Drug Hypersensitivity: Diagnosis, Genetics, and Prevention
Diagnosis, genetics, and prevention
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Background: Adverse drug reactions (ADRs) can be divided into pharmacological ADRs (type A) and hypersensitivity reactions (type B). Type B reactions can be further subdivided into immediate (<1 h, urticaria, anaphylaxis) and delayed reactions (>1 h, variable manifestation like exanthema, hepatitis, cytopenias). Prevention of hypersensitivity is often still a challenge.
Methods: Selective literature search in Medline and Google Scholar as well as research in ADR databases like OpenVigil or SIDER.
Results: Laboratory tests ([specific] IgE, lymphocyte transformation test), histological examination, dermatological tests (prick tests, epicutaneous testing) and—under certain circumstances—provocation tests can be used for diagnostics. There are only a few pharmacogenetic biomarkers to predict hypersensitivity reactions. Currently, testing for defined HLA genes is mandatory before prescription of abacavir and before the use of carbamazepine in Han Chinese or Thai patients. Immediate discontinuation of the trigger is essential in all allergic hypersensitivity reactions. Immediate reactions are treated with antihistamines, glucocorticoids and occasionally with epinephrine. Delayed reactions are usually treated with glucocorticoids.
Conclusions: Careful, structured diagnostics in case of suspected hypersensitivity together with adequate documentation (allergy passport) is necessary in order to avoid incidents in patients receiving subsequent treatment. Consistent use of existing resources (diagnostics and documentation) can help to avoid hypersensitivity reactions or to rapidly recognize and treat them, respectively.
Drug treatment often leads to adverse events (AE). Some of these are so-called medication errors which occur due to the handling of the drug, rather than due to the drug itself (e1). Adverse drug reactions (ADR), colloquially called “side effects,” are adverse events that are due to the inherent biological effects of the drug. These, in turn, are divided into pharmacologically mediated ADR (type A) and hypersensitivity reactions (type B) (1). Type A reactions can occasionally be therapeutically useful or even lead to new indications: for example, minoxidil causes hair growth, and sildenafil has a beneficial effect on erectile dysfunction. Drug-induced liver damage is a well-known kind of type A reaction that can be caused, e.g., by an overdose of acetaminophen, whereas flucloxacillin-associated liver damage is an HLA-associated type B reaction (2). Type A reactions are generally dose-dependent, while type B reactions are generally considered to be independent of the dose once a low threshold dose has been exceeded (3).
Both classic immunological (allergic) and non-allergic hypersensitivity reactions involve activation of the immune system or of its effector pathways, such as inflammatory reactions (Table 1, Figure 1). Hypersensitivity reactions are clinically categorized as either immediate (arising less than one hour after exposure) or late (arising more than one hour after exposure). The classic allergic reactions are divided into four types, in the scheme of Coombs and Gell; types I and IV are the ones most commonly encountered.
A drug may trigger very different kinds of hypersensitivity reactions across individuals, or even in the same individual (4).
Penicillins, for example, may induce non-allergic hypersensitivity, as well as allergies of types I–IV. These different kinds of reaction can also arise simultaneously. Topical penicillin preparations are no longer on the market because of the high risk of contact allergy (10%).
This article is intended to impart knowledge of:
- the triggers and course of common kinds of hypersensitivity reaction;
- the appropriate treatment of hypersensitivity reactions; and
- strategies for the avoidance of such reactions, with the aid of phenotypic testing (laboratory tests, skin tests), pharmacogenetic testing, and desensitization.
This review is based on publications retrieved by a search in Medline and other databases that contain relevant information on adverse drug reactions (eBox 1).
The classification and etiology of hypersensitivity reactions
Hypersensitivity reactions were once thought to be unpredictable, but an improved understanding of the immune system, along with data from cohort studies and pharmacovigilance, have made it possible to identify the drugs and mechanisms that are mainly responsible for such reactions, and to delineate distinct clinical syndromes (5, e2).
Immediate reactions have variable manifestations, ranging from pruritus to edema, urticaria, and anaphylactic shock.
The etiology of type I allergic reactions
Type I allergy involves the IgE-mediated elaboration of inflammatory mediators such as histamine, heparin, tryptase, platelet-activating factor (PAF), and prostaglandins, which give rise to an inflammatory reaction. Reactions of this type are typically induced by penicillins, for example (Figure 1).
The etiology of non-allergic hypersensitivity reactions
Non-allergic hypersensitivity reactions account for approximately 77% of all hypersensitivity reactions (6) and can be induced by substances of many kinds, including penicillins and nonsteroidal anti-inflammatory drugs (NSAID) (Figure 1) (4, e3). The triggers may induce the release of histamine from storage vesicles (vancomycin, for example) or lead to activation of the complement system (e.g., radiologic contrast dye). The number needed to harm (NNH) describes the number of persons to be exposed to a certain trigger until a reaction occurs (1/incidence). The NNH is high (>1000) for vancomycin, but lower for NSAID and morphine (NNH ~100). Hypersensitivity reactions are much more common in response to food and food additives such as benzoates (NNH 11 in persons with allergic rhinitis) (e4) or sulfites (NNH 14–58) (e5).
The pharmacogenetics of non-allergic hypersensitivity reactions
Hypersensitivity reactions may be provoked by variants in genes being involved in the synthesis or degradation of inflammatory mediators such as bradykinin, histamine, prostaglandins, or leukotrienes, or in the activity of the corresponding receptors. The most prominent example is an asthma attack induced by a nonsteroidal anti-inflammatory drug such as diclofenac (7). Another, potentially dangerous reaction of this type is angioedema induced by ACE inhibitors. The latter reaction is associated with a genetic variant of plasma aminopeptidase (8).
Delayed reactions, too, may be due to immunologic or other reactions (eFigure).
The etiology of type II and III allergic reactions
In type II allergic reactions, antibodies bind to the active substance when it is bound to blood cells, thereby leading either to hemolysis or to thrombocytopenia. In type III allergic reactions, antibodies bind to the free active substance in the blood, forming immune complexes which, in turn, damage the vascular walls and glomeruli (4).
The etiology of type IV allergic reactions
Type IV allergic reactions are mediated by T-cells (Figure 1). These reactions belong to subtypes a through d, depending on the participating subgroups of T cells (Table 1) (9). Common syndromes include:
- drug-induced agranulocytosis (DIA)
- drug-induced skin disorders (DISI) such as:
– contact allergy
– fixed drug eruption (FDE)
– acute, generalized exanthematic pustulosis (AGEP)
– maculopapular rash (MPR), also called morbilliform rash
– drug reaction with eosinophilia and systemic symptoms (DRESS)
– Stevens-Johnson syndrome / Lyell syndrome (synonym: toxic epidermal necrolysis) (SJS/TEN)
- drug-induced liver injury (DILI)
- drug-induced renal injury (DIRI)
Contact allergies of the skin, usually consisting of contact eczema, are also type IV allergies; these can be induced, for example, by topically applied neomycin. This classic allergic reaction after obligate prior sensitization is also, to some extent, dose-dependent (3). It depends on the HLA type as well (10).
These reactions can be hard to distinguish from type A side effects. For example, glutathione deficiency may be cytotoxic, paracetamol is indirectly hepatotoxic, and clozapine can cause agranulocytosis. Even DRESS has a relevant metabolic component (eFigure).
Although delayed reactions make up only a small percentage of all undesired events, they are highly important because of their severity. Acute generalized exanthematic pustulosis, Stevens-Johnson / Lyell syndrome (synonym: toxic epidermal necrolysis) and DRESS carry a high mortality (>1%) are are therefore also called severe cutaneous reactions. The mortality of drug-induced agranulocytosis is approximately 5% (11), that of DRESS 2–10% (12, e6), that of Stevens-Johnson / Lyell syndrome approximately 34% (13), and that of drug-induced liver damage in a range from 0% to over 10% (14).
The high metabolic activity of the skin and liver presumably accounts for their vulnerability to such reactions. The skin, in particular, is constantly immunologically stimulated by pathogens and noxious substances because of its exposed position. The same can be said of the gastrointestinal mucosa, which is another preferred site for hypersensitivity reactions (cramping, diarrhea).
Biomarkers (mostly human leukocyte antigens, HLA) have been identified for a number of delayed reactions. HLA genes code for proteins of the major histocompatibility complex (MHC). HLA-A, HLA-B, and HLA-C code for MHC class I proteins, while HLA-DM to HLA-DR code for MHC class II proteins that interact with T-cells. The nomenclature includes at least the following:
Delayed reactions that take place within the body, rather than on the skin, may remain unrecognized. In patients who were not sensitized to the inducing drug at the beginning of their treatment, delayed reactions can arise after a delay of days to weeks—sometimes even after the drug has been discontinued—without causing any symptoms until then.
Antibiotics (particularly beta-lactams) and anticonvulsants are the most common triggering drugs, accounting for three-quarters of all cases of hypersensitivity (e7). Further triggers, e.g., NSAID, antiretroviral drugs, sulfonamides, and allopurinol, are listed in Figure 1 (classic examples), in eTable 1 (spontaneous reports), and eTable 2 (manufacturers’ summaries of product characteristics, via SIDER).
An overview of pharmacogenetic biomarkers can be seen in the HLADR database (15).
Certain diseases alter the probability of hypersensitivity reactions: HIV patients react more commonly to sulfonamides, while persons with mastocytosis react variably to a wide range of substances (9).
The measures needed to securely establish the diagnosis of a hypersensitivity reaction and to document it adequately (Table 2) are often not carried out in routine clinical practice, either to save time and money, or else because of physicians’ inadequate experience with hypersensitivity reactions. For example, the detection of abacavir-induced cutaneous reactions was jeopardized at first by inadequate documentation of the phenotype (e8). Standardized questionnaires (16) and photographic documentation markedly improved the documentation of hypersensitivity reactions.
The diagnostic evaluation of hypersensitivity reactions consists of thorough history-taking, in vitro laboratory testing, and in vivo cutaneous tests and provocative tests (17).
The clinical history must include documentation of the time from drug exposure to the adverse event, a precise description of the event (including gastrointestinal and respiratory symptoms), and an account of the accompanying circumstances (concomitant medication, viral infections, underlying disease).
A dechallenge-rechallenge test, i.e., the regression of symptoms after discontinuation of the presumed triggering drug and their re-emergence after it is reintroduced, either deliberately (drug challenging) or unintentionally (inadvertent reexposure), is the most convincing proof of causality. Before a dechallenge can take place, a hypothesis must be formulated as to which drug (possibly one of a long list of drugs) is the trigger. Clues in this matter can be obtained from manufacturers’ summaries of product characteristics or from searches in adverse drug reaction databases such as SIDER or OpenVigil (18, 19). The interval of time from drug exposure to symptom emergence is of paramount importance: unless a delayed reaction has taken place, the last drug added is usually the one responsible for the adverse drug reaction.
In vitro testing comprises tests for specific IgE (type I allergy) and for the release of leukotrienes or histamine. Specific IgEs can be detected and semiquantitatively analyzed through their binding to an allergen-containing cellulose sponge (CAP) followed by testing with either radioactivity (RAST) or fluorescence (FEIA). Type I reactions can also be detected by the basophil activation test. The lymphocyte transformation test (LTT) also provides information about type IV allergies, but it is not standardized. All testing methods are of limited sensitivity and specificity. Not every positive finding is correlated with clinically relevant symptoms, and vice versa.
Many genetic markers (variants in, e.g., 5´-lipooxygenase, the histamine receptor, cysteinyl leukotriene synthetase, arylamine-N-acetyltransferase, aminopeptidase P, platelet-activating-factor-acetylhydrolase, and HLA) have been found to be associated with hypersensitivity reactions, but predictive testing is currently clinically relevant only with respect to HLA status when certain specific drugs are taken. Many markers are of little predictive value (9).
Dermatologic testing includes the prick test and the intracutaneous test when type I allergy is suspected (immediate response, can be read 20 minutes after application) and the epicutaneous patch test or the intracutaneous test with delayed readout when type IV allergy is suspected (delayed reaction, readout in 24–72 hours). Unlike laboratory tests, these tests may pose a risk to the patient (e.g., an anaphylactic reaction in type I allergy or sensitization in type IV allergy).
As drug metabolites often cause hypersensitivity reactions, the results of testing on the skin, which has a different liver metabolic profile, cannot simply be extrapolated to other modes of application of the presumed triggering substance. Moreover, cutaneous irritation can occur.
In drug-induced cutaneous reactions, skin biopsies can be taken to prove the diagnosis of type III (vasculitis) and type IV reactions, especially because a number of serious drug-induced cutaneous reactions cannot be detected by epi- or intracutaneous testing.
Drug challenging, i.e., systemic reexposure to the presumably triggering drug (by the intravenous, oral, or other route), may be contraindicated in cases of severe hypersensitivity. For example, reactions to reexposure with abacavir are markedly faster (occurring within a few hours) and carry a higher mortality (20).
The clinical features of selected delayed reactions
The diagnosis is made by a peripheral blood count with differential (<500 granulocytes per µL of blood). An unexpectedly rapid and severe course of a usually trivial infection is often the first clinical sign. Sepsis with uncommon pathogens (e.g., mycoses, Brucella, Helicobacter) may be another sign. The classic manifestation is severe inflammation at the typical portals of pathogen entry—the rectum, bladder, and pharynx. If the condition is untreated, sepsis and death ensue. The presumed triggering drug should be discontinued, the patient should be isolated, and prophylactic antibiotics should be given to cover both Pseudomonas aeruginosa and fungal infections.
The pharmacogenetics of clozapine-induced agranulocytosis
Clozapine-induced agranulocytosis has a frequency of 0.8% (e10) and is due to an interaction of this atypical antipsychotic drug with HLA-DQB1 and an HLA-B variant (158T) in which the drug itself acts as a hapten. The frequencies of these genetic traits are 12% and 17%, respectively, with a 4% frequency of joint occurrence in the study population (21). For example, individuals carrying the HLA-DQB1 trait are 2.6 times as likely to develop agranulocytosis after taking clozapine (22).
Severe cutaneous reactions
Drug reaction with eosinophilia and systemic symptoms (DRESS)
DRESS has variable manifestations, generally a maculopapular rash initially, followed later by lymphadenopathy, hepatitis, and eosinophilia. Abacavir-induced hypersensitivity differs from hypersensitivity reactions to other drugs only in that eosinophilia is rarer (e11, e12); the abacavir reaction is nonetheless considered a type of DRESS (e13). Scoring systems enable objective diagnostic evaluation (23). In these cases, too, discontinuation of the trigger is the only available causal treatment.
Acute, generalized exanthematous pustulosis
This condition manifests with erythema and numerous pinhead-sized pustules on the face, skin folds, and trunk. A scoring system is available as an aid for diagnostic evaluation (24).
Stevens-Johnson syndrome /
toxic epidermal necrolysis
Stevens-Johnson syndrome and toxic epidermal necrolysis, which are considered to be variants of a single condition, manifest themselves with blisters and erosions occupying large areas of the skin (mainly on the trunk and face) and mucous membranes, progressing in a cranial-to-caudal direction. The histologic findings include mainly subepidermal cleavage and epidermal necrosis. The differential diagnosis includes erythema exsudativum multiforme, which must be ruled out; this entity is not a hypersensitivity reaction and generally arises after an infection, but it bears some clinical resemblance to Stevens-Johnson syndrome / toxic epidermal necrolysis. It is distinct from them in presenting with raised, target-shaped lesions (called bull’s-eye lesions or cockades). A generalized bullous fixed drug eruption is a further, rare element of the differential diagnosis.
The assessment of rashes
The following can be warning signs of a serious reaction carrying an elevated mortality: a bullous skin reaction, facial and mucosal involvement, eosinophilia, elevated liver enzymes, dyspnea, and systemic symptoms such as fever above 38.5 °C and lymphadenopathy (Figure 2). Infectious rashes should be excluded in the differential diagnosis (e.g., Epstein-Barr virus, Staphylococcus exotoxin). Viruses are the most common cause of rash in children, drugs in adults. A preceding sore throat and skin involvement beginning on the face are indications of a probably viral rash.
The pharmacogenetics of severe drug-induced cutaneous reactions
The finding of HLA-B*57:01 before the administration of the antiretroviral drug abacavir has a 50% positive predictive value for severe cutaneous reactions, while the absence of this finding has a negative predictive value above 99% (25). The documentation of HLA status is therefore mandatory in Europe before this drug can be given, as the drug may not be prescribed to to carriers of HLA-B*57:01 (70% probability of a reaction in a median time of 11 days), while the risk of a cutaneous reaction is much lower (ca. 2%) in non-carriers (25, e14). Cutaneous hypersensitivity reactions to carbamazepine are also associated with certain HLA alleles (HLA-A31:01, HLA-B*15:02), whose prevalence is markedly dependent on the patient’s ethnic origin (Table 3) (26, e15). The risk of a severe cutaneous reaction to carbamazepine a few days to approximately one month after the onset of treatment is ca. 3% in general, but 100% among carriers of the biomarker HLA-B*15:02, when it is found in persons of Han Chinese or Thai ethnicity (27). Likewise, HLA-B*15:02 is associated with severe cutaneous reactions to lamotrigine, another anticonvulsant (28).
Drug-induced liver damage
Typical externally evident signs of severe liver damage include fatigue, weakness, abdominal pain, nausea, dark urine, jaundice, pruritus, and fever. Laboratory testing reveals elevated concentrations of the hepatic aminotransferases (ALT, AST) and alkaline phosphatase (AP). The ratio of ALT/AP enables further differentiation of the hepatobiliary damage. Isolated ALT elevation, or an ALT elevation that is five times higher than the AP elevation (when the measured concentration of each drug is compared to the upper limit of its normal range), indicates hepatocellular damage (e.g., due to acetaminophen). Conversely, predominant elevation of AP may reflect cholestasis (induced, for example, by an ACE inhibitor) or fibrosis (induced, for example, by methotrexate) (29). The degree of severity can also be estimated (30). Reexposure usually leads to a renewed hypersensitivity reaction whose course is faster (days, not weeks) and more severe than the original one (31).
Viral hepatitis is the main differential diagnosis to be ruled out. Aside from the antibiotics listed in Figure 1 and the substances mentioned above, further triggers can be found in the LiverTox database (32). A history of consumption of certain botanical extracts and food supplements is relevant; the so-called natural anxiolytic Kava kava, for example, was forbidden at one time and is now available only by prescription because of its hepatotoxicity, which is associated with variants of UDP-glucuronosyltransferase 1A1 (UGT1A1) (e16).
Certain types of drug-related hepatotoxicity are associated with HLA markers, e.g., hepatotoxicity due to the beta-lactam antibiotics flucloxacillin (2) and amoxicillin/clavulanic acid (33) in carriers of HLA-B*57:01. Moreover, HLA-A*33:01 is associated with hepatotoxicity due to enalapril, erythromycin, fenofibrate, methyldopa, sertraline, terbonafine, and ticlopidine (30), while HLA-DRB1*16:01-DQB1*05:02 is associated with hepatotoxicity due to flupirtine (34).
The diagnosis of drug hypersensitivity must be properly documented. Hospital information systems now enable the deposition of such information in the patient’s record so that it will be available when the patient undergoes further treatment or is readmitted. Such information must also be noted in hospital discharge summaries to prevent the readministration of the provoking drug later on. Unfortunately, this is estimated to occur within six months in 27% of all patients who have suffered hypersensitivity reactions, solely because of inadequate communication (35).
If a drug reaction is documented on the basis of information provided by the patient, the reliability of this information should be proven and documented as well. The patient should be provided with an allergy passport in which the triggering substance and examples of drugs containing it are explicitly mentioned. A common type of inadequate documentation is that of a so-called penicillin allergy; in many such cases, a type A side effect (e.g., gastrointestinal discomfort) has been misinterpreted as a hypersensitivity reaction. Physicians are also occasionally confronted with vague information dating back to the patient’s childhood that the patient cannot remember at all, or, if so, then only incompletely. The uncritical acceptance and documentation of such “allergies” leads to the unnecessary avoidance of effective treatments in favor of others that may be less effective or more costly. No more than 20% of so-called penicillin allergies are really allergies in the strict, classic sense (36).
Drugs of second choice can also be tested and documented in the allergy passport so that valid options will be available later if treatment is needed. It must be kept in mind, however, that such tests cannot be anything more than snapshots of the current situation, and that “prophetic” tests, such as patients often request, are not possible. HLA genotyping is the method of choice for the prevention of certain type IV reactions (e2).
Several further types of genetic testing are available but are of relatively low predictive value and are fraught with a high number needed to screen (NNS) and a high cost/benefit ratio (Table 3). Such genetic markers could rather be used for the scientific explanation of hypersensitivity reactions that have already occurred, with an eye toward strategies of preventing reexposure.
When a hypersensitivity reaction arises, the immediate discontinuation of the triggering drug is the safest option. The reaction itself can only be managed with supportive care, as there is no causally directed treatment (Table 1). Drug rashes have traditionally been treated with glucocorticoids, despite their questionable efficacy (e17, e18). Stevens-Johnson syndrome and toxic epidermal necrolysis seem not to respond reliably to either glucocorticoids or anti-inflammatory drugs (e19, e20). Cyclosporine A might lower mortality (37). High-dose intravenous immunoglobulins are given to treat DRESS, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Their efficacy in this situation is thought be mediated by antibodies directed against the apoptosis-associated molecules Fas (first apoptosis signal receptor) and FasL (Fas-ligand L) (e21).
The avoidance of hypersensitivity reactions
Considering the estimated mean cost of €2700 for an undesired event in Germany (e22), the avoidance of such events is not just an ethical imperative, but an economic one as well. Many of these events could, indeed, be avoided (Table 1).
If a patient reports having suffered from an “allergy” in the past, this should prompt further allergological testing, unless precise documentation (an allergy passport) is already available. Often, multiple testing methods must be used to confirm or refute the suspected diagnosis.
In case reexposure is possible or medically necessary, patients who have sustained immediate-type reactions could undergo desensitization therapy (e23).
The avoidance of undesired events seems economically meaningful. In particular, pharmacogenetic testing (as it is now established in modern oncology, for example, in the form of companion diagnostic testing) can help prevent serious drug reactions. Genetic testing before carbamazepine treatment, for example, has been found to be cost-effective (e24).
Data from the Hong Kong health-care system have revealed, however, that physicians generally did not perform the required genetic testing for HLA-B*15:02 before using carbamazepine, but rather went ahead and directly prescribed the more expensive alternative drugs (38). This approach prevents the use of drugs that are known to be highly effective in favor of others of less certain efficacy, while burdening the health-care system with unnecessary costs and, furthermore, complicating the evaluation of the current guidelines, because recent data are inevitably distorted by this kind of evasive behavior.
Conflict of interest statement
The authors state that they have no conflicts of interest.
Manuscript submitted on 1 May 2017, revised version accepted on
7 June 2018.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Dr. rer. nat. Ingolf Cascorbi
Institut für Experimentelle und Klinische Pharmakologie
Arnold-Heller-Str. 3, 24105 Kiel, Germany
Department of Dermatology, Allergology and Venerology, University Medical Center Schleswig-Holstein, Kiel: Prof. Dr. med.
Dr. rer. nat. Ehrhardt Proksch, Prof. Dr. med. Thomas Schwarz
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