An approach to the patient with drug allergy

INTRODUCTION — A systematic approach to the evaluation of patients with suspected drug allergy, particularly those receiving multiple medications simultaneously, will be presented here. Evaluation of patients with specific symptoms or laboratory findings that may represent drug hypersensitivity is discussed separately:

●(See "Drug eruptions".)

●(See "Approach to the patient with unexplained eosinophilia".)

●(See "Fever and rash in the immunocompetent patient".)

●(See "Fever and rash in immunocompromised patients without HIV infection".)

DEFINITION AND CLASSIFICATION — "Drug hypersensitivity" is a general term that includes both allergic and pseudoallergic drug reactions, which are a subset of idiosyncratic drug reactions.

A drug allergy is an adverse drug reaction that is caused by an immunologic reaction elicited by a drug. Some immune reactions occur when drugs act as antigens. Alternatively, drugs may cause reactions by interacting with receptors on immune cells, stimulating the cells directly. (See "Drug allergy: Pathogenesis".)

Classification systems — There are different classification systems for drug allergy, which are briefly reviewed here and discussed in detail elsewhere. Briefly, drug hypersensitivity reactions can be classified based upon timing of appearance of symptoms, action of drugs, or immunologic mechanism. (See "Drug hypersensitivity: Classification and clinical features" and "Drug allergy: Pathogenesis".)

Timing of appearance — The World Allergy Organization (WAO) has recommended dividing immunologic drug reactions into two types:

●Immediate reactions, occurring within one hour of the first administered dose

●Nonimmediate (also called delayed reactions), occurring after one hour, but usually more than six hours and occasionally weeks to months after the start of administration

The WAO distinction between immediate and delayed drug reactions is helpful in distinguishing type I, immunoglobulin E (IgE) mediated reactions from the other types. Type I reactions carry the risk of immediate life-threatening anaphylaxis if the drug is readministered. These reactions most commonly appear within minutes after exposure but may begin after one hour following oral administration, especially if the drug is taken with food, which further slows absorption.

Delayed reactions are usually not IgE mediated and result instead from types II, III, and mainly type IV hypersensitivity or from multiple or unknown pathophysiologic mechanisms. Some of these reactions can also be life threatening, and, as a group, delayed reactions probably account for more deaths than anaphylaxis.

Action of drug — A novel classification of drug hypersensitivity reactions is based on the action of drugs [1]. This system delineates three types of reactions: immunologic/allergic reactions, p-I reactions, and pseudoallergic reactions. This approach explains the relationships between the clinical manifestations, dose of the drug, human leukocyte antigen (HLA) linkage, and crossreactivity.

●Immune/allergic reactions – Immune/allergic reactions arise with proteins that are used as drugs, as well as small molecules (drug or drug metabolites) that bind covalently as haptens to a carrier protein (hapten-carrier complex). Both a humoral and cellular immune response might develop and can result in allergic symptoms as outlined in the Gell and Coombs classification. (See 'Immunologic mechanisms' below.)

●p-i reactions (pharmacologic interaction with immune receptors) – In p-i reactions, the drug binds noncovalently to immune receptors (eg, certain HLA molecules or certain T cell receptors), which are not the intended target of the drug. This binding leads to exclusive stimulation of those T cells, with clinical features of alloimmune and possibly autoimmune reactions [2-4].

●Pseudoallergic reactions – Pseudoallergic reactions are due to noncovalent drug binding to certain enzymes or receptors on effector inflammatory cells (ie, mast cells, eosinophils, basophils, neutrophils). Clinically, pseudoallergic drug reactions are similar or identical to immunologic reactions, but they are not mediated by the immune system (table 1). Pseudoallergic reactions, such as those to nonsteroidal antiinflammatory drugs (NSAIDs), can be as severe as IgE-mediated anaphylaxis and are managed acutely in the same manner (ie, with epinephrine). However, the evaluation and future prevention of these reactions is different from that of immunologic reactions. Other drugs, such as rocuronium and ciprofloxacin, activate mast cells through the receptor Mas-related protein coupled receptor member X2 (MRGPRX2). Pseudoallergic drug reactions are discussed in more detail elsewhere. (See "Drug hypersensitivity: Classification and clinical features".)

Immunologic mechanisms — Immunologic drug reactions have classically been divided into four categories according to the Gell and Coombs system (table 2):

●Type I – Immediate in onset and caused by IgE-mediated activation of mast cells and basophils

●Type II – Delayed in onset and caused by antibody (usually immunoglobulin G [IgG]) mediated cell destruction

●Type III – Delayed in onset and caused by immune complex (IgG:drug) deposition and complement activation

●Type IV – Delayed in onset and T cell mediated

To correlate this system to the action of the drug, type I through IV reactions involve drugs that act as antigens (allergic/immune, hapten reactions). Type IV reactions can be due to hapten or the p-i mechanism. Some drugs like beta-lactams are notorious for eliciting all four types of reactions; but many drugs do not give rise to antigens and stimulate only via p-i (eg, various antiseizure medications). Some beta-lactams stimulate by both hapten and/or p-i mechanism (eg, flucloxacillin [5]).

TREATMENT OF ACUTE REACTIONS — The treatment of various types of drug reactions is discussed in specific topic reviews. The suspected culprit drug is immediately discontinued in most cases, except for some of the milder delayed reactions in situations in which the drug is essential.

Immediate reactions (ie, urticaria, angioedema, or anaphylaxis):

●(See "Anaphylaxis: Emergency treatment".)

●(See "New-onset urticaria", section on 'Treatment'.)

Delayed reactions:

●(See "Exanthematous (maculopapular) drug eruption", section on 'Management'.)

●(See "Drug fever".)

●(See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●(See "Serum sickness and serum sickness-like reactions", section on 'Treatment'.)

●(See "Acute generalized exanthematous pustulosis (AGEP)", section on 'Management'.)

●(See "Fixed drug eruption".)

●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

RISK FACTORS FOR DRUG ALLERGY — Risk factors for the development of drug allergy include female sex, prior history of drug allergic reactions, recurrent drug exposure, genetic factors, and certain disease states.

●Female sex – Females are at greater risk than males for allergic reactions to some drugs for reasons that are not well defined. Females can experience higher rates of both immediate and delayed reactions. As an example of the latter, females of childbearing age developed delayed-onset rashes to gemifloxacin (a quinolone) in 30 percent of administrations compared with 3 percent in males [6]. Intraoperative reactions to neuromuscular-blocking agents are also much more frequent in females. In contrast, neither immediate nor delayed allergic reactions to penicillins differ by sex.

●Prior history of allergic drug reactions – A prior history of allergic reactions to one or more drugs increases the risk of developing additional drug allergies. This is obviously true in patients with past drug reactions who are subsequently given the same or a related medication. It is also true with pseudoallergic reactions due to nonsteroidal antiinflammatory drugs (NSAIDs), since structurally different NSAIDs may cause similar reactions. Pseudoallergic reactions are reviewed separately. (See "Drug hypersensitivity: Classification and clinical features".)

●Repeated drug exposures – Repeated courses of therapy with the same drugs or related drugs are associated with higher rates of drug allergy [7,8]. As an example, patients with cystic fibrosis who require recurrent courses of the same or related antibiotics are at increased risk for developing allergies to those drugs.

●Exposure to drugs with high allergenic potential – The different types of immunologic drug reactions and the categories of drugs that are most commonly implicated in each are summarized in the table (table 3).

●Human leukocyte antigen (HLA) type – There is evidence for a familial propensity to develop immunologic drug reactions [9]. Data on a variety of drugs and severe drug allergies demonstrated that certain HLA alleles (often HLA-B) represent highly significant risk factors for severe side effects to a particular drug and are also involved in presenting the drug to the immune system [10-12]. As many of the HLA alleles implicated in drug allergy differ in different ethnic groups, associations are often defined only within certain ethnic groups [13]. For example, HLA-B*15:02 is common in Han Chinese populations but very rare in European patients; thus, it makes sense to test for this allele in Chinese patients but not in Europeans.

•Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) caused by carbamazepine and, to a lesser degree, oxcarbazepine in Han Chinese patients shows a strong association with HLA-B*15:02 [10,14]. However, HLA-B*15:02 is not increased among Han Chinese patients with milder, maculopapular drug eruptions, nor is it associated with SJS/TEN in White Europeans [15]. Instead, European carriers of the HLA-A*31:01 allele have an increased risk of developing drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) [16,17]. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.)

•SJS/TEN and possibly DIHS/DRESS caused by allopurinol also shows a strong association with HLA-B*58:01 [18,19]. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Allopurinol'.)

•A severe hypersensitivity syndrome is caused by the reverse-transcriptase inhibitor abacavir and is highly associated with HLA-B*57:01 in White populations [20,21]. Typing of HLA-B*57:01 reduced the incidence of side effects dramatically [22]. The same allele is also implicated in flucloxacillin-induced hepatitis but with a very low penetrance of the disease. Thus, typing is not recommended [23]. This syndrome is discussed in detail elsewhere. (See "Abacavir hypersensitivity reaction".)

There are now multiple instances of associations between HLA alleles (mostly class I) and hypersensitivity reactions to specific medications [24]. Some associations have a high specificity (eg, dapsone hypersensitivity, HLA-B*13:01 and the dapsone hypersensitivity syndrome) [25], although, for the majority, the odds ratio is rather low (<10), implying that, besides HLA alleles, other still unknown factors play a crucial role. Predictive HLA typing is recommended for only a few drugs (abacavir, carbamazepine in patients of Chinese and Southeast Asian origin, possibly allopurinol and dapsone). However, there may be patient-specific scenarios, like a severe drug hypersensitivity to the drug in the past in the family history that warrants HLA typing before using a "dangerous" drug in patients with lower risk. The pathophysiologic mechanisms that may underlie these associations are discussed separately. (See "Drug allergy: Pathogenesis", section on 'Type IV (T cell-mediated)'.)

●Certain disease states – Some allergic drug reactions are much more likely to occur if the drug is administered to patients with particular underlying conditions.

•Reactions to aminopenicillins occur more commonly in patients with atypical or abnormal lymphocytes (eg, in massive immune stimulations, such as Epstein-Barr virus [EBV] infection or leukemia) [26,27]. (See "Infectious mononucleosis", section on 'Rash'.)

•Patients with acquired immunodeficiency syndrome (AIDS) have very high rates of dermatologic reactions to sulfonamides and other drugs [10,28,29]. Human immunodeficiency virus (HIV) infection may create an inflammatory milieu that enhances drug allergy. A similar phenomenon is seen in generalized herpes virus infections. Indeed, activated, atypical lymphocytes are frequently found in the circulation of persons infected with either of these viruses. Other contributing factors may include reduced hepatic glutathione levels due to polypharmacy and immunologic dysfunction associated with AIDS [30].

•A common problem is exanthematous skin reactions in small children treated with antibiotics, in particular penicillins. These mostly mild and transient skin reactions appear to be due to a combined effect of the drug use and various viral infections causing immune stimulation [31]. The vast majority of children will tolerate penicillins if given them again later. Many adults claiming to be "penicillin allergic" are falsely labelled as such because of these mostly mild and transient reactions in childhood. (See "Penicillin allergy: Delayed hypersensitivity reactions", section on 'Studies in children'.)

•Patients with mast cell disorders may react to a variety of unrelated medications, such as aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs), opioids, antibiotics (most commonly vancomycin), radiocontrast agents, and certain muscle relaxants used during anesthesia.

●Drug metabolism – The role of drug metabolism in drug hypersensitivity was previously centered on an assumed role of generating reactive intermediates. However, such a role for creating immunogenic drugs could rarely be shown, probably because reactive intermediates were rapidly bound by glutathione or were immunologically not active due to intrahepatic tolerance mechanism [32]. On the other hand, a reduced drug metabolism may result in an enhanced availability of elevated drug concentrations. An example may be certain cytochrome p450 related genes, which reduce metabolism: This was shown for CYP2C9*3 and phenytoin-related drug hypersensitivity reactions [33].

In some pseudoallergic reactions, different polymorphisms, such as platelet 2 receptor gene (P2RY12) and of dipeptidyl peptidase 10 gene, have been described but are not of diagnostic value [34].

In general, typing for pharmacogenetic predisposition has not yet entered clinical practice for the purposes of assessing risk of drug hypersensitivity.

●Atopy – Atopy may be defined as an inherited phenotype that includes the predisposition to develop allergen-specific IgE to inhaled or ingested allergens. Patients with atopic/allergic disorders, such as allergic asthma or food allergy, are not at increased risk for the development of drug allergy. However, atopic conditions may aggravate the clinical manifestations of IgE-mediated drug allergies. As an example, positive penicillin skin tests do not occur more frequently in atopic individuals [35], but an atopic background is a substantial risk factor for severe and fatal penicillin anaphylaxis [36].

Multiple drug allergy syndrome — The term "multiple drug allergy syndrome" is correctly used to describe a small subgroup of patients with immunologic reactions to at least two (usually more) unrelated drugs, in which the culprit drugs can be demonstrated by skin tests or in vitro tests [37]. This appears to arise because of an enhanced responsiveness of the patient's T cells to pharmaceutical substances [37,38]. The implicated drugs are often antibiotics, although hypnotics, antidepressants, and other drug classes were also reported. In a typical clinical scenario, a patient might initially develop DIHS/DRESS (eg, a type IV reaction) to an antiseizure medication. Weeks to months after this event, the patient develops additional "flare-up reactions" (mostly exanthema, liver enzyme elevations) shortly after receiving a new drug [39]. This flare-up reaction might be transient, particularly if the second drug is stopped immediately. However, the second drug is often tolerated if given again later on [40].

A subgroup of patients do, however, develop a true second drug allergy with a second immune reaction with positive skin tests and/or in vitro tests to the second drug as well. The clinical manifestations might be similar to the first reaction but can also be more severe (fulminant hepatitis, necrotizing eosinophilic carditis, agranulocytosis). It appears that the nature of subsequent reactions depends upon the structure/type of allergy normally associated with the drug in question. For example, if the same patient is later given amoxicillin, the reaction is typically an exanthema. If given phenytoin, another DIHS/DRESS reaction may ensue. DIHS/DRESS reactions are described separately. (See "Drug hypersensitivity: Classification and clinical features".)

The term "multiple drug allergy syndrome" should not be applied to the numerous patients who report adverse reactions to many drugs in whom symptoms are often not typical of immunologic reactions. Rather, "multiple drug intolerance" may be a more appropriate description. (See 'Inclusion of placebos' below.)

DIFFERENTIAL DIAGNOSIS OF REPEATED DRUG REACTIONS — Some patients claim or actually do react to multiple different drugs: This could be simple crossreactivity against structurally related drugs (eg, amoxicillin and penicillin, ciprofloxacin and moxifloxacin), undiagnosed chronic spontaneous urticaria, pseudoallergy (eg, to nonsteroid antiinflammatory drugs [NSAIDS]), or enhanced reactivity through the receptor MRGPRX2.

Chronic spontaneous urticaria — An important differential diagnosis and a rather common cause for wrongly labelled drug hypersensitivity is the appearance of urticarial lesions just after drug intake, which may be just the manifestation of a chronic spontaneous urticaria. A detailed history may reveal urticaria even without prior drug intake, and dermatographism on physical examination often reveals increased skin reactivity. The strategy of empirically taking an antihistamine when starting a new medication can help prevent additional reactions.

Conditioned responses — Some patients experience unintentional anticipatory reactions (classic Pavlovian conditioning), particularly following a true allergic reaction or a frightening experience in association with drug treatment. The possibility of a conditioned response should be considered when multiple unrelated drugs elicit very similar symptoms with immediate or slightly delayed onset. Another clue that the reactions may be conditioned responses is a history of allergic-like symptoms to many drugs, including some that uncommonly cause true immunologic drug reactions (eg, macrolide antibiotics, glucocorticoids, and local anesthetics).

APPROACH TO THE PATIENT — The onset of hives within a few hours of taking a new medication is easily recognized as possible drug hypersensitivity. However, many clinical presentations of drug hypersensitivity are more complex or take place in the setting of illness and/or polypharmacy. The patient in intensive care who develops a rash while receiving multiple medications or the ambulatory patient with complex chronic diseases who develops a new and unexplained symptom while taking many medications illustrates two common presentations of drug allergy.

A systematic approach to the evaluation of putative drug allergy in patients receiving multiple medications begins with the following questions:

●Is the adverse event related to a drug? Are there any other possible explanations, and, if so, how plausible are they?

●Is the presentation consistent with the action of the drug on the immune system or with an immunologic drug reaction? If so, what type (table 2)? Is the drug to which the patient was recently exposed known to cause such symptoms, or does it usually cause pseudoallergic reactions (eg, nonsteroidal antiinflammatory drugs [NSAIDs])? (See "Drug hypersensitivity: Classification and clinical features".)

●Is the drug known to act as hapten or via p-i?

●How severe is the reaction, and what organ systems are involved? This can be assessed with a meticulous skin examination, followed by further evaluation of any other organ system that appears to be affected. A complete blood count and differential and tests of liver and kidney function should be obtained. This evaluation is indicated if the exanthema is substantial, bullous or pustular, confluent, involves a substantial portion of the body surface area, or if general symptoms (malaise, skin pain, lymphadenopathy) are present.

●Are known cofactors for drug hypersensitivity present (eg, generalized viral infections, active systemic autoimmune disease, graft-versus-host disease, prior/ongoing drug hypersensitivity)?

●Which drug is responsible? This assessment can be approached in a stepwise manner:

•Step 1 – Gather information, as discussed in detail below. (See 'Clinical history' below and 'Review the medical record' below.)

•Step 2 – For each suspect drug, consider the likelihood of it causing the type of allergic reaction in question based upon the published literature.

•Step 3 – Stop or substitute any/all suspect drugs with known allergic potential that demonstrate a temporal relationship with the symptoms. Observe the consequences of stopping these medications.

●Is testing possible?

•Step 4 – For reactions that are suspected to be IgE mediated, consider skin testing (see 'Skin testing for drug-specific IgE' below). In vitro tests are available for some type I and IV reactions (table 2). Both skin and in vitro tests (if available) to identify the eliciting drug are normally done after the reaction has resolved completely [41]. An exception may be in vitro testing for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), where early testing may be more informative [41].

•Step 5 – If there is ambiguity surrounding which drug induced an immunologic reaction and multiple drugs were stopped, plans should be made to continue the evaluation after the patient's convalescence, particularly for drugs that the individual may need in the future. Entering multiple "possible" drug allergies in the medical record will lead to confusion and is not in the patient's best interest.

IDENTIFICATION OF THE SUSPECT DRUG — The suspect drug is identified using the patient's clinical history of present and past drug reactions and review of the medical record for temporal associations between administration and symptoms, combined with an understanding of what types of drugs cause various reactions. If available, objective tests (eg, skin testing, in vitro testing) may also support the diagnosis.

Clinical history — The initial step involves determining all the medications to which the patient has had adverse reactions in the past. Additional history can sometimes be obtained from relatives or primary care providers. This information should be documented in the patient's permanent medical record.

The following specific questions should then be answered for each of the reported drugs in question:

●What were the symptoms and signs? What is known about the reaction?

●How long ago did the reaction take place? Some forms of drug hypersensitivity will be lost with time. For instance, approximately 80 percent of patients with IgE-mediated penicillin allergy have lost the sensitivity after 10 years. (See "Penicillin allergy: Immediate reactions", section on 'Time elapsed since the reaction'.)

●Did the patient require medical treatment or hospitalization because of the reaction? An affirmative answer usually identifies the more serious forms of drug hypersensitivity.

●Why was the medication taken (indication for use)? Drug eruptions to antibiotics are more common in the setting of viral infections. In addition, if the drug and indication are not consistent, the interviewer should regard the details of the history with skepticism.

●What was the dose and route of medication taken (if known)?

●Had the patient taken the medication on a previous occasion? Patients with IgE-mediated immediate reactions have usually taken the drug at least once in the past before the reaction occurred.

●Was the patient taking other concurrent medications when the reaction occurred? Were any of these newly started? Opioids can potentiate reactions that involve direct mast cell release (such as vancomycin-flushing syndrome).

●What was the timing of onset of the reaction (from both the precipitating dose, as well as from the initiation of that course of therapy)? This information helps distinguish immediate from nonimmediate reactions.

●Was any treatment given, and what was the response to that treatment (including the duration of reaction)?

●Has the patient received that medication or a related medication again since the reaction? If so, were there recurrent symptoms? Sometimes, the interviewer will learn that the patient has taken the implicated drug subsequently without problems, essentially eliminating the possibility of a true hypersensitivity reaction.

Limitations of the clinical history — History alone is often not sufficient for establishing current drug sensitivity. Studies performed on large series of patients with histories of drug allergy have shown that less than 20 percent actually react to the offending drug(s) upon direct challenge [42,43]. There are multiple reasons why a previously reactive patient may tolerate a drug upon subsequent administration:

●The suspect drug may never have caused symptoms but was implicated based upon a temporal association. This is probably the most common reason.

●The patient could have had a true IgE-mediated reaction in the past but has lost sensitivity to the drug over time.

●Biologic states required for reactivity may wane over time and render the patient less vulnerable. For example, patients with chronic idiopathic angioedema may develop exacerbations of their symptoms in response to nonsteroidal antiinflammatory drugs (NSAIDs) when the disorder is active but tolerate these medications with the chronic urticaria is in remission.

●Many patients report a penicillin allergy based on the history of a "rash" in childhood [44]. Most of these individuals tolerate penicillins later on. Viral infections alone or in combination with penicillin therapy were probably responsible for the reactions in childhood [31].

Conversely, even for IgE-mediated immediate reactions, which usually require previous exposure to the causative drug in order to become sensitized, there are reasons that they patient may react on the first administration:

●IgE-mediated, immediate-type allergic reactions can appear with the first known encounter with a drug, even though these types of reactions require preexisting sensitization (ie, formation of IgE antibodies) to the drug. This most often occurs with drugs that are administered intravenously. The explanation for this phenomenon is that sensitization has occurred as a result of exposure to a different but cross-reacting compound, typically a different medication or a cosmetic. The best-studied example is that of muscle relaxants (ie, neuromuscular-blocking agents), which can trigger anaphylaxis upon first exposure because patients can become sensitized to over-the-counter cough remedies (pholcodine in Europe) or cosmetics (in the United States) [45]. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Neuromuscular-blocking agents'.)

●Another example of individuals with preformed IgE molecules reacting upon first exposure to a drug was identified in patients with anaphylaxis to cetuximab [46]. Some of these patients had antibodies against the oligosaccharide galactose alpha-1,3-galactose found in the drug and developed anaphylaxis upon intravenous administration of cetuximab. This oligosaccharide is also found in beef, pork, and lamb, and a subset of patients had experienced allergic reactions when eating these meats. Because most of the affected patients lived in the Southeastern United States, it has been postulated that patients become sensitized to the oligosaccharide as a result of bites from ticks or other ectoparasites [47].

Review the medical record — The medical record should be reviewed, if possible. In critically ill patients who cannot communicate, it may be the only available source of information. One approach is the creation of a timeline of medication starts and stops on which the appearance and resolution of symptoms is also charted. It is important to note the onset of fever or the appearance of relevant laboratory abnormalities, such as blood eosinophilia or urine eosinophilia or hematuria.

OBJECTIVE TESTING — Objective testing may be appropriate for some types of allergic drug reactions. Skin testing for type I reactions is supported by extensive clinical experience but is not standardized or validated for most drugs. The majority of in vitro tests for drug allergy are investigational. In addition, immunodiagnostic tests for drug allergy can require experience to interpret properly.

Testing for immediate reactions — Type I, IgE-mediated reactions typically begin within one hour of the first administered dose, as discussed previously. (See 'Definition and classification' above.)

Markers of anaphylaxis — Elevations in tryptase (serum or plasma) may be detectable in blood samples collected within several hours of an acute allergic event because this mediator is released by mast cells and basophils (table 4). Histamine may also be detectable, but assays are less reliable, and elevations are seen only during a very short time interval after the reaction.

Any elevation of tryptase is consistent with anaphylaxis, although normal levels do not exclude the diagnosis. Tryptase levels should be tested again after the reaction has resolved to detect a relative increase as well as to exclude indolent mastocytosis, an important risk factor for severe anaphylaxis. Elevations are most likely to be detectable following anaphylaxis with hemodynamic changes and if blood is collected one to three hours from the onset of symptoms [48]. The interpretation of tryptase in the diagnosis of anaphylaxis is not always straightforward. As an example, a tryptase level of 9 ng/mL during anaphylaxis and 3 ng/mL the following day is suggestive of anaphylaxis, even though both levels are below the upper limit of normal (ie, 11.4 ng/mL) [49]. In this example, the serum level tripled, which may be meaningful, since personal tryptase levels are usually quite constant. The interpretation of tryptase levels is discussed in greater detail separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

Skin testing for drug-specific IgE — A variety of medications can be used to perform prick and/or intradermal skin testing for the purpose of determining if the drug interacts with drug-specific IgE bound to cutaneous mast cells. This type of testing is only used to evaluate suspected type I allergic reactions. A positive wheal-and-flare response appearing within 15 to 20 minutes indicates the presence of drug-specific IgE on the patient's mast cells and supports the diagnosis of a type I reaction (table 2).

The clinician must first ascertain that the medication does not cause direct mast cell degranulation, as described with opioids, quinolones, and vancomycin. Medications that activate mast cells directly cannot be studied with this type of skin testing. In addition, the drug solution used for testing should not be nonspecifically irritating to the skin. Nonirritating concentrations for a variety of medications have been determined [50].

For most drugs, the full range of metabolites and intermediate forms of the drug to which patients may become allergic has not been defined, and testing reagents are not available. Thus, just the native (unmetabolized) form of the drug is used in testing, and this may only detect a fraction of allergic patients. Penicillin is the one exception to this, and the important metabolites and metabolite/protein complexes that are required to detect allergic patients have been characterized. Penicillin skin testing is discussed in detail separately. (See "Penicillin skin testing".)

Skin testing for immediate reactions with the native (unmetabolized) form has proven useful in identifying a subset of allergic patients:

●Beta-lactam antibiotics (amoxicillin, cephalosporins, and imipenem). (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics".)

●Neuromuscular blockers, chlorhexidine, and dyes used to localize lymph nodes intraoperatively (ie, patent blue, isosulfan blue, methylene blue) [51]. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions".)

●Carboplatin and other platin drugs. (See "Infusion reactions to systemic chemotherapy", section on 'Platinum drugs'.)

●Pyrazolones, such as metamizole [52].

●Thiobarbiturates. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions".)

●Therapeutic monoclonal antibodies, even if fully humanized, can still elicit immune reactions. The majority of reactions involve IgG antibodies, some neutralizing the efficacy of the therapeutic antibody. IgE-mediated reactions do occur but are rather rare [53]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)

The results of skin testing with one of the above agents should be interpreted as follows:

●A positive result is indicative of allergy, provided nonirritating concentrations of the drug were used.

●A negative result does not exclude allergy, because the patient may be allergic to metabolites of the medication, or metabolite/protein complexes, which are generally not available as skin-testing reagents (with the notable exception of penicillin).

Skin testing may be falsely negative if performed too soon after an anaphylactic reaction. For this reason, a period of one to four weeks should be allowed between a severe reaction and skin testing to the suspect drug. However, if skin testing is performed in this period, positive results are still valid. False-negative results can also occur in patients taking medications that blunt immediate skin responses, such as H1 and H2 antihistamines and tricyclic antidepressants. (See "Overview of skin testing for IgE-mediated allergic disease", section on 'Medications that should be discontinued'.)

In vitro tests — In vitro tests for immediate drug reactions are available and can be helpful when skin testing is not available, but these are largely considered investigational.

●Solid-phase immunoassays, such as the radioallergosorbent test (RAST) and enzyme-linked immunosorbent assay (ELISA), have been developed for a wide variety of drug-specific IgE, using sera from skin test-positive patients for standardization. These tests have been useful in research settings [54]. However, when systematically compared with skin testing, which has only been done for beta-lactam antibiotics, pyrazolone (analgesic not available in the United States), and chlorhexidine, in vitro tests consistently prove less sensitive [51,52,55]. Many immunoassays for drug-specific IgE have been commercialized without published validation, and some of these are highly suspect since IgE-mediated reactions have never been documented.

●Flow cytometry assessing drug-induced basophil activation (BAT) by means of increase in surface markers, such as CD63, has been studied in the diagnosis of immediate drug allergy [56,57]. Determination of cysteinyl leukotrienes released from blood leukocytes after drug incubation has been suggested to increase the diagnostic value of flow cytometry alone [58]. The specificity of these assays is in general very good (>95 percent). However, the sensitivity is often highly variable among different research or diagnostic laboratories, and its overall sensitivity appears to be limited [59,60].

Testing for delayed reactions — A maculopapular rash appearing several days into a course of a systemic medication is the most common form of delayed-onset drug allergy [61,62]. Most of these reactions are mediated by T cells (type IV) (table 2). In contrast to IgE-mediated reactions, delayed drug reactions can recur after decades, even in the absence of interim reexposure [63].

Types II and II reactions — The diagnosis and evaluation of types II and III hypersensitivity reactions are discussed separately (table 2):

●Type II reactions (antibody [usually IgG] mediated cell destruction) – (See "Drug-induced immune thrombocytopenia" and "Drug-induced neutropenia and agranulocytosis" and "Drug-induced hemolytic anemia", section on 'Immune-mediated'.)

●Type III (immune complex deposition and complement activation) – (See "Serum sickness and serum sickness-like reactions" and "Overview of cutaneous small vessel vasculitis" and "Drug fever".)

Type IV reactions — The majority of drug reactions involve dermatitis and/or hepatitis, occasionally with systemic involvement (eg, drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms [DIHS/DRESS]). They are principally mediated by T cells and are classified as type IV reactions (table 2). However, it has been argued that these severe reactions (DIHS/DRESS) as well as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are immune reactions elicited by p-i mechanism (drug binding to immune receptors and not due to hapten-carrier antigen formation) [64]. This direct drug binding to only some immune receptors would also explain the association to a certain human leukocyte antigen (HLA) phenotype as only this particular HLA allele is able to bind the drug with high affinity. Type IV reactions may be evaluated with various diagnostic tests, including patch testing, intradermal testing with delayed cutaneous readouts, or lymphocyte activation assays using proliferation, cytokine release, or cytotoxicity as read outs [65].

●Patch testing – Drugs to be used in patch testing are mixed into petrolatum or 0.9% saline, applied to a small area of skin under occlusion for 48 hours, and then removed. The site is examined 48 to 96 hours after placement. Concentrations of various drugs for use in patch testing have been established [66,67]. (See "Patch testing".)

Patch testing with drug preparations may be useful in evaluating patients with maculopapular exanthema, acute generalized exanthematous pustulosis, DIHS/DRESS, and flexural exanthema. Mild systemic reactions (eg, transiently appearing generalized exanthema) can occur even after patch (or intradermal) tests in patients with very high sensitivity (eg, patients with DIHS/DRESS). It is only occasionally positive if the delayed-appearing skin reaction was mainly macular (no or only moderate cutaneous cell infiltration) or urticarial or isolated hepatitis or nephritis. Patch testing to evaluate DIHS/DRESS is reviewed separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Patch testing to the culprit drug is less likely to be positive (9 to 23 percent) in patients with past blistering reactions, such as SJS and TEN. It is not dangerous to perform such testing, contrary to previous belief [67].

●Intradermal testing with delayed readout – This type of testing should only be performed if a commercially available injectable form of the drug is available. The concentration used should be known to be nonirritating, and a prick test should be performed initially to assure there is no immediate response [68]. A positive result consists of erythema and induration at the site, and the site is examined at 24 to 48 hours after placement [66].

Intradermal testing with delayed readout is slightly more sensitive than patch testing but somewhat less specific [62]. It has the same indications as patch testing and may be used in evaluating exanthems, acute-generalized exanthematous pustulosis, DRESS/DIHS, fixed drug eruption, and symmetrical drug-related intertriginous and flexural exanthema. It has low sensitivity for blistering skin reactions, as well as for isolated macular or urticarial skin eruptions. Some patients with DRESS/DIHS may show a slight reappearance of symptoms, even if the dose was minimal.

Only a few preparations of drugs for skin testing are commercially available, so preparations are often made by individual clinicians or centers. This makes it difficult to standardize the procedure or compare results. Overall, patch and intradermal testing with delayed readout appear to have good drug-related specificity, although they can be positive even when recent drug treatment did not cause a reaction. In addition, more work is needed to increase their sensitivity [61,69].

●In vitro tests for delayed reactions – In vitro tests for delayed reactions include lymphocyte transformation/activation tests, upregulation of activation markers on T cells (eg, CD69), cytokine production, and drug-induced cytotoxicity assays [65,70]. These tests are done in certain centers only, need to be done with a preparation of pure drug, and are still considered research tools. If available, such tests may help in diagnosis because they can be positive when skin tests are negative or when skin tests are not available. Their specificity for most drug classes seems to be very good (mostly >95 percent), but the sensitivity needs to be improved [71].

Where available, in vitro testing may be useful in evaluating patients with maculopapular exanthema, acute-generalized exanthematous pustulosis, DIHS/DRESS, and flexural exanthema. The sensitivity of tests based on cell expansion, cell activation, or cytokine release is high in DIHS/DRESS but low in blistering reactions. The role of tests evaluating drug-induced cytotoxic reactions needs to be further evaluated and may be particularly interesting for bullous skin reactions [65], as well as for isolated drug-induced hepatitis or nephritis, where skin tests are often negative.

GRADED CHALLENGE AND DRUG PROVOCATION — Graded challenge and drug provocation testing (DPT) both involve administration of a medication to a patient in a gradual manner under close observation. These procedures are based on the principle that a certain amount of the medication is needed to elicit symptoms. The main difference between graded challenge and DPT is the likelihood of a reaction and the purpose of the procedure.

●DPT is a diagnostic procedure performed when the patient is in a good state of health with no sign of active disease. The purpose of DPT is proving/disproving a diagnosis and the involvement of certain drug. DPT may result in symptoms, although these are of milder severity than the initial reaction, because the drug is given gradually in incrementally increasing doses. In Europe, DPT is used to prove that a drug is indeed tolerated when skin and in vitro tests are negative. Frequently, DPT is used to find a well-tolerated alternative drug potentially useful for the patient in the future or to exclude crossreactivity [72,73].

●Graded challenge is a similar procedure but is usually performed when the patient requires immediate treatment with the drug in question. The purpose of a graded challenge is to provide a drug that is anticipated to be tolerated as quickly and as safely as possible [74]. If the drug is tolerated, the patient may be continued on therapy. Examples of patients in whom graded challenge might be performed are those with human immunodeficiency virus (HIV) infection, cystic fibrosis, or tuberculosis in whom an immediate reintroduction of antibiotic therapy/prophylaxis is required [75].

Graded challenge/DPT is assumed not to modify the allergic response to the drug or prevent recurrent reactions. Therefore:

●Patients who tolerate a drug upon graded challenge are not considered allergic to the drug given at the dose used.

●A challenge procedure in a patient with a suspected IgE-mediated drug allergy could potentially induce anaphylaxis and should be performed by an allergy expert in a setting equipped to manage possible reactions.

Indications and procedures — Graded challenge/DPT is carried out in patients who are unlikely to be allergic to the drug [76]. They should not be performed in a patient with a positive response in a prior drug allergy test (skin or in vitro).

The starting dose depends on the severity of the prior reaction. Typically, it is 1/100^th or 1/10^th of a full dose; the maximal dose is reached in two to five steps. DPT/challenge procedures start with higher concentrations and are substantially faster than the procedures used for desensitization, where one tries to achieve a transient "tolerance" to the drug. In desensitization protocols, starting doses are much lower (often 1/1000^th or lower) and generally increase twofold rather than 10-fold as in a challenge. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Graded challenge is assumed not to modify the allergic response to the drug or prevent recurrent reactions. Therefore:

●Patients who tolerate a drug upon graded challenge are not considered allergic to the drug given at the dose used.

●A challenge procedure in a patient with a suspected IgE-mediated drug allergy could potentially induce anaphylaxis and should be performed by an allergy expert in a setting equipped to manage possible reactions.

Contraindications — Graded challenge to the suspect drug is contraindicated in patients with the following types of reactions:

●Blistering dermatitis (eg, Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN]).

●Sloughing of the skin.

●Severe generalized hypersensitivity reactions involving internal organs (drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms [DIHS/DRESS]). In DIHS/DRESS, even minute amounts of the suspect drug, such as those used in skin testing, can reactivate these reactions, and the response can then escalate even though no further drug is given.

●Milder dermatoses with mucous membrane lesions (eg, erythema multiforme).

Inclusion of placebos — Inclusion of a placebo is strongly recommended to exclude false-positive reactions in patients with suspected conditioned responses or anxiety. These can often be elicited by placebo doses, thus reassuring the clinician and patient alike that the response is not due to the drug in question.

Challenge protocols — The pace of the challenge and degree of caution exercised depend upon the likelihood that the patient may be allergic, the patient's medical stability, and the clinician's experience and level of comfort with the procedure.

Other considerations include:

●Patients should not be premedicated with antihistamines or glucocorticoids, because these agents may mask early signs of an allergic reaction.

●Beta blockers taken for control of hypertension should be withheld for 24 hours before challenge as these agents can interfere with treatment of anaphylaxis with epinephrine, should that be necessary. In contrast, beta blockers that are taken to control arrhythmias should not be withheld without consulting a cardiologist.

●Patients with asthma, chronic obstructive lung disease, or other pulmonary diseases should have their pulmonary symptoms optimally controlled prior to undergoing challenge.

For immediate reactions — If the previous reaction occurred less than one hour after drug administration and there is concern about a possible IgE-dependent reaction, then the challenge should be performed by an allergy expert and in a setting equipped to treat anaphylaxis.

●The starting challenge dose depends on the severity of the past reaction. In general, when the symptoms may be caused by IgE-mediated allergy and, in DPT, when a reaction is more likely, a lower starting dose may be used (even <1/100^th), while, in delayed-appearing reactions, 1/10^th or 1/20^th may be sufficient. Using this strategy, any symptoms that are elicited should be mild.

●The oral route is preferred, when possible, since oral administration is generally associated with less severe symptoms compared with intravenous administration.

●Tenfold-increasing doses are administered every 30 to 60 minutes until the full therapeutic dose is reached.

Interpretation — Although simple in theory, graded challenges can require experience to interpret. Some patients develop nonspecific and subjective symptoms during the procedure, which can mimic symptoms of true allergy. These may be anxiety related, and spending time with the patient explaining the safety of challenge procedures in advance may help to reduce the incidence of these nonspecific reactions.

●If the patient develops convincing signs and symptoms consistent with an immediate reaction during or shortly after the graded challenge (within a few hours of receiving the full dose), no further drug should be given, and symptoms should be treated appropriately. These patients should be diagnosed with immediate allergy.

●If only subjective symptoms are reported, the patient can often be reassured, and the challenge can be continued. However, repeat challenge including placebo controls may occasionally be warranted.

●Patients with a negative challenge may still develop delayed reactions to the drug in question, but these should not be serious. (See 'Negative predictive value of challenge procedures' below.)

For delayed reactions — Challenge schemes for simple delayed exanthema to drugs are usually performed either in the context of research (to document sensitivity) or at a time that the patient actively needs the drug. In the latter situation, the drug may be slowly increased and the patient instructed to contact the clinician immediately if any adverse events are noted.

For delayed or nonimmediate types of reactions, challenge procedures are less standardized and are based upon the time course of the patient's reaction and the pharmacology of the drug involved [77]. The optimal approach is not known, and experts have differences in practice. In general, the time between doses should be long enough that delayed symptoms have time to develop before the next higher dose is administered. Some protocols may take days or even weeks.

An example of a challenge procedure for delayed reactions to cephalosporins involved administering doses at weekly intervals, starting with 1/100^th of a usual dose on day 0, 1/10^th of a dose on day 7, and a standard dose on day 14 [78]. However, other studies have documented that some delayed reactions only develop after several days at a full therapeutic dose or in the presence of a concomitant viral infection [79]. Thus, there may be certain drug reactions that cannot be easily elicited with any challenge protocol [80].

Other published examples of challenge protocols, when available, are discussed in specific topic reviews. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Desensitization'.)

Negative predictive value of challenge procedures — If a patient tolerates a drug challenge, it is highly unlikely, but not impossible, that that drug will cause symptoms if taken again in the future. If the reaction was not life threatening, the drug can be given in the normal manner in the future. However, for patients with a recent and severe anaphylactic drug reaction, even if the skin testing and challenge are negative, it is prudent to give the causative drug again only under medical surveillance. The author is aware of rare fatalities caused by penicillin in which the patient had demonstrated negative testing and had a negative challenge but then suffered fatal anaphylaxis when given the drug again. It is possible that skin testing and challenge were falsely negative due to the absence of important cofactors or that the exposure involved in testing and challenge reactivated the sensitization, although this is also believed to be very rare.

A small number of studies have examined the negative predictive value of challenges for immediate and delayed reactions:

●A study examined the negative predictive value of drug challenges in 203 children [81]. Of these, 163 of the children underwent allergy evaluation for immediate or delayed reactions. All were labeled as "not allergic to the drug" based on 175 negative drug challenges, consisting of one full dose of the drug. Reevaluation after at least a three-month interval showed that 91 (52 percent) of the 175 tested drugs were reported to have been used again: 65 children took the same antibiotic, 20 took the same nonsteroidal antiinflammatory drug (NSAID), and 6 took other drugs. An immediate reaction was reported in five (5.5 percent) of these (four antibiotics, one NSAID). One patient developed an anaphylactic reaction and was skin test positive upon repeat testing, suggesting either resensitization from the challenge or an error in original skin testing. The other patients who reacted had delayed reactions.

●Other studies have described similar findings. Recurrent reactions in spite of negative prior challenges were reported in 7.6 percent of 118 adults reexposed to the same beta-lactam antibiotic. All reactions were nonimmediate, and none were severe [82].

Such studies demonstrate that single-dose challenge procedures have higher negative predictive values for immediate reactions than for delayed-onset reactions. Challenges may rarely result in resensitization, and thus a prior negative challenge is not a guarantee that the drug will be tolerated, especially regarding delayed reactions.

OPTIONS FOR FUTURE TREATMENT — There are three options for future treatment in patients with a confirmed drug allergy:

●Administration of an unrelated medication

●Careful administration of a related medication

●Desensitization to the culprit drug

Administration of an unrelated medication — The most straightforward option is administration of an unrelated medication that is safe and effective for the disorder in question. However, second-line therapies may confer their own risks, such as toxicities and higher costs.

Penicillin allergy illustrates the issues involved. Patients labeled "penicillin allergic" often receive non-beta-lactam antibiotics, which can be more expensive, associated with side effects, and, in some cases, less efficacious [83-85]. Specifically, patients carrying the diagnosis of penicillin allergy are more likely to be treated with vancomycin or quinolones [83,86]. The use of these broad-spectrum antibiotics contributes to the development and spread of drug-resistant bacteria [87]. One study assessed various risk factors for the development of vancomycin-resistant Enterococcus (VRE) in a medical intensive care unit (MICU) [88]. Among pre-MICU treatment with various classes of antibiotics, quinolones had the strongest association with subsequent development of VRE (odds ratio 8.6), whereas treatment with penicillins/beta-lactamase inhibitors was not associated with developing VRE [89]. Some broad-spectrum antibiotics are also associated with Clostridioides difficile infection. Thus, use of alternative, unrelated medications is not without risk.

Administration of a related medication — The second alternative for drug-allergic patients is to receive a medication similar, but not identical to the offending drug.

The likelihood of crossreactivity among similar drugs is partly dependent on the type of allergic reaction in question. As an example, a patient with a T cell-mediated exanthema to amoxicillin is at low risk for reacting to a cephalosporin, whereas a patient with IgE-mediated anaphylaxis to amoxicillin is at some increased risk if given a cephalosporin. The related medication may be one for which skin testing is informative, or it can be initially given via graded challenge. Crossreactivity within classes of medications is discussed in specific topic reviews. (See "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics" and "Infusion reactions to systemic chemotherapy".)

Desensitization to the culprit drug — The third option is desensitization to the culprit drug. Classical desensitization is predictably successful for type I, IgE-mediated allergy, although gradual dose escalation may be attempted with variable success to several other types of immunologic and nonimmunologic drug reactions. Drug desensitization is reviewed in detail separately. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

LONG-TERM MANAGEMENT OF PATIENTS PRONE TO DRUG ALLERGY — Once a drug allergy has been identified, the affected patient should be educated about avoidance and provided with a written list of the generic and brand names of the culprit drug, as well as possibly cross-reactive drugs. Patients with potentially severe reactions should carry wallet cards, wear identification jewelry, or register with a drug allergy information service [90].

As discussed previously, some individuals are vulnerable to allergic drug reactions as a result of genetic or metabolic abnormalities (eg, multiple drug allergy syndrome), frequent and recurrent drug exposure (eg, antibiotics in cystic fibrosis), or certain disease states related to immune dysfunction (eg, human immunodeficiency virus [HIV] infection). In a drug allergy-prone population, pharmacotherapy requires special management to avoid adverse events and to prevent (to the degree possible) sensitization or resensitization.

Limit antibiotic use — Efforts should be made to limit unnecessary exposure to antibiotics. These include the diagnosis and treatment of underlying conditions that predispose to infections. As examples, rhinitis and asthma should be aggressively treated with glucocorticoid nasal sprays and inhalers to minimize sinopulmonary infections, and diabetes mellitus should be tightly controlled. Less commonly, undiagnosed immunodeficiency is present. In addition, it is advisable to use the lowest effective doses of drugs whenever possible [37].

Age-appropriate vaccinations should be administered and repeated at the recommended intervals. Avoidance of unnecessary exposures to contagious diseases may be helpful, especially in children and patients with immunodeficiency.

Proactive efforts to obtain culture data before initiating antibiotics can help to limit cumulative antibiotic exposure by avoiding treatment of viral infections and minimizing mid-treatment changes in antibiotic regimens. Enlisting the cooperation of the patient's other providers is important.

Consideration should be given to treating through mild cutaneous reactions, such as itching or mild rashes, especially early in therapy when an alternative antibiotic will usually be required. Treating through is possible in delayed-onset exanthema. This is typically considered when alternative treatments are problematic and an allergy specialist considers continued exposure to the drug to be low risk. Ongoing vigilance for clinical and laboratory danger signs is necessary, and concomitant use of glucocorticoids (prednisone 0.5 mg per kg) may be required if the exanthem intensifies rather than improves.

Approach to initiating new drugs — In drug allergy-prone patients, new drugs should be started at lower-than-normal doses when feasible. Administration under medical observation is sometimes necessary.

Patients with past Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) should be taught about the earliest symptoms of these reactions, such as fever or mucosal irritation, and know to stop medications immediately should these appear. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Prodromal symptoms' and "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Prevention'.)

Many patients with prior DIHS/DRESS experience a period of drug intolerance during the weeks after the initial reaction, meaning that any new drug may exacerbate symptoms (exanthems, hepatitis), often without proof of a new sensitization [37]. The symptoms may lead to the suspicion of a new drug allergy and further limit treatment. However, when the immune system is less activated (documented by circulating activated lymphocytes) the new drugs are again tolerated. This phenomenon has been termed a "flare-up" reaction [40]. However, some patients with prior DIHS/DRESS do develop genuine sensitizations to new compounds, and some develop multiple drug hypersensitivity [37,40].

Patients with past IgE-mediated reactions to drugs should not be given premedications before gradual dose escalation of new drugs. Neither antihistamines nor glucocorticoids can prevent IgE-mediated anaphylaxis, and premedications may mask early symptoms and allow dosing to proceed more rapidly than advisable.

In contrast to the above scenarios, patients who have reacted with uncomplicated exanthemas, including mild urticaria, to a variety of different drugs may benefit from administration of an antihistamine when new drugs are initiated.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Drug allergy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk factors for drug allergy – Risk factors for developing drug allergies include past drug allergy, recurrent drug exposure, genetic factors, and certain diseases (eg, human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome [AIDS]). Individuals with two or more immunologic drug reactions to chemically unrelated medications are said to have "multiple drug allergy syndrome." (See 'Risk factors for drug allergy' above.)

●Approach to the clinical history – Patients who develop signs/symptoms of drug allergy while receiving multiple medications simultaneously are best approached in a systematic manner. Evaluation involves a meticulous history of past and present drug reactions, additional information gathering from the medical record, and analysis of temporal patterns between drug administration and onset of symptoms. Once this information has been assembled, it is combined with knowledge about the types of allergic reactions most often caused by various classes of drugs to identify potential culprit agents. (See 'Approach to the patient' above and 'Clinical history' above and 'Review the medical record' above.)

●Objective testing – Overall, objective testing for the diagnosis of drug allergy is limited. Skin testing is helpful for some medications that cause type I, immediate hypersensitivity reactions, although skin testing has been fully validated only for penicillin. In some cases, types II, III, and IV reactions can be evaluated with in vitro studies, although the majority of these tests are still investigational. (See 'Objective testing' above.)

●Graded challenges – Allergy to a drug can be excluded by performing a graded challenge. However, graded challenge does not modify the allergic response to the drug or prevent recurrent reactions. Thus, challenges should only be performed in patients who are suspected of not having a true allergy, and all challenges must be performed with caution and in a monitored setting. Patients who tolerate drug challenges prove that they are not allergic to that medication. (See 'Graded challenge and drug provocation' above.)

●Options for future therapy – There are three options for future treatment in patients with a confirmed drug allergy: administration of an unrelated medication, careful administration of a related medication, and desensitization to the culprit drug. (See 'Options for future treatment' above.)