patients taking multiple medications. Often there is also uncertainty as to whether the rash may be due to the underlying disease (eg, an infection) or to the antibiotic prescribed to treat it.

Trying to determine whether a causal relationship exists (and, if so, with which medication), the true nature of the reaction, and implications for future drug prescription can be a frustrating experience for both doctors and patients. Lack of knowledge and experience in this important area can lead to fear of multiple “drug allergies” and unnecessary avoidance of appropriate medications, with reliance on more expensive, or less effective, alternatives without a rational basis.

The pragmatic approach taken in my article is to consider carefully all patients presenting with a supposed “drug allergy”, give a clinical framework to determine causality, and clarify which reactions are likely to be the result of true drug allergy in the context of all adverse drug reactions. Specialist procedures such as drug challenge or desensitisation are beyond the scope of my article, but the principles behind them will be explained. This will also help guide doctors as to which patients would benefit from referral for such investigation and management.

Adverse drug reactions

The World Health Organization defines an ADR as a response to a drug that is noxious, unintended or undesired occurring at doses normally used for the prevention, diagnosis or treatment of disease.1 A pharmacological classification2 divides most ADRs into one of two major subtypes: type A and type B reactions.

Type A reactions are pharmacological effects that are predictable and dose-dependent. Most ADRs (about 80%) are type A reactions, which include toxic effects (such as digoxin toxicity, and serotonin syndrome caused by selective serotonin reuptake inhibitors); side effects; secondary effects (eg, antibiotic-associated diarrhoea); and drug interactions.

Type B reactions are hypersensitivity reactions that are unpredictable and not dose-dependent. They lead to objectively reproducible symptoms or signs at a dose tolerated by normal people.3 Type B reactions comprise about 10%–15% of all ADRs. Drug allergies, which comprise 5%–10% of ADRs,4 are hypersensitivity reactions that involve an immune mechanism (IgE- or T cell-mediated, or, rarely, involving an immune complex or cytotoxic reaction). All other hypersensitivity drug reactions without an immune mechanism (5%–10%) — or in which an immunological process is not proven — are classified as non-immune (or non-allergic) hypersensitivity reactions (Box 1).3

Making the diagnosis
Clinical history: is it an adverse drug reaction?

The most important step in assessing a possible ADR is to take a detailed clinical history — to assess causality, determine the underlying mechanism (pharmacological effect or hypersensitivity reaction) and assess whether the reaction may be allergic in nature (ie, immune-mediated hypersensitivity reaction). Careful documentation by the attending doctor of the circumstances and type of reaction of the suspected ADR is critical. Important initial questions on clinical assessment include the following:

If a clear clinical history and supportive documentation are available, a probability (or index of suspicion) can often be assigned to the likely cause. For example, a high probability can be assigned if there was a clear temporal relationship, a reaction consistent with known adverse reactions to the drug, an improvement after cessation of the drug or recurrence of a reaction after re-challenge, and no reasonable alternative explanation for the reaction (such as reaction to another drug or underlying condition).

The pharmacological features of type A adverse reactions (toxicity, side effects, secondary effects and drug interactions) can often be determined by searches of pharmacological references and databases such as the Australian medicines handbook5 or MIMS annual.6 However, doctors are sometimes faced with an unclear history or lack of supportive documentation, making this important part of the evaluation indeterminate.

Clinical history: is it a true drug allergy?

If there is high probability of a causal relationship and the reaction is not pharmacologically mediated, the following three questions can help to distinguish immune-mediated (allergic) from non-immune-mediated hypersensitivity:

What was the time course of the reaction?

Immediate reactions (occurring from several minutes to 1 hour after drug administration) suggest an IgE-mediated event caused by pre-formed IgE antibodies.

Non-immediate reactions (occurring more than 1 hour after drug administration) suggest a drug-specific T cell-mediated mechanism.7 These late reactions may present in a variety of ways, including fixed drug eruptions, maculopapular morbilliform rashes, and bullous or pustular exanthems. Other non-cutaneous manifestations may include unexplained pyrexias, arthralgia, myalgia, eosinophilia or other haematological abnormalities, and derangement of liver function. These non-immediate reactions are not IgE-mediated, which has implications for diagnostic testing and management.

Detecting allergen-specific IgE
Skin testing

Skin testing (by skin prick or intradermally) is of predictive value for only a limited group of IgE-mediated drug allergic reactions. The best characterised drug is penicillin, for which the immunogenic isotopes (the parts of the molecule recognised by the immune system) have been identified. They consist of a major determinant (accounting for 95% of penicillin degradation metabolites) and minor determinants (accounting for 5% of metabolites). Testing with major and minor determinants is done with a skin prick test, followed by an intradermal test if the skin prick test is negative. (The commercial product Pre-Pen [Hollister-Stier], which contains the major determinant of penicillin, is currently unavailable anywhere, but alternatives may be available in the near future.) A weal diameter of at least 3 mm greater than that of the negative control, together with erythema, constitutes a positive test. US studies have shown that a negative test in patients with an indeterminate clinical history indicates that penicillin can be administered with less than 4% risk of an immediate reaction8 (similar to the risk in the general population). However, more recent European research indicates that the predictive value is much lower in patients with a documented high probability clinical history of immediate reaction.9

Amoxycillin and ampicillin should be included in the skin test array to improve the diagnostic value.10 This is because, with changes in drug prescription patterns, some patients are developing immunological reactivity to β-lactam sidechains specific to amoxycillin and ampicillin molecules, rather than the classical major and minor determinants common to all synthetic penicillin β-lactams.

Other drugs for which skin prick and intradermal tests are of predictive value include muscle relaxants, insulin, and biological agents such as Gelofusine (B. Braun) (a plasma volume expander) and streptokinase. Patch tests are done by making a 5% concentration of the relevant drug in a vehicle such as petrolatum, applying it to the skin and measuring the reaction after 48–72 hours. They are used to study non-immediate reactions, although their clinical diagnostic value is limited.11 However, for the vast majority of allergic drug reactions, there are no validated skin tests that have been shown to be of predictive value. This is because the reactions are either not IgE-mediated, or the relevant immunogenic epitopes (which may be derived from unidentified drug metabolites or breakdown products) have not been identified for most drugs.

Evaluation: to challenge or not?

A drug provocation challenge is the controlled, graded administration of a drug in order to diagnose a drug hypersensitivity reaction. There are three situations in which a drug provocation challenge may be considered when evaluating allergic drug hypersensitivity:

The general principle of a drug challenge is to start at a very low dose (well below the normal therapeutic dose) and give repeated administration at increasing (usually doubling) doses of the drug until a threshold of reaction is reached, when first objective symptoms occur. (If no symptoms appear, the challenge stops when the therapeutic dose is reached.) Intervals between dosing may range from 15 minutes to several hours, depending on the drug, and it may be given orally or intravenously.

Provocation tests should be done in specialised clinics or hospitals with established protocols and resuscitation facilities, and should never be conducted in patients with a history of severe, life-threatening vasculitic syndromes, exfoliative dermatitis, erythema multiforme major, drug-induced hypersensitivity reactions with eosinophilia, or toxic epidermal necrolysis.13

Management of ADRs

The approach to the patient with a suspected ADR must be very methodical (Box 5). Firstly, as outlined above, a causal relationship must be established between the drug and the reaction. Then the reaction type must be determined, if possible.

For type A (pharmacological) drug reactions, dosage modification may be all that is necessary before drug re-administration. Toxicity, as well as drug-induced side effects and secondary effects (eg, nausea and vomiting caused by opiates, or antibiotic-associated diarrhoea) may resolve at lower drug doses.

For type B (hypersensitivity) drug reactions, several options may be considered. After severe or life-threatening reactions, the drug should not be re-administered. For less severe reactions, a drug provocation challenge may be considered. For type B immunologically-mediated (allergic) reactions, the management option depends on the mechanism responsible for the reaction. If validated confirmatory tests are available, they should be used to determine the allergic status of the patient (eg, tests for penicillin-specific IgE antibodies). If such tests are not available — and in most cases they are not — several approaches can be taken. The simplest approach is to avoid the drug if an alternative agent is available. If an alternative drug does not exist, a graded challenge with the implicated agent can be done if the previous reaction was not life-threatening and not consistent with an IgE-mediated reaction. However, if the medication is needed as the drug of choice, then desensitisation should be considered.14

Some specific drugs
β-lactam antibiotics

Allergic reactions to β-lactam drugs are the most common group of type B hypersensitivity ADRs. The clinical, diagnostic and management approach to IgE-mediated immediate penicillin allergy has already been discussed (see “Detecting allergen-specific IgE: skin testing”, above).15 For the majority of reactions that produce non-immediate exanthems (and are probably mediated by T cells rather than IgE), the approach depends on the severity of the reaction and the potential need for penicillin-based therapy in the future.

Lifelong avoidance of a drug is necessary for the rare but severe reactions such as erythema multiforme major or toxic epidermal necrolysis. With more common morbilliform maculopapular exanthems, as seen when amoxycillin is administered concurrently with a viral infection (eg, infectious mononucleosis), the exact mechanism is not clear, but may be due to viral infection altering the immune status of the host. In this situation, the drug can be administered safely again once the viral infection has resolved,16 highlighting the critical role of taking a detailed clinical history and making a careful assessment.

When a patient with immediate penicillin allergy requires an alternative β-lactam drug, consideration can be given to prescribing a cephalosporin. A review of 11 studies of cephalosporin administration to patients with a history of penicillin allergy found cephalosporin reactions in 4.4% of patients with positive skin tests for penicillin.17 A practical approach is to ascertain whether the previous penicillin reaction was an immediate IgE-mediated allergy, and, if not, a graded challenge can be performed to determine whether the cephalosporin is a safe alternative. If the previous penicillin reaction was immediate, evaluation with penicillin skin testing should be done first.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Hypersensitivity reactions to aspirin and other NSAIDs may have a number of clinical manifestations. One clinical syndrome is late-onset asthma (onset age in the 30s or 40s) with nasal polyposis, and later development of aspirin hypersensitivity, with NSAID ingestion provoking asthma and rhinitis. This may affect 5%–10% of people with asthma. It involves a non-immune hypersensitivity mechanism of increased leukotriene production caused by inhibition of the cyclo-oxygenase-1 (COX-1) enzyme.18 Such people are sensitive to aspirin and all older non-specific NSAIDs, but tolerate specific COX-2 inhibitors (such as celecoxib). However, there are other clinical syndromes in which there is no history of asthma or rhinitis and the patient has an isolated sensitivity to a specific NSAID.19 This may have an immunological basis with a putative IgE mechanism. Clarifying the history and recognising the clinical patterns can allow specific provocation challenges to ascertain safe alternatives and prevent unnecessary avoidance of aspirin or other NSAIDs (see Box 6).

Angiotensin-converting enzyme (ACE) inhibitors

Angioedema is a well recognised adverse reaction that affects 0.1%–0.5% of patients taking ACE inhibitors.20 Angioedema can first appear anywhere from a few hours to 8 years after an ACE inhibitor is taken, with up to 20% of cases being life-threatening.20 The reaction involves a non-immune hypersensitivity mechanism caused by the accumulation of plasma kinins (such as bradykinin) as the result of inhibition (by ACE inhibitors) of the kininases that normally metabolise and inactivate bradykinin.21 If a patient taking an ACE inhibitor develops angioedema, the cause must be assumed to be the ACE inhibitor, and the drug should be ceased immediately (until such time as the drug is proven not to be the cause) (Box 7). Rare instances of angioedema have also been reported after taking angiotensin-receptor antagonists, but these reactions may not be mediated by bradykinin.

When to refer

In assessing ADRs, it is important for physicians to distinguish between those that represent hypersensitivity from those that are pharmacological. If possible, hypersensitivity reactions need to be differentiated further into those that are truly allergic in nature and those that are not immunologically mediated. Clinical evaluation is the most important means of assessment, with supportive skin tests and laboratory tests helpful if validated and available. Referral for specialist assessment is warranted:

However, until we have a better understanding of the mechanisms responsible for hypersensitivity drug reactions, our management tools will remain limited.

6 Case scenario*

A 45-year-old man who was previously well (apart from mild seasonal hayfever, treated occasionally with antihistamine) presented for review of a recent documented anaphylactic reaction. He had woken one morning with a sore knee, for which he took a tablet of naproxen 500 mg after his usual breakfast. Within 10 minutes (while sitting on the toilet), he felt itching on his scalp, which became generalised. When he got up to wash his hands, he felt dizzy and fainted. On regaining consciousness (within a minute, according to his wife), he felt shortness of breath and the need to open his bowels again. When he fainted again, this time on the toilet seat, his wife rang for an ambulance.

At the hospital emergency department, he was noted to be faecally incontinent, with an unrecordable blood pressure and slow respiration. Treated with adrenaline, intravenous fluids and steroids, he recovered within an hour and was discharged the following day.

On further questioning, it was found he had injured his knee while playing football and had taken a 1-week course of naproxen within the previous 3 months, with no side effects. He had taken no other medications at that time.

In this case, naproxen was the “smoking gun”, with no other reasonable or rational alternative explanation for the witnessed events. No supportive skin or in-vitro tests are available for naproxen or other non-steroidal anti-inflammatory drugs (NSAIDs). As there were no alternative explanations, a confirmatory drug challenge was not needed; in any case, the severity of the reaction ethically precluded it. However, the issue of whether the patient could take other NSAIDs or aspirin for future cardiovascular prophylaxis was an important one to resolve.

The patient had no history of asthma or nasal polyposis (for which the clinical syndrome includes sensitivity to all cyclo-oxygenase-1 [COX-1] inhibitors), suggesting that this was a single-drug immune hypersensitivity reaction. The reaction was possibly mediated by an as yet unidentified IgE mechanism — perhaps involving sensitisation after the previous course of naproxen.

A negative reaction on challenge with aspirin confirmed that the mechanism of the patient’s anaphylactic reaction was not COX-1 inhibition, and that he could take aspirin safely for cardiovascular prophylaxis in future. He was also challenged with diclofenac, which is structurally unrelated to naproxen, to which he had no reaction. Thus, he was advised to use diclofenac in the future if an NSAID was required. He was instructed to avoid naproxen lifelong, as well as its structurally related NSAIDs (including ibuprofen, ketoprofen and flurbiprofen), in order to avoid possible, but as yet unproven, immune cross-reactivity to structurally related drugs.

* This is a fictional case scenario based on similar real-life cases.

  • Francis C K Thien

  • Department of Allergy Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, VIC.



The research for this article was supported, in part, by a grant from the Harold Mitchell Foundation.

Competing interests:

I am on advisory boards for GlaxoSmithKline and Reckitt Benckiser, for which I receive honoraria. I have received speaker fees from GlaxoSmithKline, Schering-Plough, AstraZeneca and Boehringer-Ingelheim, and travel assistance to attend international meetings from GlaxoSmithKline and AstraZeneca.

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