How to Know If You Are Allergic to Medications

Adverse drug reactions can be divided into 2 main types:

• immune-mediated hypersensitivity reactions, more commonly referred to as allergies;
• non-immune-mediated reactions, often referred to for simplicity as intolerances.

“Drug allergy is a reaction in which the immune system responds abnormally to a medication. The most common manifestation is skin involvement, with symptoms such as itching, skin redness or urticaria. In some cases, acute respiratory symptoms may also occur, as well as gastrointestinal symptoms such as vomiting or acute diarrhoea.

An intolerance or side effect is more likely when only gastrointestinal symptoms are present, such as nausea, vomiting or diarrhoea, without other signs.

In general, skin manifestations are the most common sign of drug allergy, but their absence does not completely rule out an allergic reaction. Some drugs, such as anti-inflammatory medications, can cause respiratory symptoms without skin manifestations, particularly in patients with underlying asthma,” explains Dr Yacoub.

The fact that a drug has been tolerated in the past does not rule out the possibility of a reaction developing later. This can occur particularly when the medication is taken intermittently rather than continuously. In these cases, the immune system may “learn” to recognise the drug as foreign and develop sensitisation. It is as though the normal mechanism of tolerance is disrupted.

For this reason, some of the most common drug allergies involve antibiotics, which are often taken in courses, or iodinated contrast media used in CT scans. Even after many previous exposures without problems, a sudden reaction may develop in some predisposed individuals.

Drug reactions may be immediate or delayed.

Immediate reactions occur shortly after taking the medication, usually within 1 hour, and are often the most typical allergic reactions. The most common symptoms are:

• urticaria (hives);
• angioedema, meaning swelling of the face, lips or other areas.

“These are often IgE-mediated reactions, which in the most severe cases can lead to anaphylactic shock, a potentially life-threatening condition requiring urgent treatment,” she continues.

Delayed reactions occur later after treatment has started, hours or days afterwards, and may present as:

• widespread skin eruptions (maculopapular rash);
• skin redness.

In some rarer but severe cases, extensive blistering lesions may develop, with significant skin involvement. The most severe forms include Stevens-Johnson syndrome and toxic epidermal necrolysis, both of which require urgent hospital admission. When skin involvement is extensive, the clinical picture can become very serious, resembling a major burn.

Drug hypersensitivity reactions can involve many different classes of medication, but some are more frequently implicated in clinical practice. This is mainly due to the widespread use of certain drugs and, in some cases, to individual predisposition, including clinical conditions associated with a more vulnerable immune system that may be more prone to abnormal and excessive reactions to certain agents.

Antibiotics

Antibiotics are among the most common causes of allergic drug reactions in the general population. The classes most frequently involved are beta-lactam antibiotics, particularly penicillins, and sulfonamides.

Reactions may be immediate, often presenting with urticaria, angioedema or anaphylaxis, or delayed, with skin eruptions or more complex clinical presentations.

It is important to emphasise that not all reactions to antibiotics are true allergies. In some cases, particularly when the patient has only gastrointestinal symptoms, they are side effects rather than immune-mediated reactions.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Another particularly important category is non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac, ketoprofen and others.

In this context, it is essential to distinguish between 2 different mechanisms:

• selective allergy to a single drug: the patient reacts to one specific molecule, for example ibuprofen, but may tolerate other NSAIDs. In this case, it is a true drug-specific IgE-mediated or T-cell-mediated allergy;
• cross-reactive NSAID hypersensitivity: some patients react to several different NSAIDs, regardless of the individual molecule. In these cases, the problem is not the specific drug but the shared mechanism of action related to cyclooxygenase inhibition and altered prostaglandin synthesis.

These patients often have an underlying condition such as chronic bronchial asthma or chronic spontaneous urticaria. In such individuals, NSAID use may trigger respiratory and/or skin symptoms.

Anticonvulsants and allopurinol

Anticonvulsants, used mainly in the treatment of epilepsy, are associated with hypersensitivity reactions that are often delayed and potentially severe. One important characteristic is the timing of onset: reactions may occur 2–8 weeks after treatment has started.

One of the most significant conditions is DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), a systemic syndrome that can involve the skin (extensive rash), blood (eosinophilia, anaemia, thrombocytopenia) and internal organs, such as the liver, kidneys or heart.

Another important drug associated with delayed reactions is allopurinol, used to treat gout, which can also cause severe hypersensitivity reactions.

Drugs used in hospital and perioperative settings

In hospital settings, particularly during surgery, severe allergic reactions such as perioperative anaphylaxis may occur. The main triggers include:

• general anaesthetic agents;
• antibiotics administered in the operating theatre for prophylaxis;
• chlorhexidine, a widely used antiseptic;
• latex, found in gloves and medical devices.

These reactions are particularly serious because they often occur shortly after intravenous drug administration and are frequently characterised by severe hypotension and/or severe bronchospasm.

In hospital settings, iodinated contrast media used for CT scans are also frequently involved in both immediate and delayed hypersensitivity reactions. This occurs more often in patients who undergo repeated imaging studies, such as oncology patients.

More rarely, MRI contrast agents, which are paramagnetic contrast media and belong to a different class from iodinated contrast agents, can also cause allergic reactions.

Chemotherapy drugs

Chemotherapy agents can cause hypersensitivity reactions, particularly immediate reactions, which in most cases occur during drug administration.

These reactions have become more frequent in recent years for several reasons:

• longer survival of cancer patients;
• repeated treatment cycles over time;
• reintroduction of drugs previously used after a period of discontinuation.

This interruption may promote sensitisation, meaning that the patient initially tolerates the drug but develops a reaction during subsequent administrations.

Immunotherapy drugs

Immunotherapy agents, increasingly used in oncology, may be associated with hypersensitivity reactions that can sometimes overlap with immune-related adverse events. This can make diagnosis more complex, because it is not always straightforward to distinguish a true allergic reaction from an immune-mediated adverse effect of the drug. For this reason, management requires a multidisciplinary approach involving allergists and clinical immunologists, oncologists and, when necessary, other specialists.

“The diagnosis of drug hypersensitivity reactions always begins with one essential element: the medical history, meaning a detailed discussion with the patient. It is particularly important to establish precisely which drug was taken, which symptoms occurred and how long after administration they appeared. This information alone can often help identify the likely type of reaction and guide the most appropriate diagnostic pathway,” explains the specialist.

Blood tests

Some blood tests are available, but their use is limited. These include:

• specific IgE testing, available only for a limited number of drugs, particularly beta-lactam antibiotics such as penicillins and cephalosporins;
• the basophil activation test (BAT), in which the patient’s blood is exposed to the drug to assess activation of basophils, cells involved in allergic reactions. BAT is mainly useful in the evaluation of immediate reactions, but it is not widely available and is performed only in specialised laboratories.

In some situations, particularly in more complex or severe cases, these tests can be useful as an initial diagnostic aid before skin testing.

Skin tests

Standard diagnostic assessment for drug allergy relies mainly on skin tests with immediate and delayed readings, including readings at 48–72 hours. These include:

• skin prick testing;
• intradermal testing.

These tests must be carried out according to precise protocols and guidelines, because not all drugs can be tested safely. Non-irritating concentrations must be used to avoid false-positive results.

Skin tests generally have good sensitivity and are considered safe when performed correctly. However, sensitivity may decrease over time. In some cases, particularly many years after the original reaction, test results may be negative even in genuinely allergic patients. For this reason, testing may sometimes need to be repeated after a drug provocation test.

Drug provocation test or drug challenge

“If skin tests are negative, a drug provocation test, or drug challenge, may be performed in selected cases. This involves the controlled administration of the drug to the patient,” she explains.

The decision depends on the clinical risk. If the medical history is highly suggestive of a true allergy, for example penicillin-induced anaphylaxis, a challenge with the same suspected drug is not performed. Instead, an alternative drug within the same class may be evaluated, in which case the procedure is referred to as a tolerance test.

A drug challenge with the suspected medication is used mainly when the probability of true allergy is low. For example, if a patient reports mild skin redness during childhood or many years earlier while taking penicillin, and all tests are negative, the drug may be administered again in a controlled environment to confirm tolerance.

This procedure is known as drug allergy delabelling, because it allows an incorrect allergy label to be removed and can be extremely useful in selected cases.

As mentioned above, when a reaction occurred many years earlier, after an initial negative test both skin tests and the drug challenge may be repeated after approximately 1 month to exclude possible reactivation of sensitisation.

In patients with hypersensitivity reactions to contrast media, a challenge using a contrast agent that tested negative on skin testing may be performed to allow future imaging procedures without the need for premedication, thereby avoiding the potential harms associated with repeated systemic corticosteroid use.

In patients who are allergic to drugs that are essential for treatment, for example chemotherapy agents, monoclonal antibodies, certain antibiotics or acetylsalicylic acid, the medication may be administered through a drug desensitisation protocol.

This protocol lasts approximately 6 hours and makes it possible to administer a drug that previously caused an allergic reaction without triggering another reaction. These protocols are particularly useful in oncology, where they can avoid the need to switch to less effective alternatives, and they have a very high success rate.

Delayed reactions: patch testing and delayed-read skin testing

Additional diagnostic tools are available for delayed reactions. In addition to skin tests with delayed readings, patch testing may be used. In this test, the drug is applied to the skin using patches placed on the back. Patch testing is less sensitive than delayed-read intradermal testing, but it is safer and is therefore usually the first step in patients with severe reactions. If the patch test is negative, delayed-read skin testing may subsequently be considered.

If a patient develops a mild allergic reaction, such as itching, urticaria or an isolated skin rash, they will generally contact their general practitioner or an out-of-hours medical service for an initial assessment. But what should be done in the event of a severe allergic reaction to a medication?

The situation becomes more urgent when the reaction does not affect only the skin but involves several organ systems.

A systemic reaction is suspected when symptoms involve at least 2 organ systems, for example:

• skin: rash, urticaria or angioedema;
• respiratory system: difficulty breathing;
• gastrointestinal system: significant gastrointestinal symptoms;
• cardiovascular system: marked weakness, dizziness or signs suggestive of circulatory involvement.

In these cases, anaphylaxis should be considered. Anaphylaxis is a severe, potentially life-threatening allergic reaction.

It is a medical emergency because it can worsen rapidly over minutes or hours. For this reason, patients with these symptoms should seek immediate emergency medical care so that appropriate treatment can be given without delay.

“In immediate reactions, the main warning sign is the development of systemic symptoms, with multi-organ involvement and suspected anaphylaxis, or even a single severe symptom at onset, such as faintness, difficulty breathing or a sensation of throat tightness. With delayed reactions, management may be more complex. It is important to assess the severity of the clinical picture carefully:

• if skin lesions progressively worsen and blisters appear;
• if signs of systemic involvement develop, such as fever or generalised malaise.

In these cases, assessment in the emergency department is also recommended,” Dr Yacoub concludes.