Diagnosis and management of suspected drug allergies

Transcription

1 Diagnosis and management of suspected drug allergies SPL Sophie Farooque MRCP Allergic reactions can be caused by commonly prescribed drugs and can lead to fatal anaphylaxis. Here, the author describes the typical reactions to the drugs implicated and how and when to investigate a suspected drug allergy. Figure 1. Skin prick testing, where a small amount of a suspected drug is injected under the skin, is useful in diagnosing drug allergy where there is a good clinical history Adverse drug reactions (ADRs) have been defined by the World Health Organization (WHO) as any noxious, unintended and undesired effect of a drug that occurs at doses used for prevention, diagnosis or treatment. In a four-week prospective cohort study of primary-care clinics 25 per cent of patients reported ADRs, 13 per cent of which were serious. 1 ADRs affect quality of life, may lead to unnecessary investigations or even death. In secondary care, over a six-month period, it was found that ADRs accounted for 4 per cent of hospital bed capacity with a projected cost 466 million. 2 Between 1998 and 2005 serious ADRs increased 2.6-fold. 3 The cost to the NHS is therefore substantial. Allergic reactions to drugs are ADRs and anaphylaxis to drugs is the commonest cause of fatal anaphylaxis in adults with a mean time to death of around five minutes. 4 Antibiotics, NSAIDs, general anaesthetics and radiocontrast media are listed as the commonest culprit drugs in fatal anaphylaxis. 5 Therefore drug allergy needs to be taken seriously. Drugs causing 38 Prescriber 19 April

2 ADRs often presenting to the allergy clinic are listed in Table 1. The term drug allergy refers to immunologically-mediated drug hypersensitivity reactions. These may be either immunoglobulin E (IgE)-mediated (immediate) or non-ige-mediated (delayed) hypersensitivity reactions. Patients will, however, often use the term drug allergy to refer to side-effects of medication. This article will specifically focus on the diagnosis, management and referral criteria for patients with drug allergy. Taking a history from a patient with suspected drug allergy The patient history is the startingpoint when assessing drug allergy and whether to refer. All drug allergies require the patient to be exposed to the same or a cross-reacting compound (sensitisation) at a dose tolerated by the majority of individuals, although patients do not always give a history of prior drug exposure. Immediate reactions (urticaria, angioedema, rhinitis, bronchospasm or anaphylaxis) are usually induced by an IgEmediated mechanism and frequently will occur following the first dose of a course of a drug and often within minutes of ingestion. Therefore the timing of the onset of symptoms after dosing and type of clinical reaction are important pointers to the likely immune mechanism. Sometimes it will be unclear, however, whether the symptoms a patient describes are due to the patient s underlying condition or to the treatment. For example, an urticarial rash may be provoked by an underlying infection or may occur as a result of antibiotic allergy, although earlyonset urticarial reactions are more likely to be IgE mediated. The diagnosis of drug allergy also becomes more difficult if the patient is taking more than one drug, eg paracetamol and amoxicillin. Therefore the histor y of the events surrounding the onset of the adverse reaction is often most important and it is essential to ask patients about both prescribed and over-the-counter preparations taken at the time of the reaction. Most allergic drug reactions will occur within 30 minutes of a patient taking a drug, but there may be a delay between drug exposure and the onset of a reaction with enterically coated preparations or suppositories, eg slowrelease diclofenac. Table 2 details the key questions to be asked when taking a history from a patient with suspected drug allergy. Managing patients with suspected drug allergy Stopping medication If there is a suspicion that a patient has experienced a drug allergy or drug hypersensitivity reaction, the patient should not be prescribed the same drug again without specialist evaluation and an alternative drug should be prescribed instead. This applies even if the history of allergy is vague, eg a rash in childhood. When to refer to a drug allergy clinic Investigation and management of drug allergy is best carried out in specialist centres with large patient numbers and adequate competence and resources to manage complex cases. This is because the diagnosis of drug allergy is a difficult and complex area of medicine and a missed or incorrect diagnosis of drug allergy can have serious consequences. Furthermore, routine or validated tests are not available for the majority of drugs and considerable experience is required for the penicillins and other beta-lactams nonbeta-lactam antibiotics reactions during general anaesthesia to: neuromuscular blockers anaesthetic agents latex (during general anaesthesia) local anaesthetics aspirin/nsaids ACE inhibitors plasma expanders, eg gelofusine others: insulin heparin opiates vaccines radiocontrast media chlorhexidine corticosteroids Table 1. Drugs that are known to cause ADRs often presenting to the allergy clinic investigation of allergic drug reactions and to undertake specific drug challenge. Unfortunately, in the UK and a number of other countries, there are still limited numbers of specialist allergy clinics and so this expertise is limited in availability. The commonest group of patients with a history of drug allergy seen in primary care will be those patients who believe they are allergic to an antibiotic, often penicillin. In many patients avoidance of the suspect drug is sufficient especially if an alternative antibiotic can be prescribed. However, if treatment options are becoming limited or a patient is highly likely to require a particular antibiotic in the future, then they should be referred for further investigation. For example, a patient with COPD who is thought to be allergic to both beta-lactams and a macrolide, and therefore has restricted treatment options, should be referred to a drug allergy clinic. Another example is the patient with chronic pain who has a histor y of developing urticaria while taking an NSAID, who should Prescriber 19 April

3 Is there a temporal relationship between ingestion/administration of the drug and the onset of reaction? How long had the drugs been taken before the onset of reaction? Is the nature of reaction in keeping with known adverse reactions to the drug? Did the reaction resolve with cessation of the drug? Has the patient taken the same drug since and remained well? Were other drugs administered at the same time that could cause the reaction? Was/were there any underlying condition(s) that could explain the reaction? Witness description/photograph? Has the patient been suspicious of this drug before the course of treatment? Table 2. Key questions to ask when taking a history from a patient with suspected drug allergies be referred to the drug allergy clinic for an oral challenge either to confirm the diagnosis of NSAID hypersensitivity or to find out whether they can tolerate an alternative anti-inflammatory such as a COX-2 inhibitor. For specific guidance about which groups of patients should be referred to a drug allergy clinic for further investigation, see Table 3. When a patient is referred on for further investigation there are three groups of tests that an allergist can perform to assess drug allergy: in-vitro allergen-specific IgE (radioallergosorbent test or RAST) skin prick and intradermal tests challenge testing. RAST tests are of value if a reaction is due to IgE-mediated hypersensitivity. However, a basic problem when tr ying to diagnose drug allergy purely by in-vitro immunological methods stems from the fact that most drugs (especially antibiotics) are not complete antigens but rather haptenic metabolites of the parent drug coupled with a carrier tissue protein. With the exception of penicillin, immunoreactive drug metabolites have rarely been identified. Therefore RAST tests tend to be far less sensitive than skin tests, give less information and are expensive. Crucially, a negative RAST to a drug does not exclude drug allergy. Skin prick tests and intradermal tests, where a small amount of the suspected drug is injected under the skin, are more sensitive than RAST or in-vitro tests. Skin tests are a very useful tool in diagnosing allergy to drugs where there is a good clinical histor y. They are highly sensitive and specific. However, they should not be used to screen for drug allergy in the absence of a clear history and, like RAST tests, their usefulness is limited to IgE-mediated immediate hypersensitivity reactions. They are most often used in the diagnosis of penicillin and cephalosporin allergy and when investigating anaphylaxis under anaesthesia. Unfortunately, a negative skin test does not exclude the drug as the cause of the reaction (if the reaction is not IgE mediated, eg anaphylaxis to NSAIDs) and a test may be falsely negative because of limitations in the availability of the relevant skin test reagents (even if IgE mediated). Skin tests can be particularly difficult to interpret for drugs known to be histamine releasers, eg opiates or some neuromuscular blocking agents (NMBAs), or if the drug has been tested at a concentration causing local skin irritation. Therefore it is essential that patients are referred to clinics where there is local expertise and large numbers of patients with suspected drug allergy are seen. 5 Challenge tests or drug provocation tests are performed where there is suspicion of a drug allergy and a need to confirm the diagnosis in the setting of negative skin (or in-vitro) tests. Skin tests are almost always unhelpful for drugs such as aspirin, NSAIDs, opiates, macrolide antibiotics and local anaesthetics and therefore challenge with the suspected drug is needed to confirm hypersensitivity or tolerance. Challenge testing is also used to search for a suitable alternative that might cross-react with the suspect drug, eg challenging with a COX-2 inhibitor in a patient with known NSAID hypersensitivity. Because challenge testing involves giving a patient a drug that they are potentially allergic to, these tests must only be performed by appropriately trained medical specialists where resuscitation facilities are available. After the diagnosis of drug allergy has been established, communication of results and patient education are vital components of overall patient management. It is essential that the patient also takes responsibility for avoiding the drug Forum If you have any issues you would like to air with your colleagues or comments on articles published in Prescriber, the Editor would be pleased to receive them and, if appropriate, publish them on our Forum page. Please send your comments to: The Editor, Prescriber, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, or to prescriber@wiley.com 40 Prescriber 19 April

4 that they are allergic to in the future and obtains a MedicAlert bracelet. This is often overlooked and needs to be reinforced. The allergy clinic will usually give the patient a copy of the clinic letter written to the referring physician for their records. Common drug hypersensitivity or allergic reactions in primary care ACE inhibitor-induced angio edema ACE inhibitors are associated with angioedema (but not urticaria) and the angioedema can develop after a patient has been taking the drug for many years. The lips, face and tongue are the commonest sites involved and the swelling is often unilateral and not associated with pain or itching. Laryngeal involvement is seen in around 10 per cent of patients and can lead to significant airway compromise and even asphyxiation. Angioedema is most often seen in those over 65 years of age and is more prevalent in the Afro- Caribbean population. 6 If a patient develops angio - edema and they are taking an ACE inhibitor, the ACE inhibitor must be discontinued immediately and a different ACE inhibitor should not be prescribed. ACE inhibitors are contraindicated in all patients with a history of angioedema. In patients with ACE inhibitorinduced angioedema, angiotensin- II receptor blockers (ARBs) are often used as alternative medications. Limited data suggest that for patients who develop angioedema while taking an ACE inhibitor, the risk of persistent angioedema when subsequently switched to an ARB is less than 10 per cent. 7 Penicillin and cephalosporin allergy Studies of fatal anaphylaxis in the UK have shown that widely prescribed beta-lactam antibiotics are patients with a history of penicillin allergy who have a significant probability of requiring future antibiotic therapy patients with a history of penicillin allergy in which a penicillin-class anti - biotic is the drug of choice patients with histories of multiple drug allergy/intolerance patients who might be allergic to protein-based biotherapeutic agents and require use of these materials patients with histories of adverse reactions to NSAIDs who require aspirin or other NSAIDs patients who require chemotherapy medications for cancer or other severe conditions and have experienced a previous hypersensitivity reaction to those medications patients with a history of possible allergic reactions to local anesthetics patients with a history of reactions to induction agents or to nonpenicillin antibiotics Table 3. When to refer to a drug allergy clinic responsible for 26 per cent of fatal drug-induced anaphylaxis and 11 per cent of all cases of fatal anaphylaxis. 8 A history of allergy to a penicillin or cephalosporin is common in both community and hospitalised patients and therefore cannot be ignored and must always be recorded. However, there are numerous reports that around 90 per cent of individuals who believe they are allergic to penicillins will in fact tolerate penicillin use; 10 for the patient this places unnecessary constraints on antibiotic use, potentially resulting in less effective and more expensive treatment. Furthermore, due to concerns about penicillin cross-reactivity with cephalosporins, these patients are unable to access a second beneficial group of antibiotics. Cephalo - sporins share a common beta-lactam ring with the penicillins but the degree of cross-reactivity is quite low, with around 3 7 per cent of those with penicillin allergy reporting allergic reactions to cephalo - sporins as well. Patients who are highly likely to require antibiotics in the future or whose treatment options are being limited by presumed penicillin allergy should therefore be referred to a specialist drug allergy clinic. Skin testing is of definite value in assessing allergy to penicillin and the vast majority of penicillin-allergic individuals will be identified by these tests. This must be done by an allergist in a place where appropriate emergency equipment is available, since the skin test itself can cause anaphylaxis in patients with extreme penicillin allergy. If the skin tests are positive, the patient is allergic to penicillin. If negative, the results provide a strong indication that the patient is not penicillin allergic but do not rule it out completely. Therefore the final stage of testing is oral challenge with penicillin, which again must be carried out in an environment where resuscitation can be carried out if necessary (see Figure 2). If a penicillin must be given to a patient with proven penicillin allergy, then desensitisation is necessary and must be carried out in hospital by a specialist allergist. A final note: most nonpruritic maculopapular rashes (common in children) will not be predicted by skin testing, which is only helpful in predicting reactions caused by IgE antibodies. Maculopapular Prescriber 19 April

5 history suggestive of allergy to beta-lactam positive drug allergy skin prick test positive Figure 2. Diagnosis of suspected beta-lactam antibiotic allergy exanthems are not IgE mediated and are probably viral or associated with drug/virus interactions. They often occur many hours after last drug intake and several days into a course of treatment and do not necessarily preclude future penicillin use. Hypersensitivity to NSAIDs Aspirin and other NSAIDs can cause a spectrum of drug-induced allergic reactions, including exacerbation of underlying asthma and rhinosinusitis, urticaria, angio - edema and anaphylaxis. Aspirin-exacerbated respiratory disease (AERD) affects between 5 and 10 per cent of all asthma patients. It involves both upper and lower airways and is characterised by chronic eosinophilic rhinosinusitis, nasal polyposis and usually moderate-severe asthma. negative intradermal skin test positive negative oral challenge negative The ingestion of aspirin and other COX-1 inhibitors induces exacerbations of air way disease that may be life-threatening, but avoiding aspirin does not ameliorate the course of the disease. It is more common in women than in men with an average age of onset of around the age of 30 years. Asthma might be present since childhood or might develop de novo, on average two years after the onset of nasal congestion and polyposis. 10 Other hypersensitivity reactions to aspirin or other NSAIDs can also occur. Patients with chronic urti - caria/angioedema may note an acute worsening following ingestion of NSAIDs but often can tolerate COX-2 inhibitors. Patients without a history of underlying chronic urticaria/ angioedema can also develop acute urticaria/ angioedema following the ingestion of aspirin or NSAIDs. Some of these patients demonstrate cross-reactivity to other COX-1 inhib itors, whereas others have selective reactions to a particular NSAID. Finally, anaphylactic reactions to NSAIDs are usually drug specific, and these patients typically tolerate other NSAIDs. Some patients are not easily categorised and have blended reactions with overlap of various clinical features from the above well-described aspirin/nsaid reaction syndromes. 11 Therefore individuals with a history of adverse reactions to NSAIDs who require aspirin or other NSAIDs should be referred for further evaluation. Conclusion Drug allergy is one type of adverse reaction to drugs and encompasses a spectrum of hypersensitivity reactions with heterogeneous mechanisms and clinical presentations. A thorough history is essential when assessing patients with suspected drug allergy. Skin testing with drugs requires considerable expertise for both performance and interpretation, and graded dose challenges and procedures to induce drug tolerance might be required when there is a definite need for a particular agent. Expertise in performing these investigations is essential and patients should be are referred to an appropriate national centre (the British Society for Allergy and Clinical Immunology website will provide details of your nearest allergy centre; Patients will often carr y an incorrect label of drug allergy and investigation will help to identify a significant proportion in whom allergy can be excluded and alternative, more costly treatments avoided. 42 Prescriber 19 April

6 References 1. Gandhi TK, et al. N Engl J Med 2003;348: Pirmohamed M, et al. BMJ 2004; 329: Moore TJ, et al. Arch Intern Med 2007; 167: Pumphrey RS. Clin Exp Allergy 2000;30: Mirakian R, et al. Clin Exp Allergy 2009;39: Khan DA, et al. J Allergy Clin Immunol 2010;125(2 Suppl 2):S Haymore BR, et al. Ann Allergy Asthma Immunol 2008;101: Pumphrey R. Curr Opin Allergy Clin Immunol 2004;4: Gadde J, et al. JAMA 1993;270: Farooque SP, et al. Annu Rev Physiol 2009;71: Quiralte J, et al. J Investig Allergol Clin Immunol 2007;17: Dr Farooque is clinical lead in allergy at Imperial College Healthcare NHS Trust (St Mary s Hospital), a member of the British Society for Allergy and Clinical Immunology Standards of Care Committee and runs the drug allergy skin testing and drug challenge service at St Mary s Hospital in Paddington Prescriber 19 April