INTRODUCTION — A drug allergy is an adverse drug reaction that results from stimulation of the immune system by a medication. The pathogenesis of different types of drug-allergic reactions will be reviewed here. The classification and clinical features of drug-allergic reactions are discussed elsewhere. (See "Drug hypersensitivity: Classification and clinical features".)
INTERACTION OF DRUGS WITH THE IMMUNE SYSTEM — Drugs can elicit drug-specific immune responses in two ways (table 1):
●The drug may act as an antigen and elicit one of several classic immune responses.
●The drug may directly interact with immune receptors and under certain circumstances, lead to activation of specific immune cells [1].
Some drugs can bind directly to effector cells of the immune system (eg, mast cells) and cause mast cell degranulation with the clinical symptoms of urticaria or anaphylaxis [2]. Such symptoms are very similar to some drug-allergic reactions (immunoglobulin E [IgE]) and are called pseudoallergic or nonallergic hypersensitivity reactions. They do not involve drug-specific antibodies or T cells and are thus not truly immune-mediated reactions. Common examples include most reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents, which are discussed elsewhere (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions" and "Diagnosis and treatment of an acute reaction to a radiologic contrast agent".)
The use of checkpoint inhibitors (antibodies to programmed cell death-1 [PD-1]/programmed death-ligand 1 [PD-L1] and cytotoxic T lymphocyte-associated antigen 4 [CTLA4]) in patients with cancer (mostly melanoma and renal cell carcinoma) has been linked to adverse effects, including gastrointestinal problems (eg, severe and long-lasting diarrhea), rashes and dermatitis, hepatitis, pneumonitis, and endocrinopathies (thyroiditis, diabetes mellitus, hypophysitis). These symptoms have been described as immune-related adverse effects, and they are also observed when the checkpoint inhibitors are combined with tyrosine kinase inhibitors. The mechanism is unclear but may be related to blocking of immunologic control mechanisms [3]. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
Drugs acting as antigens — Most medications are small molecular weight compounds with simple chemical structures, which are not easily recognized by immune cells and are considered too small to interact with immune receptors with sufficient strength to activate T or B cells. Thus, most drugs are not effective antigens and are not immunogenic in their native state.
However, small chemicals (ie, <1 kilodalton in size) can become immunogenic by binding covalently to larger macromolecules (usually host proteins on or inside cells or in plasma). The drug is then referred to as a "hapten," and the newly formed complex is called a hapten-carrier complex. Examples of molecules that may become bound by haptens include integrins or albumin. Hapten-carrier complexes are not only immunogenic for B cells (antibody responses) but also for T cells [4,5]. T cell responses require processing of the hapten-carrier complexes and presentation of hapten-peptide fragments on human-leukocyte antigen (HLA) molecules. As in other protein-specific reactions, some activation of the innate immunity is essential to start the immune activation [6]. Drugs that cannot act directly as haptens but give rise to metabolites that can are referred to as prohaptens.
Drugs as haptens — Penicillin is one of the few drugs that haptenates host proteins directly. When penicillin is administered and exposed to the physiologic conditions within the body, the beta-lactam ring structure readily breaks open. The opened ring reacts with lysine residues in proteins, forming a hapten-carrier protein complex referred to as the major penicilloyl determinant, which is capable of stimulating T cell and/or antibody responses [7,8]. The majority of immediate-allergic reactions to penicillin and other beta-lactam drugs arise from this mechanism. The pathogenesis of penicillin allergy is reviewed in greater detail separately. (See "Penicillin allergy: Immediate reactions".)
Drug manufacturers have made efforts to avoid the introduction of new drugs that can spontaneously haptenate macromolecules, but the following groups of agents already in use have this capability:
●Penicillins and other beta-lactam antibiotics (ie, cephalosporins, carbapenems, and monobactams)
Reactive metabolites — Some drugs are unreactive with host macromolecules in their native state but are converted into reactive intermediates during drug metabolism [9-11]. Drug metabolism occurs mainly in the liver through the actions of cytochrome P450-associated enzymes [12]. (See "Drugs and the liver: Metabolism and mechanisms of injury".)
During drug metabolism, reactive drug metabolites are often generated within hepatocytes. Some of these reactive metabolites may escape detoxification and subsequently bind to (haptenate) intracellular proteins [13-15] or may be secreted from the cell and further processed by antigen-presenting cells (APCs). Such drugs are called prohaptens. Drug metabolism can also occur within APCs directly, and their binding to intracellular proteins may be important for activating dendritic cells and thus providing activation of innate immunity. In addition, the modified proteins are processed and presented as drug-peptide antigens on the cell surface, which provides new antigenic epitopes for activation of T cells. The T cells can then produce cytokines to stimulate B cells, in which case both T cell- and antibody-mediated responses would ensue [15].
Sulfonamide antimicrobials are examples of medications that form reactive metabolites. The sulfamethoxazole component of trimethoprim-sulfamethoxazole (TMP-SMX) is partly acetylated, giving rise to harmless compounds, and partly metabolized to sulfamethoxazole-hydroxylamine (SMX-NHOH). SMX-NHOH can be secreted in the urine but is also oxidized to sulfamethoxazole-nitroso (SMX-NO), which is highly reactive with proteins [14-16]. The SMX-NO protein complexes can stimulate both T and B cell responses. The metabolism of sulfonamides and sulfonamide allergy are reviewed in more detail elsewhere. (See "Sulfonamide allergy in HIV-uninfected patients".)
Many drugs give rise to reactive intermediates during metabolism, but most are immediately neutralized (eg, by glutathione). The following drugs form reactive metabolites that may escape neutralization and may potentially form immunogenic hapten-protein complexes [17,18]:
●Sulfonamide antimicrobials (but not other sulfonamide drugs)
●Phenacetin
●Halothane
●Phenytoin, carbamazepine, and lamotrigine
Stimulation of an antibody response — The mechanisms though which an antigen gives rise to an antibody response are reviewed in detail separately. Briefly, most antigens are processed by APCs and presented to T cells in the context of proteins of HLA. This results in activation of the T cell, which in turn produces cytokines that activate B cells. The B cell recognizes the "antigen" (= protein or hapten-modified protein) via its immunoglobulin receptor, becomes activated, and subsequently produces antigen-specific immunoglobulins. (See "The adaptive humoral immune response".)
Quite a few modern pharmaceuticals are proteins, which like other soluble proteins, preferentially stimulate an antibody response (and also some T cell responses). The following are examples:
●Recombinant proteins, such as monoclonal antibodies, solubilized receptors, and cytokines
●Insulin and other hormones (both of animal and human origin)
●Enzymes and protamine
●Antisera
●Vaccines
A limited number of drugs are high molecular weight macromolecules containing many repetitive motifs/epitopes, which may even induce antibody formation without T cell help. There are also a few agents of low molecular weight that contain multiple recurrences of a single epitope. If an antibody response develops, these drugs can cross-link antibodies despite their small size and elicit rapidly severe reactions. The best known examples are carboxymethyl cellulose, a stabilizing agent in injectable preparations for intramuscular administration. Some quaternary ammonium compounds used as neuromuscular blockers in anesthesia induction are also divalent (such as vecuronium, atracurium, succinylcholine, and others) and cause reactions by this mechanism [19,20]. Allergic reactions to these agents are reviewed in detail separately. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management".)
A growing number of modern "biologic" therapies are proteins, which often imitate human proteins as closely as possible. They elicit a great variety of immune reactions, including rare classic immune reactions to the drug/protein itself or more commonly, reactions that directly or indirectly result from the manner in which these agents target specific immune functions. The mechanisms of action of various biologic therapies and the immunologic reactions that can result in some patients are reviewed elsewhere. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases" and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)
Pharmacologic interaction of drugs with immune receptors (the p-i concept) — A novel mechanism was proposed for interaction of drugs by the immune system in the late 1990s. This theory arose from the observation that certain drugs in their native state, without processing or metabolism, can stimulate T cells, even though the drugs are unable to bind covalently to larger protein structures in this state. This was called the "p-i concept" for "pharmacologic interaction of drugs with immune receptors" because the interaction is similar to that between a drug and its target therapeutic receptor [21,22].
The p-i concept proposes that some drugs can interact directly with certain T cell receptors (TCRs) or HLA molecules that are not their primary therapeutic targets. Of note (and in contrast to haptens), the drugs bind to the receptor proteins themselves and not the immunogenic peptides presented by HLA molecules. This "off-target" activity of the drug on immune receptors is peculiar for the following reasons:
●In p-i, the drug interacts with a highly complex and polymorphic receptor system. The TCR is highly polymorphic with more than 109 to 1011 different TCRs per individual. The HLA is polymorphic within the individual (>12 to 16 HLA class I/II proteins), as well as in the population (>10.000 HLA class I alleles and >3000 class II alleles [23]. Thus, the ability of drugs to bind to some of these immune receptors varies enormously between different individuals and depends on the immunogenetic background. This explains why many of the severe drug hypersensitivity reactions due to p-i mechanism occur in carriers of certain HLA alleles [24].
●The effect of p-i is restricted to T cell stimulations, in contrast to hapten-dependent reactions. Some drugs, (eg, abacavir, phenytoin, carbamazepine) elicit only T cell stimulations (eg, exanthems, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome [DRESS/DiHS]) and never elicit an antibody reaction (eg, IgE-mediated anaphylaxis). Others (eg, flucloxacillin, sulfamethoxazole) can stimulate both T cell- and antibody-mediated reactions.
●The p-i-based stimulation is an off-target activity of the drug on a receptor and thus highly dependent on (local) drug concentration. Many severe drug hypersensitivity reactions occur with drugs given in high doses (>1 gram daily), and further dose increases are known precipitating factors in reactions like DRESS/DiHS. These observations have been supported by the finding that a genetic variant of CYP2C, including CYP2C9*3, known to reduce phenytoin clearance, is linked to severe cutaneous hypersensitivity [25]. In allopurinol hypersensitivity, impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-induced severe cutaneous hypersensitivity [26].
●An important distinction of p-i to classic off-target activities of drugs is the fact that immune stimulatory consequences of p-i occur only if the TCR-HLA interaction takes place. Symptoms are always dependent on a T cell activation, even if the drug binds to HLA. Drug binding to one immune receptor (HLA or TCR alone) is not sufficient to activate the immune system.
There are different possibilities of drugs to bind to the immune receptors, and different functional consequences have been described [27]. The main distinction is p-i TCR and p-i HLA [28].
●In the p-i TCR model, a drug interacts with a particular TCR. In addition to this interaction, a second interaction between the TCR and HLA molecules on APCs is required to stimulate cellular proliferation, cytokine production, and cytotoxicity by the drug-stimulated T cells (figure 1) [21,22,29-33]. As an example, sulfamethoxazole may bind to a unique complementarity-determining region 3 (CDR3) of TCR-Vbeta. Other sulfonamides may inhibit this binding and stimulation [34]. Alternatively, it may bind to the complementarity-determining region 2 (CDR2) of TCR-Vbeta 20-1 [35]. This interaction alters the conformation of the TCR, and the allosteric effect leads to activation of the T cell. Interestingly, this binding site for sulfamethoxazole is actually present on a public epitope and thus available in all individuals. It is assumed that drug binding is stimulatory only if the T cell is activated by some other factor, such as a generalized viral infection [36].
●In the p-i HLA model, a drug binds preferentially to a certain HLA molecule. This explains the strong association between some HLA alleles and certain drug hypersensitivity reactions [37-41]. This binding of drug can alter the conformation of the HLA molecule, particularly if it binds to the peptide-binding site [42], which leads to stimulation of T cells by HLA drug complexes [43]. The drug binding to the peptide-binding site in HLA has two possibly important consequences:
•The HLA molecule may acquire features of an alloallele. In other words, drug binding to HLA makes a self-HLA protein look like an allo-HLA. This has been shown for HLA-B*57:01, which with abacavir bound to its F-pocket, can look like HLA-B*58:01 [44]. This concept of alloallele-like features of HLA drug complexes would also explain the finding that stimulation of dendritic cells is not required in abacavir-induced immune reactions, similar to allostimulations [44].
•A second consequence of drug binding to the peptide-binding site may be the presentation of an altered peptide repertoire. This requires the drug binding to the HLA molecule in the endoplasmic reticulum (ER). Compared with the unaltered HLA, the altered HLA molecule may allow the presentation of a different set of peptides to T cells. Since T cells are tolerant only to those HLA-restricted peptides to which they were exposed during development in the thymus, the alternate set of peptides may be interpreted as foreign by the T cells and result in an autoimmune-like T cell reaction (investigated for abacavir only) [42,45,46].
Evidence for the p-i concept was initially based upon in vitro studies showing that drug-specific T cell clones can be stimulated directly by drugs in monomeric form [22,30,32]. Studies of cells from patients with carbamazepine-induced Stevens-Johnson syndrome (SJS), allopurinol, or abacavir-induced T cell reactions, later supported the p-i concept and underlined the importance of a suitable, high affinity TCR [43,47-49]. Subsequently, in vitro evidence for this mechanism for abacavir, including the crystallographic structure of abacavir binding to the F-pocket of HLA-B*57:01 molecule, were published [42,45,46]. (See "Abacavir hypersensitivity reaction".)
Drugs that have this ability to interact with immune cells in this manner, at least in vitro, include:
●Sulfamethoxazole (p-i TCR)
●Carbamazepine (p-i HLA, with interaction with TCR as well)
●Allopurinol (p-i HLA, predominantly the main metabolite oxypurinol)
●Lidocaine and mepivacaine
●Some radiocontrast agents, such as iomeprol (p-i HLA)
●Flucloxacillin (p-i HLA)
●Abacavir (p-i HLA)
The p-i concept may be involved in drug-induced hypersensitivity syndromes as well as severe blistering drug reactions (see 'IVb' below and 'IVc' below). T cells from blister fluid of patients with cotrimoxazole-induced SJS can be stimulated by exposure to the causative drug [31]. The pathophysiology of SJS is reviewed elsewhere. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
Flucloxacillin-induced hepatitis occurs selectively in carriers of HLA-B*57:01. Flucloxacillin can bind covalently like a hapten to proteins but also via p-i to HLA molecules. This p-i binding occurs best in HLA-B*57:01, while hapten-carrier formation occurred independently on the HLA allele. The author believes that the selective p-i stimulation as it occurs in B*57:01 contributes to a more dangerous disease manifestation (cholestatic hepatitis), while hapten-like reactions are more related to maculopapular exanthems [50,51].
The interaction between drug and TCRs or HLA molecules occurs within seconds in vitro. However, hypersensitivity reactions appear days to weeks after the culprit drug is started. This may reflect the number of T cells that are stimulated by a particular drug. If many clones are stimulated, symptoms could appear rapidly. If just a few clones are stimulated, symptoms may take weeks to appear as those clones replicate and expand in number. If the patient is exposed again to the causative drug, symptoms appear more quickly. (See "Drug hypersensitivity: Classification and clinical features", section on 'Timing of type IV reactions'.)
Overlap of mechanisms — It is likely that some drugs can stimulate immune reactions through more than one mechanism simultaneously. Some drugs believed to be stimulatory by the p-i mechanism also form hapten-carrier compounds either directly (eg, flucloxacillin) or after metabolism (eg, sulfamethoxazole, lamotrigine, and carbamazepine) [17,18,32]. In the clinic, the symptoms of drug hypersensitivity can occur either via hapten or p-i mechanism, sometimes even simultaneously in one individual.
PATHOGENESIS OF SPECIFIC REACTION TYPES — Historically, immunologic reactions, whether caused by drugs, infections, or autoimmune processes, have been divided into four categories according to the Gell and Coombs system (table 2). Types I, II, and III are mediated by antibodies, while type IV is mediated by T cells.
The Gell and Coombs classification was established before detailed analyses of T cell subsets and functions were technically possible. As new immunologic tools were developed, type IV reactions were further subdivided into types IVa, IVb, IVc, and IVd [33]. (See 'Subdivisions of type IV' below.)
This classification is based on an exclusive "immune-based" approach to drug hypersensitivity. The newly formed hapten-protein complex can give rise to B and T cell responses and follows the normal rules of an immune response. This means that the occurrence of a well-documented type I reaction (demonstration of drug-specific IgE) as well as type II and type III reactions are normally due to hapten- or protein antigen-based reactions. However, under certain circumstances, the sensitization and the effector mechanism are elicited by different, cross-reactive compounds. This may explain the appearance of anaphylactic reactions without prior known exposure to the culprit drug. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Neuromuscular-blocking agents'.)
The type IV reactions can be hapten- or p-i-based stimulations. They appear delayed, often after 7 to 10 days, sometimes even after weeks. The appearance and further aggravation of symptoms then happens often quite rapidly, sometimes within one day (in Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN]).
Type I (IgE-mediated) — Type I reactions require the presence of drug-specific immunoglobulin E (IgE). Certain patients form drug-specific IgE upon exposure to a medication.
As previously discussed, the drug or its metabolite may act as a hapten, forming hapten-carrier complexes that can be processed by antigen-presenting cells (APCs) (eg, penicillins and platinum agents) (see 'Drugs as haptens' above). Less commonly, the drug may be a complete antigen in its native form (eg, foreign proteins). An additional mechanism by which IgE-mediated reactions arise is previous sensitization to a cross-reacting agent (eg, sensitization to quaternary ammonium compounds in personal products leading to type I reaction to neuromuscular-blocking agents used in anesthesia induction).
Sensitization stage — The formation of drug-specific IgE normally requires the coordinated actions of B cells and T helper cells. In the best understood scenario, the drug or its metabolite forms a drug-protein complex. The drug-protein complex cross-links the immunoglobulin surface receptors on B cells and activates these cells (figure 2). Simultaneously, these B cells process the hapten-carrier complex and present haptenated peptides to T cells. B and T cells interact via the human-leukocyte antigen (HLA) complex and T cell receptor (TCR) and through CD40 (on the B cell) and CD40L (on the T cell).
These interactions, in conjunction with T cell-derived cytokines, enable immunoglobulin class-switching by the stimulated B cells. The B cells then proliferate, mature, and finally secrete drug-specific IgE molecules, which diffuse through the circulation and attach to the surface of mast cells and basophils throughout the body. The production of drug-specific IgE and its binding to mast cells and basophils is called sensitization and is clinically asymptomatic.
Effector stage — The effector stage of a type I drug-allergic reaction may develop when the sensitized individual is re-exposed to the medication again. Upon readministration, the drug must again couple to carrier proteins and this time, must cross-link drug-specific IgE on the surface of mast cells and/or basophils, resulting in sudden and widespread activation and release of an array of vasoactive mediators (figure 2).
IgE-mediated reactions are referred to as "immediate" in onset, as signs and symptoms usually appear within minutes to one hour of drug exposure. The timing of allergic reactions is discussed in more detail elsewhere. (See "Drug hypersensitivity: Classification and clinical features".)
Type II (antibody-mediated cell destruction) — Type II reactions are uncommon and involve antibody-mediated cell destruction. These reactions require the presence of high titers of preformed drug-specific immunoglobulin G (IgG) (or rarely immunoglobulin M [IgM]) antibodies, which are only made by a very small percentage of individuals and usually in the setting of high-dose, longer-term drug exposure. The factors predisposing to the formation of these antibodies are not fully understood.
Type II reactions arise when drugs bind to surfaces of certain cell types (most often red blood cells or platelets and occasionally neutrophils) and act as antigens. The drug may haptenate a macromolecule on the surface of the cells. Binding of the antibodies to the cells' surface results in the cells being targeted for clearance by macrophages. Type II reactions sometimes involve complement activation, but this is not true in all cases.
Drugs known to cause type II reactions include cephalosporins, penicillins, nonsteroidal anti-inflammatory drugs (NSAIDs), quinidine, and methyldopa. As mentioned previously, these reactions are usually seen in the setting of high-dose, prolonged, or frequent drug treatment.
Specific forms of type II hypersensitivity reactions are discussed separately. (See "Drug-induced immune thrombocytopenia" and "Drug-induced neutropenia and agranulocytosis" and "Drug-induced hemolytic anemia".)
Type III (immune complex deposition) — Type III reactions are mediated by antigen-antibody complexes and present as serum sickness or serum sickness-like reactions, vasculitis, or drug fever. Similar to type II reactions, type III reactions most often develop in the context of high-dose, prolonged drug administration. The drug acts as a soluble antigen and binds drug-specific IgG. Small immune complexes may form and precipitate in various tissues, including blood vessels, joints, and renal glomeruli. These immune complexes activate complement, and an inflammatory response ensues. Re-exposure to similar or higher doses of the same drug can cause more rapid and severe symptoms.
Specific forms of type III reactions are reviewed separately. (See "Serum sickness and serum sickness-like reactions" and "Overview of cutaneous small vessel vasculitis" and "Drug fever".)
Type IV (T cell-mediated) — Type IV drug reactions involve the activation of T cells and may involve several other cell types, such as macrophages, eosinophils, or neutrophils. Type IV reactions are not mediated by antibodies, in contrast to the other three types above.
Clinically, reactions involving T cells present with prominent skin findings because the skin is a repository for an enormous number of T cells [52]. Many cutaneous T cells are primed memory effector cells, which react rapidly if immunogenic agents penetrate the skin barrier or reach the skin by diffusing from the circulation [53]. The stimulation of cutaneous T cells may be further facilitated by close contact with various types of HLA-expressing dendritic cells in the skin.
An array of different clinical presentations has been attributed to type IV mechanisms. The precise mechanisms responsible for each clinical presentation are largely theoretical. Quite a number of drugs can elicit severe hypersensitivity reactions like SJS/TEN, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS), or hepatitis, when they carry a certain HLA allele (table 1). Some of these associations are very strong and appear only in carriers of the risk HLA allele (negative predictive value [NPV] of 100 percent). In subsequent years, many further associations, some also with HLA class II alleles, but with lower strengths of HLA associations, have been described [24,54].
The HLA linkage in drug reactions is unusual as immune responses to haptens are normally not HLA-linked. Haptens (eg, beta-lactams) bind to a certain amino acid (eg lysine), which is abundantly present in a larger protein. Normally, multiple lysines are modified by the beta-lactam and then presented in a number of peptides by various HLA proteins. Thus, the immune reaction to a hapten-modified protein is not linked to a particular HLA protein [41].
In contrast, the immune reactions to abacavir, carbamazepine, allopurinol/oxypurinol, flucloxacillin, and dapsone occur if the HLA is present, with a NPV of approximately 100 percent [24,55]. This high NPV means that the particular HLA allele is required for the immune reaction to occur. In vitro analysis revealed that these HLA-linked immune reactions are due to p-i HLA reactions and explain the association by the availability of a suitable binding site in the involved HLA protein [42,45,49]. However, the same drugs can also cause milder reactions (mostly rashes), which are not HLA-linked. These may, for example, occur via a hapten mechanism (suggested for flucloxacillin). The data show a link between severity of the reaction (SJS/TEN, DRESS/DiHS), HLA association, and p-i HLA mechanism. This also means that a strong HLA association in a drug hypersensitivity suggests a p-i HLA mechanism and that SJS/TEN and DRESS/DiHS are mainly or exclusively due to p-i stimulations.
Why a drug like carbamazepine or allopurinol elicits either DRESS/DiHS or SJS/TEN is unclear. In SJS/TEN, CD8+ T cells and natural killer (NK) cells are predominantly involved in keratinocyte damage [56]. In DRESS/DiHS, in vitro studies have revealed drug-induced CD4+, CD8+, and CD4/CD8+ T cells [18]. Epidemiologic data suggest that the HLA allele itself may be involved in steering the immune reaction more to SJS/TEN or DRESS/DiHS-related symptoms. As an example, HLA-B*31:01+ individuals develop more DRESS/DiHS than SJS/TEN, while B*15:02 carriers develop more SJS/TEN than DRESS/DiHS [37,57].
The positive predictive value (PPV) of having the high-risk allele for appearance of drug hypersensitivity symptoms upon exposure is mostly low (<5 percent), with the exception of abacavir, where the PPV is 55 percent (table 1) [24]. The reason for nonreactivity in individuals carrying the risk allele is unclear. In vitro, 100 percent of blood lymphocytes of HLA-B*57:01+ individuals can be stimulated to react with abacavir [58], showing that it is not a deficit in T cell reactivity to the compound. Additional factors or missing immunologic control mechanisms may be responsible for the development of hypersensitivity in persons with the risk allele [1].
Subdivisions of type IV — T cells, stimulated either by p-i or by hapten-peptide presentation, can orchestrate different forms of inflammation, depending upon the cytokines produced and upon the other types of cells that become involved, leading to the subcategories of types IVa to IVd (figure 3) [33].
This system of classifying T cell responses places emphasis on interactions with other effector cells (eg, eosinophils or neutrophils), as reflected in the histology of inflamed tissues and laboratory findings from affected patients. The types of T cells involved include cytotoxic T cells, as well as T helper type 1 (Th1), T helper type 2 (Th2), and interleukin-8 (IL-8), probably together with T helper type 17 (Th17) cells. (See "The adaptive cellular immune response: T cells and cytokines".)
Only some of these mechanisms have been demonstrated in allergic drug reactions, and often, different reactions occur together. These interactions between T cells and other cell types are also involved in infectious, autoimmune, and autoinflammatory diseases. Thus, this system provides a theoretic framework for future study of T cell-mediated reactions in general.
IVa — Type IVa reactions involve Th1 immune reactions. Th1 cells activate macrophages by secreting large amounts of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-18 (IL-18). (See "The adaptive cellular immune response: T cells and cytokines", section on 'Th1'.)
Pure type IVa-mediated drug reactions have not been identified, but the inflammation of contact dermatitis appears to involve a component of the type IVa response (as well as type IVc). (See "Contact dermatitis in children".)
Non-drug-related examples of type IVa reactions include delayed swelling reaction to a tuberculin skin test or granuloma formation in sarcoidosis. Type IVa responses by Th1 cells are important in the formation of the complement-fixing antibody isotypes (IgG1, IgG3) involved in Gell and Coombs type II and III reactions.
IVb — Type IVb reactions involve a Th2 immune response. Th2 cells secrete the cytokines IL-4, IL-13, and IL-5, which promote B cell production of IgE and IgG4, macrophage deactivation, and mast cell and eosinophil responses. Type IVb reactions may also be involved in the late phase of allergic inflammation, such as that seen in the bronchi of patients with allergic asthma. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Th2'.)
IL-5 leads to eosinophilic inflammation, which is the characteristic inflammatory cell type in many drug hypersensitivity reactions [33].
●Morbilliform or maculopapular eruptions that show prominent eosinophil infiltration on biopsy are probably mediated by type IVb T cell responses [59].
●DRESS/DiHS is a severe drug hypersensitivity reaction involving rash, fever (38 to 40°C [100.4 to 104°F]), and multiorgan failure [60-62]. The liver, kidneys, heart, and/or lungs are most often affected. Debate is ongoing about the most accurate name for this syndrome, as not all cases have eosinophilia, or the eosinophilia may not be present with the initial presentation of the disease. For example, reactions caused by abacavir or lamotrigine typically do not feature eosinophilia. The presence of circulating atypical lymphocytes (CD8+) is a more consistent finding, which may persist for months after drug withdrawal. One study demonstrated that Epstein-Barr virus-specific CD8+ T cells were responsible for the tissue destruction in DRESS/DiHS. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
IVc — Type IVc reactions involve T cells functioning as cytotoxic effector cells. Cytotoxic T cells can emigrate to the inflamed tissue and kill or induce apoptosis in resident cells, such as hepatocytes or keratinocytes [31,63-65]. Cytotoxic T cells are believed to be important in the pathogenesis of multiple types of drug-induced, delayed-type hypersensitivity (DTH) reactions, such as contact dermatitis, maculopapular and bullous drug eruptions, and drug-induced hepatitis [66]. (See "Fixed drug eruption" and "Drug-induced liver injury".)
Some of the most severe cutaneous drug reactions, such as SJS and TEN, are believed to involve type IVc responses. These disorders are marked by blistering and exfoliation of the skin and mucus membranes, and they often develop suddenly with generalized signs and symptoms of a fulminant immune reaction (picture 1 and picture 2 and picture 3) [31,67,68]. This dramatic presentation (often after weeks on drug treatment) may represent uncontrolled expansions of polyclonal or oligoclonal cytotoxic CD8+ T cells and activation and recruitment of NK cells [56].
In contrast to milder drug eruptions, cytotoxicity had been previously thought to be mediated by granzyme B and perforin or Fas ligand, but the cytotoxic peptide granulysin is also known to play a major role [69]. Granulysin is the major cytotoxic mediator in SJS/TEN [69]. It is also found in acute graft-versus-host disease [70,71], suggesting that a massive allo-stimulation of cytotoxic T cells, which may appear after p-i HLA, is the main trigger for such a deleterious immune response. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
Occasionally, type IVc T cells responses may be limited to a single organ, without skin involvement. This type of drug reaction presents as isolated, drug-induced, immune-mediated hepatitis, isolated interstitial nephritis, or isolated pneumonitis, which makes the diagnosis of a drug-allergic process more difficult.
IVd — Type IVd reactions involve T cell-mediated sterile neutrophilic inflammation. Acute-generalized exanthematous pustulosis (AGEP) is an example of this type of reaction in the skin (picture 4 and picture 5). T cells in AGEP release IL-8 to recruit neutrophils and also prevent neutrophil apoptosis via granulocyte monocyte colony-stimulating factor (GM-CSF) release [72]. Similar mechanisms have been described in Behçet syndrome and pustular psoriasis [73]. Th17 cells, which secrete the neutrophil-activating cytokine IL-17, may also be involved in these reactions. AGEP and Th17 cells are reviewed in more detail elsewhere. (See "Drug eruptions" and "Normal B and T lymphocyte development", section on 'Th17 cells'.)
SUMMARY
●A drug allergy is an adverse drug reaction that results from a specific immunologic response to a medication. (See 'Introduction' above.)
●In order to cause an allergic reaction, drugs must be recognized by the immune system (table 1) (see 'Interaction of drugs with the immune system' above):
•Most pharmaceutical agents in their native forms are small, chemically simple molecules that function poorly as antigens. However, they may covalently bind to serum or tissue proteins or be metabolized to a reactive intermediate and then form hapten-carrier complexes that act as full antigens.
•Drugs with multiple repetitive motifs/epitopes can give rise to antibody-mediated reactions.
•Some drugs may stimulate T cells through noncovalent and concentration-dependent interactions with immune receptors, which is referred to as the pharmacological-interaction (p-i) model.
●Immunologic reactions, including drug-allergic reactions, are divided into four categories according to the Gell and Coombs system (table 2). Types I, II, and III are antibody-mediated, while type IV is mediated by T cells. (See 'Pathogenesis of specific reaction types' above.)
●Type I, immunoglobulin E (IgE)-mediated reactions involve an asymptomatic sensitization stage, in which drug-specific IgE antibodies are formed and bind to the surface of mast cells and basophils throughout the body, and a symptomatic effector stage, in which the patient is re-exposed to the drug and develops immediate symptoms (usually within one hour of administration). (See 'Type I (IgE-mediated)' above.)
●Type II reactions involve immunoglobulin G (IgG)-mediated cell destruction and arise when drugs bind and modify certain cell types, resulting in the targeting of the affected cells by antibodies for clearance by macrophages. (See 'Type II (antibody-mediated cell destruction)' above.)
●Type III reactions occur when a drug or drug-carrier complex acts as a soluble antigen and binds drug-specific IgG, forming small immune complexes that precipitate in various tissues and activate complement. An inflammatory response ensues, which may take various forms, such as serum sickness, hypersensitivity vasculitis, or drug fever. (See 'Type III (immune complex deposition)' above.)
●Type IV reactions are mediated by T cells in conjunction with other cell types, rather than by antibodies. The resultant reactions can take many forms, depending upon the cytokines produced by the T cells and the other cell types involved, but skin findings are usually prominent. Type IV T cells responses are divided into four subtypes. (See 'Type IV (T cell-mediated)' above and 'Subdivisions of type IV' above.)
