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JussiLiippo

Hypersensitivity to Drugs

Essentials

  • Skin eruptions are the most frequent manifestations of drug hypersensitivity, but also changes in blood picture or liver function are possible. Elevation of the body temperature, muscle and joint pain and other general symptoms are present in the most severe drug reactions.
  • Antimicrobial drugs, NSAIDs as well as drugs affecting the central nervous system are the most common causative agents.
  • Viral infections cause similar skin eruptions as drugs do.

In general

  • Drug hypersensitivity reactions may be based on an immunological (allergic) mechanism or on some other feature of the drug (non-immunological/non-allergic reaction).
  • An allergic reaction can always be reproduced and it occurs every time the patient uses the drug and the new reaction is often even stronger than the previous ones.
  • Some allergic reactions can be demonstrated by a skin test or an IgE-based blood test, but a test method is not available for all reactions that are based on an immunological mechanism, or the available test may be unreliable.
    • The causative agent of non-immunological (non-allergic) reactions cannot be determined through skin or blood tests (e.g. ASA/NSAID sensitivity or immediate skin reactions or angio-oedema typically associated with ACE inhibitors).
  • Drug reactions may be immediate or delayed.
  • An immediate allergic/immunological reaction is often IgE-mediated (type I immunological hypersensitivity reaction, e.g. anaphylaxis). Non-allergic reactions may, on the other hand, also be immediate.
  • A delayed allergic/immunological reaction may be e.g. T-cell mediated drug reaction (type IV immunological hypersensitivity reaction, e.g. drug-induced exanthema). Delayed drug reaction can, alternatively, be based on other immunological mechanisms as well.
  • Evaluation of the possible cause of a skin reaction cannot be reliably carried out based on the reaction's clinical appearance Dermatological Diagnosis at a Glance. One drug can cause several types of eruptions, and conversely, clinically similar eruptions can be induced by different drugs.
  • The most common types of drug eruptions are exanthema (picture 1), urticaria (picture 2) and angio-oedema. Other manifestations include erythema fixum (picture 3), erythema multiforme (picture 4), Stevens-Johnson syndrome (SJS; picture 5), toxic epidermal necrolysis (TEN/Lyell's syndrome; picture 6), eczematous reactions, generalized erythrodermia, acute generalized exanthematous pustulosis (AGEP), lichenoid reactions, lupus erythematosus -type reactions (subacute cutaneous lupus erythematosus [SCLE] or systemic lupus erythematosus [SLE]) and erythema nodosum. In some cases a drug may trigger a disease that is generally regarded endogenous (e.g. psoriasis, lichen planus, bullous diseases) or worsen the symptoms of an already existing disease.
  • In the drug-induced DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) with systemic symptoms and organ lesions the skin eruption consists of extensive reddening and scaling and/or blistering, associated with eosinophilia, leucocytosis, elevated body temperature and changes in the liver and kidney tests.
  • The drug reaction may need an external factor, such as ultraviolet light, to occur.
    • A systemic photosensitivity reaction is most commonly caused by doxycycline or chlorpromazine (rarely by other tetracyclines, sulphonamides, sulphonylureas, thiazide diuretics, quinidine and fluoroquinolones).
    • The reaction is usually a phototoxic reaction caused by UVA-range light, limited to skin areas exposed to light.
  • Topical skin application may result in delayed-type T-cell mediated hypersensitivity reaction (type IV immunological reaction) which is manifested clinically as allergic contact dermatitis (eczema). Sensitization to e.g. neomycin or gentamycin cream may later lead to a so-called systemic contact dermatitis after administration of the same or related drug in tablet or infusion form.

Causative drugs

  • The most common causes of drug reactions are antimicrobials (e.g. sulphonamides, beta-lactams, fluoroquinolones and terbinafine), non-steroidal anti-inflammatory drugs (NSAIDs) and drugs acting on the central nervous system (most commonly antiepileptic drugs phenytoin, carbamazepine [picture 7] and lamotrigine).
  • The most severe drug reactions Stevens-Johnson/toxic epidermal necrolysis and DRESS) are most commonly caused by sulphonamides, trimethoprim, antiepileptic drugs, NSAIDs, proton pump inhibitors and allopurinol, and sometimes beta-lactam antimicrobials.
  • Serum sickness -type reactions are caused particularly by penicillins and other beta-lactams, acetylsalicylic acid (ASA), streptomycin and sulphonamides.
  • Cross-allergy between drugs in the penicillins group and cephalosporins is relatively rare in the light of current knowledge. Cross-allergy between aminopenicillins (ampicillin, amoxicillin) and aminocephalosporins (cephalexin, cefaclor) may, however, occur due to the similar amino side chain.

Immediate reactions

  • Type I immediate allergic reactions are IgE antibody -mediated. The patient is sensitized to the drug and has formed specific IgE-type antibodies against it. A large share of acute drug reactions are, however, non-allergic (pseudoallergic), i.e. transmittors are released without an immunological (allergic) mechanism or a preceding sensitization. Drugs can e.g. release histamine directly from mast cells. The clinical symptoms are similar, but the distinction has significance in the diagnostics of reactions (only IgE-mediated reactions can be tested).
  • Pseudoallergic reactions may always not be reproduced, but allergic reactions recur after re-exposure.
  • Drug-induced pseudoallergic reactions may be caused, e.g. by codeine, opioids, hydralazine, quinine and radiographic contrast media. Angio-oedemas caused by ACE inhibitors as well as anaphylactoid reactions caused by muscle relaxants and other anaesthetic agents are examples of these pseudoallergic reactions.
  • The immediate reactions caused by NSAIDs and ASA (urticaria, angio-oedema) are usually not allergic either. Instead, they are related to the drug-induced inhibition of prostanoid synthesis.
  • Of drugs used in anaesthesia, muscle relaxants (and the drug for reversal of relaxation, sugammadex) also cause allergic immediate reactions (anaphylaxis).
  • During surgery, an immediate-type allergic reaction can also be caused by natural rubber latex in surgical gloves or by chlorhexidine in skin disinfectants.
  • 5% of immediate reactions caused by radiographic contrast media are allergic.
  • A reaction resembling an immediate-type allergic reaction can actually be a vasovagal collapse induced by local anaesthesia. Immediate IgE-mediated allergy to local anaesthetics (e.g. lidocaine) is possible but rare.

Urticaria

  • See Hives (Urticaria).
  • The most common causes are beta-lactams (picture 2), quinolones and many other antimicrobials (cause both allergic and pseudoallergic reactions) as well as ASA and other NSAIDs (pseudoallergic reactions).
  • Urticaria can be caused by several other factors (e.g. viral infections) and by different pathological mechanisms. An infection is a common underlying cause of urticaria (more rarely a drug used to treat the infection).
  • Characterized by mildly elevated wheals which are erythematous or pale and often itchy. They appear, disappear and change place within only a few hours.

Angio-oedema

  • Angio-oedema Hereditary Angioedema (HAE) and ACE Inhibitor-Induced Angioedema is a deeperinflammatory reaction of the skin and subcutaneous tissue or the mucosa. It may appear separately or together with simultaneous urticaria. Swelling often occurs in the mucosa of the lips, in fingers and around the eyes (picture 8), in the most severe cases also in the tongue and/or laryngeal area (in an anaphylactic reaction).

Anaphylactic shock

Delayed reactions

Exanthematous eruptions

  • The most common type of drug eruption (pictures 1 9)
  • Most frequently caused by antimicrobials (often beta-lactams) and antiepileptic drugs
  • The clinical symptoms vary. The rash is often formed of erythematous papules and slightly elevated patches (maculopapules) which may later merge to form large coalescent areas of skin eruption.
  • Exanthemas caused by drugs may be delayed allergic reactions.
  • Several viral infections may also trigger an exanthematous eruption.
  • When used in a patient with acute mononucleosis, ampicillin and amoxicillin often cause an exanthematous eruption (picture 10), the exact mechanism of which is unknown. During mononucleosis, however, a patient receiving amoxicillin may also develop T-cell-mediated allergy to the drug.

Purpura

  • See Easy Bruising, Petechiae and Ecchymoses.
  • A purpuric rash consisting of petechiae may sometimes also be caused by a drug.
  • Purpura and small skin erosions may be caused by leucocytoclastic vasculitis of the skin (picture 11).
  • Purpura often starts and is present on the lower limbs where the capillary pressure is at highest.
  • A drug together with the antibodies forms immune complexes that cause complement activation and a local inflammatory reaction in the small capillaries. The reaction leads to endothelial injury in the blood vessels and to petechiae manifested as purpura.
  • The classic allergic purpura may be mediated by a type III immunological reaction (immunocomplex-mediated hypersensitivity reaction). The reaction cannot be investigated by skin or allergy tests.
  • Purpura and cutaneous leucocytoclastic vasculitis can often also be caused by various infections, connective tissue diseases and tumours.

Fixed drug eruption

  • The only skin reaction type which is always provoked by a drug
  • Common causative agents include sulphonamides, trimethoprim, tetracyclines and carbamazepine.
  • A round, sharply marginated, usually intensely red patch which may develop into a blister (picture 12)
  • One or several patches on various sites of the body, also on mucous membranes
  • As the patch heals it leaves a dark brown pigmentation mark that may persist even for months and gradually becomes lighter (picture 13).
  • Always reappears at the same sites when the causative drug is readministered.
  • If the use of the drug continues, the patches often also spread to new sites.

Acute generalized exanthematous pustulosis (AGEP)

  • Reddening of skin often starting in the face and spreading to the trunk and extremities, with predilection for flexural areas
  • Sterile pustules < 5 mm in diameter appear on the flexural surfaces and elsewhere on the reddened skin.
  • Fever up to 39ºC
  • Sometimes resembles pustular psoriasis.
  • Resolves spontaneously (when the intake of the drug is discontinued) in approximately 10-14 days.
  • The most common causative agents are aminopenicillins and NSAIDs, but cases of AGEP caused by numerous other drugs have been reported.
  • A similar clinical picture may also be caused by a viral infection or by ingestion of quicksilver.

Erythema multiforme

  • See Erythema Multiforme.
  • Usually associated with an infection, but may sometimes be triggered by a drug.
  • Round cockade-shaped lesions (picture 14), often in hands
  • General symptoms are mild or absent; itching may occur.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN)

  • A severe drug reaction that causes peeling of mucosal membranes (mouth, eyes, genitals) and skin (SJS is usually and TEN practically always caused by a drug).
  • In the SJS form, the skin is affected to a maximum of 10% of the total skin area in addition to the mucosal membrane changes.
  • In the SJS-TEN borderline form, the peeling skin reaction affects 10-30% of the skin area.
  • In TEN form (Lyell's syndrome) skin peeling occurs in over 30% of the skin area.
  • Starts with prodromal symptoms that may resemble those of a common cold. Tender rash type reddening appears on the skin (maculae, purpura, cockade lesions, erythema), which begins to form blisters and leads to necrosis and peeling of the superficial layers of the skin.
  • The reaction reaches its maximum within about 3-4 days.
  • The initial phase must be recognized and the patient referred to hospital care on emergency basis. All medications used right before the start of the reaction (and, if possible, all other medications in use as well) should be discontinued.
  • SJS/TEN reaction is associated with high mortality through infectious complications (septicaemia) and electrolyte disturbances. Various organ manifestations may also develop.
  • Severe and widespread reactions are treated in intensive care/burn care units.
  • Over 200 drugs have been described as potential causes (sulpha, beta-lactams, allopurinol, NSAIDs, PPIs as the most common ones).
  • Early treatment with immunoglobulins (IVIg) is often used as first line therapy. Ciclosporin, cyclophosphamide, anti-TNF-alpha drugs and plasmapheresis have also been used as treatment alternatives. A high-dose glucocorticoid is often started as emergency treatment in the initial phase: the aim should be to rapidly taper it off.

DRESS (Drug reaction with eosinophilia and systemic symptoms)

  • A severe drug reaction causing general symptoms and organ changes
  • A severe skin reaction with varying degrees of eczema, erythema and vesicles
  • Elevated body temperature over 38°C and lymphadenopathy
  • Haematological changes (eosinophilia and leucocytosis) and organ changes (liver changes, arthralgia, renal changes, pulmonary changes). Elevation of liver values (ALT). Atypical lymphocytes may appear in the blood picture.
  • Begins 2-6 weeks after starting the medication.
  • Often reactivation of HHV6 (human herpes virus 6 )
  • Antiepileptic drugs (aromatic), sulphonamides and dapsone, allopurinol, lamotrigine, cephalosporins, fluoroquinolones, vancomycin, antituberculosis drugs, PPIs
  • Caution should be exercised when considering starting new drugs during DRESS reaction, since sensitization also towards them may occur (so called multiple drug sensitization), which may lead to the reaction becoming prolonged and/or more severe.

Diagnosis of a drug reaction

  • Based usually on patient history, use of drugs and clinical picture
  • Skin and blood tests can be used in some cases.

Patient history

  • Is the eruption really drug-induced? An exanthematous eruption or urticaria suspected to be caused by an antimicrobial or a NSAID is often caused by the underlying infection itself.
  • Which among the drugs used by the patient could be the causative one: is it one in regular use, a newly started drug or course of drug therapy, or a drug used only occasionally?
  • The clinical picture of the eruption? Some drugs, e.g. ASA and other NSAIDs, are commonly associated with a specific type of skin reaction (urticaria, angio-oedema).
  • Does the reaction reappear? Has the drug caused something similar earlier?
  • Timing? If there has been no previous exposure, the allergic reactionusually appears after a latent period of several days or even a couple of weeks of the therapy. On readministration, the reaction appears more rapidly and is often more severe.
  • Elimination? Withdrawal of the suspected drug helps to identify the cause.

Diagnostic investigations

  • Routine laboratory examinations are usually of no help.
  • Immediate allergy is usually investigated by skin prick tests and specific serum IgE antibody assays. An IgE antibody assay is available for penicillin V and G, amoxicillin, cefaclor, some large-molecule drugs such as ACTH and insulin, and for suxamethonium.
  • Skin prick tests with the suspected drugs may be performed when investigating IgE-mediated drug allergy.
    • At expert dermatology/allergology units only because of the hazard of anaphylactic reactions
    • When investigating penicillin allergy, skin prick tests are somewhat more reliable than blood assays. Skin prick tests are used to study immediate-type reactions to local anaesthetics and agents used in general anaesthesia.
  • Intracutaneous (intradermal) tests are also occasionally used for studying drug reactions (both immediate and delayed allergy).
  • Patch testing is the method for detecting delayed, cell-mediated allergy.
    • When investigating exanthematous reactions caused by systemic drugs, patch tests are moderately reliable e.g. in reactions caused by certain antimicrobials with delayed (T-cell-mediated) allergy in the background.
    • Often also used in investigating the cause of an AGEP or DRESS reaction
    • Performed approximately 6 (3-24) months after the reaction
  • If skin tests are negative, a drug challenge test may be performed if the suspected drug is essential in the treatment of the patient.

Drug challenge test

  • Drug challenge tests are time-consuming and expensive. They may also entail risks. The challenge is worthwhile only if the patient really needs the drug in the future and there are no alternatives or if the patient has several suspected drug allergies and, for example, finding a suitable antimicrobial is difficult.
  • Absolute contraindications include anaphylactic reactions, severe life-threatening skin reactions (toxic epidermal necrolysis and Stevens-Johnson syndrome), skin reactions with associated changes in the haematological picture (DRESS), and lupus erythematosus -type (SLE) systemic reactions.
  • May be performed if there is a need to confirm the suitability of a drug that would replace the original drug suspected to have caused a reaction and there are grounds to suspect possible cross-reacting.
  • Performed at the earliest 1-2 months after healing of the skin reaction
  • The suspected drug is given in controlled circumstances, usually in a hospital, orally at a test dose significantly lower than the therapeutic dose. If no reaction occurs, the test can be repeated with a larger dose until the normal therapeutic dose.
  • The test should be started in the morning, and the flare-up of the reaction, pulse rate, blood pressure and body temperature should be followed up at about 1-hour intervals. If no reaction is seen within 24 hours and the patient continues taking the drug at a therapeutic dose, follow-up is continued throughout the whole duration of the drug use so that the patient may contact the monitoring unit whenever needed. Thereby a possible delayed reaction can be established clinically and, if needed, also by skin sample.

Treatment of a drug reaction

  • First of all, the patient must stop taking the suspected drugs (preferably all drugs in use).
  • Stopping the use of the drug is usually sufficient therapy for mild exanthematous eruptions. If necessary, a glucocorticoid cream can be used which may reduce itching.
  • Urticaria reactions are treated by oral antihistamines using adequate dose (2-4 times the normal dose).
  • Prolonged and severe reactions are treated with oral glucocorticoids. The most severe cases are treated in hospital. An emergency referral should be made, if needed.
  • Anaphylactic reactions: see Anaphylaxis.

Further use of the drug

  • If the association between the drug and the skin reaction is verified (typical clinical picture, recurrences, challenge test positive), the patient must not use the drug again. The drug is included in the risk data on the patient.
  • Drug eruptions involve many false diagnoses, and in these cases forbidding the use of the suspected drug is unnecessary. On the other hand, a hazard in recurring reactions is a more severe reaction. Urticaria may develop into anaphylaxis and exanthematous eruption into a serum sickness or pseudolymphoma-type reaction.
  • The significance of uncertain reactions is decided individually, taking into consideration the type and severity of the reaction and the importance of the suspected drug in the patient's further treatment.
  • If a patient has experienced headache or gastrointestinal complaints when using a drug, the drug can usually be prescribed also later.
  • If the suspected reaction has been a severe skin eruption (TEN, SJS, AGEP, DRESS or a severe generalized reaction), the drug should not be tried again.
  • If the reaction has been of immediate type (severe urticaria/angio-oedema or anaphylaxia), giving the same drug again is not safe. If IgE antibody tests are available (penicillins,3-6 months after the reaction) they may be performed. A positive result may confirm the diagnosis. If antibodies are not detected, skin prick tests or a challenge with the drug can be considered.
  • After severe haematological or pulmonary reactions the suspected drug should not be used.
  • In special cases, desensitization of the patient to the drug that caused the reaction may be tried, if the drug is therapeutically irreplaceable and essential. Desensitization is always started under supervision in a hospital setting.

Annotations and reporting

  • A note of the allergy must be written in a clearly visible place in the patient records, including the certainty level and date of the reaction. A detailed description of the reaction is also included in the patient record.
  • A note is also written for the patient's own use regarding the established or suspected drug allergy.
  • Depending on the local policy, the reaction may have to be reported to the authorities. Also suspected allergies may be reported.