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Disease Summaries

Drug Allergies

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Updated 2014
Original posting January 2007

Bernard Thong MBBS, MRCP (UK), FRCP (Edin), FAAAAI
Tan Tock Seng Hospital
11, Jalan Tan Tock Seng
Singapore 308433
SINGAPORE

and

Daniel Vervloet MD FAAAAI
Hopital Sainte Marguerite
Service De Pneumo-allergologie
Marseille Cedex 9 132 74
FRANCE

 

DEFINITION AND CLASSIFICATION

Adverse drug reactions (ADRs) are broadly divided into predictable (related to pharmacologic actions of the drug in otherwise normal individuals) and unpredictable reactions (related to individual’s immunological response and, on occasion, to genetic differences in susceptible patients). Drug allergy is a type of unpredictable reaction.

The term "drug hypersensitivity"1 refers to objectively reproducible symptoms or signs initiated by exposure to a drug at a dose normally tolerated by non-hypersensitive persons. "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 [1].

"Nonallergic hypersensitivity reactions" refer to ADRs that are not immunologically mediated.

ADRs should be differentiated from adverse drug events (ADEs). ADEs extend beyond ADRs to include harm related to medication errors and drug/food interactions. While knowledge of ADEs is important in efforts to improve patient safety, ADRs are the primary focus of regulatory agencies and post-marketing surveillance.

MECHANISMS

Drug allergy may be IgE or non-IgE mediated.

In IgE-mediated reactions, (e.g., urticaria, angioedema, anaphylaxis). drug allergens bind to IgE antibodies, which are attached  to mast cells and basophils, resulting in IgE cross-linking, cell activation and release of preformed and newly formed mediators.
In non–IgE-mediated drug allergy, the mechanisms include

  • cytotoxic/cytolytic reactions involving the interaction of IgG or IgM antibodies and complement with a drug allergen associated with cell membranes (e.g., immune hemolytic anemia, thrombocytopenia),
  • drug immune complex reactions (e.g., serum sickness and drug-induced lupus), and
  • T-cell–mediated reactions.

By far, T-cell–mediated reactions are generally the most prevalent type of reaction. There are three main processes by which T cells are stimulated by drugs [2]:

  • Hapten concept:Haptens are chemically reactive small compounds (<1000 d) that bind to proteins/peptides and modify them covalently. These subsequently may
    • stimulate the innate immune system by covalently binding to cellular proteins, thereby transmitting a danger signal, which in turn results in stimulation; or
    • stimulate the specific immune system by forming hapten-carrier complexes, which in turn can form neoantigens. The hapten-protein complexes are processed and then presented as hapten-modified peptides to T cells, which can react with these peptides.
  • Pro-hapten concept: Pro-haptens are not chemically reactive and cannot form a covalent bond with a peptide. To become chemically reactive, they must first be converted into a hapten by being metabolized into a compound that is chemically reactive.
  • Pi (pharmacologic interaction with immune receptors) concept:A chemically inert drug, unable to covalently bind to proteins, is still able to "fit" to some of the many immune receptors (as it does to other proteins/receptors). Under certain circumstances, this reversible drug–receptor interaction can activate immune cells specific for peptide antigens, which then expand and cause inflammatory reactions of different types. A primary immune response to the drug is not necessary for such a reaction to occur, but an expansion of drug-reactive cells may be required before symptoms appear.

In toxic epidermal necrolysis (TEN), there is a specific drug hypersensitivity restricted to HLA class I antigens, resulting in clonal expansion of CD8+ cytotoxic T lymphocytes (CTLs). Cytotoxicity is mediated by CTL granzymes and possibly death receptor (DR) ligand (DR-L) and Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression.

EPIDEMIOLOGY

ADRs account for 3% to 6% of all hospital admissions and occur in 10% to 15% of hospitalized patients. Drug allergy is relatively uncommon, accounting for less than 10% of all ADRs. Drug allergy, occurs in 1% to 2% of all admissions and 3% to 5% of hospitalized patients, respectively but the true incidence of drug allergy in the community, and among children and adults, is unknown. Many children are misdiagnosed as being “allergic” to various medications, particularly antibiotics and end up carrying this label into adulthood. These patients are frequently treated with alternate medication that may be more toxic, less effective and more expensive – this in turn may result in increased morbidity, mortality and cost (economic) [3].

The true incidence of drug-induced anaphylaxis is also unknown, as most studies have been based on all causes of anaphylaxis or all causes (both allergic and nonallergic) of ADRs.

The estimated incidence of Stevens-Johnson Syndrome (SJS), which may occur secondary to ADR, is 0.4 to 1.2 per 1 million people per year; the estimated incidence for TEN is 1.2 to 6 per 1 million people per year.

RISK FACTORS FOR DRUG ALLERGY

While the development of drug hypersensitivity is impossible to predict with any certainty, some factors have been elucidated which, when present, increase the likelihood of such a reaction occurring. [3] These factors may be drug related or host (patient) related (Table 1)

Table 1 RISK FACTORS FOR DRUG ALLERGY

Drug Factors

  • Nature of the drug
  • Degree of exposure (dose, duration, frequency)
  • Route of administration
  • Cross-sensitization

Host Factors

  • Age and Sex
  • Genetic factors (HLA type, Acetylator status)
  • Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human immunodeficiency virus (HIV), asthma)
  • Previous drug reaction
  • Multiple allergy syndrome

Drug Factors

  • Nature of the drug
    It is difficult to predict the sensitizing capacity of a drug prior to widespread clinical use on the basis of its chemical structure. When a chemical substance is clearly protein-reactive, a high incidence of sensitization may be expected. Many highly allergenic drugs are not clearly chemically reactive. In this situation, it is probable that metabolic products of the drugs or minor contaminants are much more reactive, and are responsible for clinical sensitization. Although numerous drugs have been implicated in the production of allergic reactions, those frequently implicated are listed in Table 2. Penicillins, aspirin, and sulfonamides account for over 80 percent of allergic drug reactions. Approximately 1 to 3 percent of patient courses of penicillin are complicated by allergic reactions.
     
  • Degree of exposure (dose, duration, frequency)
    There is some evidence that sensitization is more likely with higher drug doses and prolonged administration, but clinically this does not appear to be important. Of greater importance are intermittent courses of moderate drug doses that clearly predispose to sensitization; prolonged treatment without free intervals is less likely to do so. The incidence of allergic penicillin reactions among patients receiving long-term prophylaxis is extremely low.During a single course of treatment, the likelihood of a reaction is greater during the first two or three weeks of therapy. With the exception of contact dermatitis, the route of administration is of little importance in the type of hypersensitivity reaction produced.
     
  • Route of Administration
    Topical application of a drug is associated with a high incidence of sensitization and should be avoided with certain agents, especially on inflamed skin.Penicillin and sulfonamides are no longer used topically because of this risk. Oral administration of a drug is generally safer than any type of parenteral administration; however, severe reactions have followed this mode of administration. The increased use of penicillin orally may be a reason why the risk of penicillin sensitization has been decreasing. The intravenous route may be the least sensitizing form of parenteral administration although it has been associated with catastrophic anaphylactic reactions.
     
  • Cross-Sensitization
    Once sensitization to a drug has occurred, the possibility exists of reactivity either to drugs with a close structural chemical relationship or to immunochemically similar metabolites. The range of cross-sensitization varies greatly among individuals and is often impossible to predict. Familiar examples include substances having a free amino group in the para acid, para-aminobenzoic acid, and sulfonamides; phenothiazine derivatives such as chlorpromazine, prochlorperazine, promethazine, trifluoperazone, trimeprazine, and triflupromazine; and the cross-reactivity seen among penicllins and cephalopsporins. Pholcodine is hypothesized to be a source of cross-sensitization among patients who developed hypersensitivity reactions to neuromuscular blocking agents.
     

Host Factors

  • Age and sex
    Some allergic reactions to drugs are probably less frequent in children and elderly patients, possibly owing to immaturity or involution of the immune response. Children have not had the repeated exposure to drugs necessary for sensitization to occur. One study did not find an age difference with cutaneous drug reactions. There is no conclusive evidence, with the possible exception of cutaneous reactions, that allergic drug reactions are more common in females than in males. The differences regarding age and sex are not significant determinants in the selection of a drug for therapy.
     
  • Genetic factors (HLA type, Acetylator status)
    Allergic drug reactions occur in only a small percentage of patients treated with a given drug. It is likely that many factors, both genetic and environmental, are involved in determining which individuals in a large random population will develop an allergic reaction to a given drug. The presence of atopy is not a risk factor for drug allergy, although patients with uncontrolled asthma may be more prone to having severe reactions (as is the case with food allergies).Theoretically, genetic factors of various kinds, operating at different levels, may need to coexist in an individual before an allergic drug reaction occurs. The patient may require genetic information to form reactive metabolites, to produce specific types of antibodies, and to elaborate various pharmacologically active mediators. As the probability of coexistence of all these factors is probably quite low, this would explain the low incidence of allergic drug reactions in the general population.
    • HLA B*1502 associated with carbamazepine induced SJS/TEN in Han Chinese in Taiwan, Hong Kong, Thais and Indians; but neither in Japanese nor Europeans of non-Asian ancestry
    • HLA B*1502 associated with phenytoin induced SJS in Han Chinese in Hong Kong and Thais but not with MPE among Han Chinese from Hong Kong
    • HLA B*5801 and allopurinol induced SJS/TEN in Han Chinese from Taiwan, Thais, Japanese and Europeans
    • HLA B*5701 and abacavir drug hypersensitivity in Caucasian males and females but not blacks. This haplotype has been found to be uncommon in Taiwanese Chinese and Korean populations.
    • IgE mediated penicillin allergy: E237G variant of FceR1b (high affinity IgE receptor b chain) gene, IL-4RaQ576R polymorphism, IL-4 IL-13-SNP polymorphisms in Chinese
    • Immediate allergic reactions to beta-lactams: IL-13 (R130Q and -1055C>T variants) and IL-4RA (150V, S478P, and Q551R variants) polymorphisms in Italians; lle75Val variant of IL-4Ra gene two linked IL-10 promotor gene polymorphisms (-819C>T and -592C>A) in Causasians
    • Antituberculous drug induced hepatitis: CYP2E1 in the Chinese (but not in Korean and British), NAT2 (N-acetyltransferase) in Koreans and GST (glutathione-S-transferase) genotypes in Caucasians.


    Pharmacogenetic testing for HLA-B*5701 is now standard of care prior to prescription of abacavir in Caucasian populations. In certain countries in East and South East Asia, testing for HLA-B*1502 has been mandated/ recommended prior to prescription of carbamazepine.
     
  • Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human immunodeficiency virus (HIV), asthma)
    The disease state may affect the development of allergic drug reactions by altering metabolic pathways and inducing variations in the immunologic responses to drugs. Drug reactions should occur less frequently among individuals whose immunologic responsiveness is impaired. For example hypogammaglobulinemia, drug allergy due to antibodies is rare, but cell-mediated reactions, such as contact dermatitis caused by topically applied drugs, may be easily induced. Conversely, patients with sarcoidosis have impaired cellular hypersensitivity, and are less likely to develop contact dermatitis and some drug exanthems, but may develop urticaria and other antibody-mediated allergic drug reactions. The initial impression that drug hypersensitivity is more common among patients with systemic lupus erythematosus has not been confirmed. Certain infections appear to be associated with the increased likelihood of drug hypersensitivity e.g. ampicillin maculopapular rashes arise commonly in patients with infectious mononumcleosis (EBV infection), although there is rather convincing evidence that this response is not immunologically-mediated. ADRs are frequently encountered in patients with HIV and AIDS, particularly those on co-trimoxazole (trimethoprim – sulfamethoxazole). Whether these frequent reactions are due to increased propensity or increase use of certain drugs is unclear.
     
  • Previous drug exposure
    There is some evidence that patients who have demonstrated drug hypersensitivity in the past may have an increased tendency to develop sensitivity to new drugs, and one should be more cautious in medicating such patients. Obviously, if the drug is somewhat related to the one causing difficulty in the past, one must be on the alert for cross-sensitization.
     
  • Multiple Drug Allergy Syndrome
    Patients with ‘multiple drug allergy syndrome” [4] may have a predilection to more than one non-cross-reacting medication. Well-defined case series of patients where multiple drug allergy have been proven with in-vivo and in-vitro tests have been described.
     

Table 2 DRUGS FREQUENTLY IMPLICATED IN ALLERGIC DRUG REACTIONS

Aspirin (other analgesics-antipyretics)
Penicillins and cephalosporins
Sulfonamides
Antituberculous drugs
Nitrofurans
Antimalarials
Griseofulvin

Sedative-hypnotics
Anticonvulsants
Anesthetics (local and general)
Phenolphthalein
Antipsychotic tranquilizers
Antihypertensive agents (hydralazine)
Antiarrhythmia agents (quinidine, procainamide)
 

Iodinated contrast media
Antisera and vaccines
Organ extracts (ACTH, insulin)
Heavy metals (gold)
Allopurinol
Penicillamine
Antithyroid drugs

DIAGNOSIS

The diagnosis of drug allergy is based on a detailed history of the onset of symptoms/signs combined with a temporal relationship between the appearance of those symptoms and drug use/discontinuation. The clinical diagnosis is followed by carefully selected diagnostic tests depending on whether the reaction is IgE or non-IgE mediated.

A few of the important principles of drug allergy include:

  1. Drug allergy usually occurs in the presence of previous/adequate sensitization to the drug. Most drug allergies develop after 5 to 7 days of exposure to the drug. However, some may develop only after 2 to 6 weeks of exposure to the drug.
     
  2. When a drug allergy develops immediately after the first dose of the drug, the allergic reaction may be due to previous exposure and sensitization to the drug or to previous sensitization from molecules similar to those in the putative drug. It is also possible that the reaction is not due to drug allergy (e.g., hypersensitivity reactions to nonsteroidal anti-inflammatory drugs [NSAIDs] or to certain radiocontrast media).
     
  3. A drug allergy may take the form of a cutaneous reaction or a systemic reaction with major organ involvement, or both.
     
  4. Potentially life-threatening drug allergies include anaphylaxis, SJS and TEN.

Clinical Diagnosis: Pattern of reactions

Cutaneous Reactions

The morphology and distribution of the drug eruption is important. Common morphologies include urticaria, angioedema, maculopapular exanthema (MPE), fixed drug eruption, eczema, photodermatoses, erythema multiforme, generalized exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), erythroderma, cutaneous vasculitis and bullous eruptions.

Severe cutaneous reactions are defined as follows:

  1. SJS: detachment of less than 10% of the body surface area plus widespread erythematous or purpuric macules or flat atypical targets with at least two mucosal surfaces involved (i.e., oral, conjunctival or genital)
     
  2. Overlapping SJS and TEN: Detachment of 10% to 30% of the body surface area plus widespread purpuric macules or flat atypical targets
     
  3. TEN: Detachment of more than 30% of the body surface area plus widespread purpuric macules or flat atypical targets

Drug-Induced Hypersensitivity Syndrome

Drug-induced hypersensitivity syndrome (DIHS)

comprises the following features, with the diagnosis confirmed by the presence of any five of the six criteria:

  1. Maculopapular rash developing ≥3 weeks after starting therapy with a limited number of drugs
  2. Lymphadenopathy
  3. Fever (≥38°C)
  4. Leukocytosis (≥10 ´ 109/L), atypical lymphocytosis or eosinophilia
  5. Hepatitis (alanine aminotransferase [ALT] ≥100 U/L)
  6. Human herpes virus (HHV)–6 reactivation

The term DIHS is now used synonymously with other nomenclature including Drug Reaction, Eosinophilia and Systemic Symptoms (DRESS) and Drug Hypersensitivity Syndrome (DHS).

Anaphylaxis

This is a severe life-threatening, generalized or systemic hypersensitivity reaction which may be IgE or non-IgE mediated. It is usually characterized by one or more of the following: generalized erythema, or flushing, urticaria, angioedema of the face, lip, tongue or uvula, stridor, rhonchi and/or hypotension. Anaphylaxis is a clinical diagnosis for which drug-induced anaphylaxis is one of the most easily avoidable causes.

Diagnostic Tests

Diagnostic tests [5,6,7] should be used as an adjunct to the clinical history and examination. The type of diagnostic test depends on whether the initial reaction was IgE or non-IgE mediated.

In Vitro Tests

Measurement of mediators (histamine, tryptase, leukotrienes) released in peripheral blood, nasal or bronchial secretions or urine may be useful in the diagnosis of immediate hypersensitivity type allergic reactions. Levels may be measured at baseline and after allergen challenge. One commercially available test measures serum total tryptase levels, with serial specimens taken at 1 and 6 hours after an acute anaphylactic reaction. Although elevated levels support a diagnosis of anaphylaxis, this criterion is not completely reliable; normal levels have been found even in cases of fatal anaphylaxis. In addition, these tests are expensive. Although histamine levels have been described to correlate better with symptoms and signs of anaphylaxis, plasma histamine levels remain elevated for only 1 hour after symptom onset - therefore, this test is not reliable.

Allergen-specific IgE levels are measured by either radioallergosorbent tests (RASTs) or radioimmunoassay (RIA). These tests are commercially available in the form of ImmunoCAP®  fluorescent enzyme immunoassay (FEIA) tests for a limited number of drugs, including penicilloyl, amoxicilloyl, ampicilloyl, cefaclor, protamine, insulin and suxamethonium. In general, these tests although generally specific, lack sensitivity compared to clinical history and/or skin tests. They have not been well validated even for beta-lactam antibiotics for which studies are the most commonly available. Thus in clinical practice, utility for these tests is limited.  

Flow cytometry–based basophil activation assays (also known as flow cellular antigen stimulation tests [CASTs]), which measure levels of CD 63 and CD 203c on activated basophils, are currently not widely used because of technical concerns, false-positive results, and lack of sensitivity and specificity. They have been used in research in the diagnosis of drug (beta-lactam and NSAID) hypersensitivity.

The CAST–enzyme-linked immunosorbent assay (ELISA) can be considered an in vitro allergy provocation test. The patient's collected leukocyte blood fraction is exposed in vitro to the suspected specific allergen. After incubation, the cellular supernatant is tested for the de novo synthesis of sulfidoleukotrienes by a highly specific ELISA. Although commercially available, the test is not widely used in the diagnosis of drug allergy because of inconsistent results from various research studies.

The presence or absence of peripheral blood eosinophilia or elevated total IgE levels is not useful in the diagnosis or exclusion or drug allergy. However, eosinophilia may be present in drug hypersensitivity syndromes.

For hematological manifestations of drug hypersensitivity (e.g. haemolytic anaemia, leukopaenia, thrombocytopaenia), there is usually no specific diagnostic test or serological test apart from recovery of the cytopaenia following withdrawal of the putative drug. A positive direct Coomb’s test is useful in screening for immune-mediated hemolytic anaemia. Drug-induced IgM and IgG have not been found to be clinically useful.

The lymphocyte transformation test (LTT) has been shown to be useful in the diagnosis of T-cell mediated delayed hypersensitivity reactions in a wide variety of delayed reactions with a wide variety of drugs. Although a positive LTT is useful in confirming the diagnosis, a negative test cannot exclude drug hypersensitivity. Positive LTT are usually drug-specific, and reaction-specific.

In Vivo Tests

Skin tests [6] are useful in the diagnosis of IgE-mediated allergy. A positive skin prick test (SPT) is defined as mean weal diameter >e;3 mm (associated with a flare response) compared to the negative control after 15 to 20 minutes.

A positive intradermal test (IDT) is defined as an increase in the mean weal diameter of ≥3 mm compared to the baseline diameter for the negative control after 15 to 20 minutes. An IDT is accomplished by injecting 0.02 to 0.05 mL of an allergen intradermally, raising a small bleb measuring 3 mm in diameter. The IDT is more sensitive than the SPT, but also carries a higher risk for inducing an irritative, falsely positive reaction and might even lead to anaphylaxis in IgE-dependent reactions. Readings should be taken after 15 to 20 minutes for evaluation of immediate reactions, and after 24 and 72 hours for evaluation of nonimmediate (late) reactions.

Patch tests [7] are used in specialized centers for the diagnosis of delayed hypersensitivity drug reactions. In these tests a patch imbedded with the suspected allergen is fixed on the back of the patient for 1 to 2 days and the result is read after 1 day and/or after 2 to 3 days. A photopatch test is a modification of the patch test used when photoallergic or phototoxic reactions are suspected. After 1 day the test patch is removed and the skin is irradiated with ultraviolet A light 5 or 10 J/cm2. This test is read after 2, 3 and 4 days.

Recommendations on non-irritating skin test concentrations for SPT, IDT and patch tests have been published.

A skin biopsy per se may not be helpful in the diagnosis of drug allergy because there are no absolute histopathologic or immunohistochemical findings in most drug exanthems. However, it may be useful when the differential diagnoses include other skin conditions with typical histologic patterns. For instance, drug-induced maculopapular exanthems may be differentiated from secondary syphilis characterized by plasma cell–rich mononuclear cell infiltrates, or from connective tissue disease characterized by interface dermatitis with epidermal atrophy, focal parakeratosis, dermal mucinosis and fibrinoid deposition in dermis.

Drug provocation (challenge) tests (DPTs) [8,9] are used to objectively reproduce the patient’s symptoms and signs of hypersensitivity using the suspected agent. A positive test does not confirm allergy (i.e. an immune-mediated reaction).

DPT involves administering the drug using slow, incremental dose escalations at fixed time intervals and observing for the presence or absence of an objective reaction. It is not without risk to the patient and should be done only under the strict supervision of clinicians/nurses with allergy training and with resuscitative equipment available.

DPT may be used in the following four instances:

  1. To exclude drug hypersensitivity when the history is nonsuggestive or the symptoms nonspecific
  2. To provide safe pharmacologically and/or structurally nonrelated drugs in cases of proven hypersensitivity (e.g., beta-lactam antibiotics)
  3. To exclude cross-reactivity of related drugs in cases of proven hypersensitivity (e.g., cephalosporin in a penicillin-allergic individual)
  4. To definitively diagnose drug allergy when the clinical history is suggestive but allergological tests are negative, inconclusive or unavailable

Specific contraindications to DPT include pregnancy; comorbidities in which DPT may provoke the medical situation beyond the ability to control it (e.g., acute infections; uncontrolled asthma; or underlying cardiac, hepatic or renal diseases); immunobullous drug eruptions; and cases in which the initial reaction was a severe cutaneous and/or systemic reaction (e.g., SJS and TEN).

The risks and benefits of any DPT must be explained to the patient and informed consent obtained. Short-acting antihistamines (e.g., chlorpheniramine or hydroxyzine) should be stopped for 3 days and long-acting antihistamines (e.g., cetirizine, loratidine or fexofenadine) for 7 days before performing any DPT. Patients should also be fasted overnight and carefully observed at all times during the DPT for symptoms or signs of an adverse reaction. Resuscitation equipment should be available at all times, and staff should be trained in the management of acute anaphylaxis.

Other investigations for drug hypersensitivity

In drug induced pneumonitis, a plain chest x-ray, pulmonary function tests and high resolution CT thorax may be useful. Bronchoalveolar lavage and open lung biopsy for histological diagnosis are usually not necessary.

TREATMENT

Apart from immediate cessation of the putative drug, the following measures should also be taken:

Acute Immediate Management of IgE-Mediated Reactions

  • Nonserious (mild cutaneous) reactions: antihistamines
     
  • Serious reactions (anaphylaxis): emergency management, including securing the airway; maintaining breathing and circulation; and use of drugs, including:
    • Intramuscular epinephrine 0.3 mL of a 1:1,000 concentration up to every 5 minutes in adults or 0.01 mg/kg in children up to a maximum dose of 0.3 mg
    • Intramuscular promethazine or intravenous diphenhydramine
    • Intravenous fluids (colloids or crystalloids)
       
    Systemic corticosteroids may be used to prevent the delayed-phase reaction in acute anaphylaxis and to prevent/treat associated angioedema and lower airway inflammation. This has been extrapolated from its use in acute asthma, with a recent Cochrane systematic review failing to identify any evidence from randomized, controlled trials to confirm the effectiveness of corticosteroids in acute anaphylaxis.

Acute Immediate Management of Non–IgE-Mediated Reactions

  • Nonserious reactions: antihistamines
     
  • Serious reactions
    • SJS: The use of tapered doses of systemic corticosteroids is not uniformly practiced by all specialists in drug allergy. Oropharyngeal hygiene and gargle solutions, as well as eye care (sterile eye management, use of topical corticosteroids), should be ensured.
    • TEN: Skin care, eye care (sterile eye management, topical corticosteroids), adequate hydration and nutrition and respiratory care are paramount. High-dose intravenous immunoglobulin (IVIG 1 g/kg/d for 2 days) has been used at various centers with generally good outcomes, especially in improving skin re-epithelialization. However, the evidence remains controversial, and the original hypothesis on the anti-apoptotic effect of IVIG now does not appear to be so. Other immunosuppressive therapies, including cyclophosphamide, plasmapharesis and systemic corticosteroids, have not been found to be uniformly useful. Recent interest has re-emerged on the possible benefits of ciclosporin provided patients have not developed acute kidney injury and uncontrolled infection.
    • DIHS: The use of tapered doses of systemic corticosteroids is not uniformly practiced by all specialists in drug allergy.

Specific Treatment

Drug Desensitization

Desensitization is a process in which the drug to which the patient is allergic is administered to the patient in small, incremental doses to induce a state of temporary tolerance to the drug. This should only be attempted if the offending drug is deemed essential and no alternatives are available [10]. This treatment has been well established for IgE-mediated drug allergy, specifically to penicillins. Hypotheses as to the mechanisms underlying successful of drug desensitization include mast cell desensitization, hapten inhibition, IgE consumption and mediator depletion.

Drug desensitization for non–IgE-mediated drug allergy has also been described for various drugs. Although treatment has been shown to be effective, the underlying mechanisms for its success remain unknown.

The methods of inducing tolerance are all similar but specifics vary. Assuming that there is a need for the drug that cannot be met in any other way and warrants the risks of desensitization, a schedule is prepared that is appropriate for the clinical circumstances. In some situations, rapid desensitization in a few hours may be required. Desensitization over a period of days to weeks may be acceptable if the need is for prophylaxis or more chronic treatment. Desensitization via the oral route may be safer than by the parenteral route, but the process is dependent on adequate absorption and may be complicated by vomiting. A beginning dose can be selected as a fraction, possibly 0.1-1%, of the subject ’s known tolerance of the agent or by arbitrarily starting with 1 per 100 to 1 per 1 000 or even less of a therapeutic concentration. Subsequent doses are then increased by approximate doubling. After the therapeutic concentration (dose) is reached, the patient should continue to receive the agent.

Induction of tolerance to the offending drug is temporary - patients should still be regarded “allergic” to that particular drug. Should the patient require the medication 3-7 days after cessation the desensitization process should be reinstituted..

Regimes have been described for many drugs including penicillins, cephalosporins, cotrimoxazole, allopurinol and the chemotherapeutic agents. Following is a list of drugs for which desensitization protocols have been described in the literature: (Table 3)

Table 3 AGENTS FOR WHICH DESENSITIZATION PROTOCOLS AVAILABLE

Antimicrobial agents

Ampicillin
Aztreonam
Cefotaxime
Ceftazidime
Ceftriaxone
Ciprofloxacin
Clarithromycin
Clindamycin
Co-trimoxazole
Daptomycin
Enviomycin
Ethambutol
Imipenem/cilastatin
Isoniazid
Linezolid
Meropenem
Metronidazole
Penicillin
Quinidine
Rifampicin
Streptomycin
Sulphadiamine
Sulphadiazine
Tobramycin
Vancomycin

Antifungal agents

Fluconazole
Itraconazole

Antiviral agents

Acyclovir
Amprenavir
Darunavir
Efavirenz
Enfuvartide
Nelfinavir
Nevirapine
Tipranavir
Zidovudine

Biologic agents

Adalimumab
Cetuximab
Glatiramer acetate
Infliximab

Chemotherapeutic agents

l-asparaginase
Carboplatin
Cisplatin
Cytarabine
Docetaxel
Imatinib mesylate
Lenalidomide
Mechlorethamine
6-Mercaptopurine
Oxaliplatin
Paclitaxel
Sunitinib
Thalidomide

Immunosuppressive agents

Azathioprine
Cyclosporine
Dapsone
Hydroxychloroquine
Mesalazine
Methotrexate
Mycophenolate mofetil
d-Penicillamine
Sulfasalazine

Nonsteroidal anti-inflammatory drugs

Aspirin
Flurbiprofen

Antiepileptic drugs

Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin

Hormonal therapies

Anastrazole
Corticotropin
Follicle-stimulating hormone
Growth hormone
Insulin

Miscellaneous

Antithymocyte globulin
Allopurinol
5-Aminosalicylic acid
Buprenorphine
Calcitonin
Calcitriol
Clopidogrel
Colchicine
Desferrioxamine
Enoxaparine
Erythropoietin
Ferrous compounds
Fluorescein
Fluoxetine
Furosemide
Heparin
Imiglucerase
Interferon
Isonicotinic acid hydrazine
Methylphenidate
Neuromuscular receptor blockers
Opioids
Radiocontrast media
Ubiquinone
Warfarin

PREVENTION

Patients and family members should be educated on the generic names of the drugs they are allergic to and other potentially cross-reacting drugs. In addition, the patient should be given a Medic Alert® card or bracelet to avoid future accidental prescription/dispensing of any drugs to which he or she is allergic. Through the use of electronic medical records, pharmacovigilance in the form of adverse drug reaction reporting to drug regulatory agencies and accurate labelling to avoid future reactions should be constantly emphasized.

INDICATIONS FOR ALLERGIST REFERRAL [11]

  • 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 antibiotic 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
  • HIV-infected patients with a history of adverse reactions to co-trimoxazole  who need this therapy
  • Patients with a history of reactions to induction agents or to nonpenicillin antibiotics

COURSE AND PROGNOSIS

The outcome of most cutaneous drug allergies is good after immediate cessation of the drug and symptom relief.

Drug-induced anaphylaxis is potentially fatal, as it is characterized by a high frequency of rapid-onset (within minutes) cardiovascular collapse, especially in older patients. Other risk factors for death include cardiopathies associated with beta-blocker therapy. The true prevalence of fatal drug-induced anaphylaxis is unknown, as the patients studied varied from children to adults, and from emergency room attendees to inpatients, and most studies included all causes of anaphylaxis rather than drug-induced anaphylaxis specifically.

In SJS/TEN, the reported mortality rate varies from 30% to 50%. The effect of IVIG on mortality in patients with TEN remains indeterminate. Ocular complications (i.e., nonhealing epithelial defects and visual impairment) are major but relatively uncommon long-term sequelae of SJS/TEN. Persistent dry eyes is the most common.

Drug allergy may result in anxiety and impairment in health related quality of life for sufferers. Health care professionals involved in the care of patients with a history of drug allergy/hypersensitivity must be aware of potential long-term psychological sequelae and effects on the doctor-patient relationships especially when new drugs have to be prescribed again.

KEY REFERENCES

  1. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004;113:832–836.
  2. Pichler WJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol 2011;127(3 Suppl):S74-81.
  3. Thong BY, Tan TC. Epidemiology and risk factors for drug allergy. Br J Clin Pharmacol 2011; 71:684-700.
  4. Chiriac AM,Demoly P. Multiple drug hypersensitivity syndrome. Curr Opin Allergy Clin Immunol 2013; 13:323-9.
  5. Lochmatter P, Zawodniak A, Pichler WJ. In vitro tests in drug hypersensitivity diagnosis. Immunol Allergy Clin North Am 2009; 29:537-54.
  6. Kränke B, Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin North Am 2009; 29:503-16.
  7. Barbaud A.Skin testing in delayed reactions to drugs. Immunol Allergy Clin North Am 2009; 29:517-35.
  8. Aberer W, Bircher A,Romano A, Blanca M, Campi P, Fernandez J, et al, for ENDA, the EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: General considerations. Allergy 2003;58:854–863.
  9. Nizankowska-Mogilnicka E, Bochenek G, Mastalerz L, Swierczyn'ska M, Picado C, Scadding G, Kowalski ML, Setkowicz M, Ring J, Brockow K, Bachert C, Wöhrl S, Dahlén B, Szczeklik A. EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity. Allergy 2007; 62:1111-8.
  10. Cernadas JR, Brockow K, Romano A, Aberer W, Torres MJ, Bircher A, Campi P, Sanz ML, Castells M, Demoly P, Pichler WJ; for the European Network of Drug Allergy and the EAACI interest group on drug hypersensitivity. General considerations on rapid desensitization for drug hypersensitivity - a consensus statement. Allergy 2010; 65:1357-66.
  11. American Academy of Allergy, Asthma & Immunology. Consultation and referral guidelines citing the evidence: How the allergist-immunologist can help. J Allergy Clin Immunol. 2006;117(2 suppl consultation):S495–S523.

SOURCE DOCUMENTS

Helpful Links: Patient Information on Drug Allergies

American College of Allergy Asthma and Immunology (ACAAI) Public Education on Drug Reactions
http://www.acaai.org/patients/resources/allergies/Pages/drug-reactions.aspx

American Academy of Allergy Asthma and Immunology (AAAAI) Adverse reactions to medications
http://www.aaaai.org/patients/allergic_conditions/medications_adverse_reactions.stm

Helpful Links: Professional Information on Drug Allergies (Latest to Earliest)

Scherer K, Brockow K, Aberer W, Gooi JH, Demoly P, Romano A, Schnyder B, Whitaker P, Cernadas JS, Bircher AJ; ENDA, the European Network on Drug Allergy and the EAACI Drug Allergy Interest Group. Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group. Allergy 2013; 68:844-52.
http://onlinelibrary.wiley.com/doi/10.1111/all.12161/pdf

Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A, Bilo MB, Bircher A, Blanca M, Bonadonna B, Campi P, Castro E, Cernadas JR, Chiriac AM, Demoly P, Grosber M, Gooi J, Lombardo C, Mertes PM, Mosbech H, Nasser S, Pagani M, Ring J, Romano A, Scherer K, Schnyder B, Testi S, Torres M, Trautmann A, Terreehorst I; ENDA/EAACI Drug Allergy Interest Group.Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013; 68:702-12.
http://onlinelibrary.wiley.com/doi/10.1111/all.12142/pdf

Mertes PM, Malinovsky JM, Jouffroy L; Working Group of the SFAR and SFA, Aberer W, Terreehorst I, Brockow K, Demoly P; ENDA; EAACI Interest Group on Drug Allergy. Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice. J Investig Allergol Clin Immunol 2011; 21:442-53.
http://www.jiaci.org/issues/vol21issue6/2.pdf

Cernadas JR, Brockow K, Romano A, Aberer W, Torres MJ, Bircher A, Campi P, Sanz ML, Castells M, Demoly P, Pichler WJ; European Network of Drug Allergy and the EAACI interest group on drug hypersensitivityGeneral considerations on rapid desensitization for drug hypersensitivity - a consensus statement. Allergy 2010; 65:1357-66.
http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2010.02441.x/pdf

Thong BY, Mirakian R, Castells M, Pichler W, Romano A, Bonadonna P, Diana D, Kowalski M, Yanez A, Lleonart R, Sanchez-Borges M, Demoly P.A world allergy organization international survey on diagnostic procedures and therapies in drug allergy/hypersensitivity. World Allergy Organ J 2011; 4:257-70.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488913/?report=reader

AAAAI Referral Guidelines for Drug Hypersensitivity
http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Referral%20Guidelines/Table-7-Drug-allergy.pdf

Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma and Immunology, the American Academy of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol 2010; 105:259-273.
http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/drug-allergy-updated-practice-param.pdf

Thong BY, Tan TC. Epidemiology and risk factors for drug allergy. Br J Clin Pharmacol 2011; 71:684-700.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093074/

Ewan PW, Dugué P, Mirakian R, Dixon TA, Harper JN, Nasser SM; BSACI. BSACI guidelines for the investigation of suspected anaphylaxis during general anaesthesia. Clin Exp Allergy 2010; 40:15-31.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2222.2009.03404.x/pdf

Mirakian R, Ewan PW, Durham SR, Youlten LJ, Dugué P, Friedmann PS, English JS, Huber PA, Nasser SM; BSACI. BSACI guidelines for the management of drug allergy. Clin Exp Allergy 2009; 39:43-61.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2222.2008.03155.x/pdf

Blanca M, Romano A, Torres MJ, Férnandez J, Mayorga C, Rodriguez J, Demoly P, Bousquet PJ, Merk HF, Sanz ML, Ott H, Atanaskovic'-Markovic' M. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009; 64:183-93.
http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2008.01924.x/pdf

Brockow K, Christiansen C, Kanny G, Clément O, Barbaud A, Bircher A, Dewachter P, Guéant JL, Rodriguez Guéant RM, Mouton-Faivre C, Ring J, Romano A, Sainte-Laudy J, Demoly P, Pichler WJ; ENDA; EAACI interest group on drug hypersensitivity. Management of hypersensitivity reactions to iodinated contrast media. Allergy 2005; 60:150–8
http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2005.00745.x/pdf

Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, Pichler WJ, Demoly P, for ENDA and the EAACI interest group on drug hypersensitivity. Diagnosis of non immediate reactions to beta-lactam antibiotics. Allergy 2004: 59:1153–60
http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2004.00678.x/pdf

Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, Brockow K, Pichler WJ, P. Demoly for ENDA, and the EAACI interest group on drug Hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003; 58: 854–63
http://onlinelibrary.wiley.com/doi/10.1034/j.1398-9995.2003.00279.x/pdf

Torres MJ, Blanca M, Fernandez J, Romano A, de Weck A, Aberer W, Brockow K, Pichler WJ, Demoly P for ENDA, and the EAACI interest group on drug hypersensitivity. Diagnosis of immediate reactions to beta-lactam antibiotics. Allergy 2003; 58:961-72.
http://onlinelibrary.wiley.com/doi/10.1034/j.1398-9995.2003.00280.x/pdf

Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002; 57:45–51
http://onlinelibrary.wiley.com/doi/10.1046/j.0105-4538.2001.00001.x-i8/pdf

Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. Allergy 1999; 54:999-1003.
http://onlinelibrary.wiley.com/doi/10.1034/j.1398-9995.1999.00247.x/pdf