Page 678 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 48 Drug Hypersensitivity 651

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understanding of the pathogenesis of these reactions. Although Heterologous responses to viral infections, in the context of
different organ systems are affected, typically the targets are the specific HLA alleles, have been implicated in severe skin reactions.
liver and skin; other organs, such as muscles (statin-induced T cell–mediated immunity can be modified by heterologous
myopathy) and neutrophils (clozapine-induced agranulocytosis), immune responses that are induced by pathogen-specific
can be affected, indicating a heterogeneity determined not just by T-effector-memory cells. Microbial pathogens, such as human
the associated HLA allele but also by the expression of homing herpes virus (HHV) and cytomegalovirus (CMV), among others,
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receptors and T-cell clonotypes. Striking ethnic variations, such can establish lifelong infections and cellular latency. From time
as the high prevalence of HLA-B*15:02 in carbamazepine-induced to time, latent virus can activate transcriptional programs,
SJS/ TEN have been uncovered in Han Chinese, Thai, and Malay resulting in viral proteins that stimulate virus-specific T-cell
populations, but not in Japanese, Korean, or Northern Europeans memory.
(Table 48.1). Some HLA alleles are associated with reactions to The induction of this type of drug hypersensitivity requires
unrelated compounds, such as B*57:01, which has been linked an HLA risk allele, a primary infection with HHV or other viruses
to reactions to abacavir and flucloxacillin, with different organ in the context of that HLA risk allele, polyclonal expansion of
target effects. In contrast, specific HLA alleles may predispose to a CD8 T cells, and the induction of memory T cells. Upon exposure
particular type of organ injury regardless of the drug involved in to the drug, the interaction with HLA induces neoantigens, and
the reaction, as seen with HLA-DRB1*15:01–associated liver injury the peptide–MHC complex is recognized by the TCR, triggering
with lumiracoxib and co-amoxiclav. Although HLA-associated activation of T cells (Fig. 48.2). 16
reactions occur within hours to days of drug exposure, additional About 25% of women who are treated with carboplatin for
factors must influence these interactions because rechallenge gynecological cancers become sensitized after several exposures
with the drug may not reproduce the symptoms, and time lags and then have type I IgE-mediated reactions, most of which
have been observed. Such factors can be influenced by the dose. are anaphylactic. Although carboplatin triggers cell death at the
High doses of phenytoin can increase the rate of cutaneous erup- cancer tissue level, it can also bind to proteins as a hapten and
tions, which suggests that genetic polymorphisms influence drug then be presented to T cells, inducing sensitization and expansion
metabolic pathways leading to a potential increase in the risk for of B cells producing IgE that recognizes the hapten. Because
idiosyncratic reactions. A recent genome-wide association study women with BRCA1 and BRCA2 mutations seem more prone
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has linked phenytoin reactions to allelic variations of cytochrome to carboplatin reactions after fewer exposures, it is possible
P450 isoform CYP2D9*3, with resulting decreased detoxification that these genetic mutations facilitate T-cell presentation. The
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activity of CYP2C9. Evidence for the association of specific HLA presence of IgE antibodies in carboplatin-sensitized women can
alleles in penicillin/beta-lactam or sulfonamide reactions is less be detected in blood and by skin test. The IgE levels may be
clear, perhaps because these medications are metabolized into transient, being lost within 6–12 months of exposure. However,
several antigenic and allergenic components that interact with memory T and B cells remain active in these patients, allow-
multiple HLA types. The recently reported association between ing clonal expansion upon reexposure months to years later.
penicillin-induced type I reactions and HLA-DRA indicates the Patients with connective tissue disorders have an increased rate
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need for strong phenotype association with the culprit drug and of reactivity to mAbs. Similarly, women exposed to endog-
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adequate sample size. The strength of the association between enous and exogenous progesterone can develop progesterone
HLA alleles and certain drug reactions can be very strong, as hypersensitivity. 25
seen with abacavir and HLA-B*57:01. Patients expressing the
relevant allele can be patch tested before exposure to the drug. CLASSIFICATION OF DRUG
Prospective DNA screening has a 100% negative predictive value, HYPERSENSITIVITY REACTIONS
eliminating all potential reactors.
Drug reactions can be classified according to whether they occur
RISK FACTOR FOR DRUG ALLERGY: HOST, as a result of the mode of action (on target) or in some other way
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PATHOGENS, AND DRUG RESPONSE (off target) (Fig. 48.3). Type A (on-target) reactions account for
over 80% of drug reactions. These are predictable, dose dependent,
Females are at higher risk for drug reactions, but the basis of and mirror the pharmacological action of the drug. Type B (off-
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this propensity has not been studied. Quaternary ammonium target) reactions comprise 20% of drug reactions. These are not
compounds present in cosmetics are thought to be cross- predictable and may be immunological or nonimmunological.
reactive with neuromuscular-blocking agents and may increase Immunological reactions include B cell–dependent reactions,
the risk of drug reactions during general anesthesia. Patients such as antibody-mediated immediate and immune complex
with cystic fibrosis and those with multiple exposures to latex reactions (Gell and Coombs types I and III) and T cell–mediated
during surgery were found to have latex IgE sensitization and reactions (type IV). Nonimmunological hypersensitivity reactions
presented severe reactions, including asthma and anaphylaxis. include idiosyncratic reactions caused by individual predisposition
Decrease in aerosolized latex particles has effectively decreased (e.g., enzymatic defect) and activation of effector cells through
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reactions. Because patients with cystic fibrosis have recurrent off-target receptors, such as the MRGPRX2 mast-cell receptor,
infections, these patients have an increased exposure to antibiot- a transmembrane G-coupled protein that can be activated by
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ics and an increased rate of type I IgE-mediated reactions, quinolone medications, such as icatibant, and neuromuscular
including anaphylaxis. Increased rates of drug reaction have blocking agents, such as atracurium. 26
been observed in patients with human immunodeficiency virus Drug hypersensitivity can cause a spectrum of hypersensitivity
(HIV) infection, especially to trimethoprim-sulfamethoxazole. diseases. These were originally classified by Gell and Coombs
Low CD4 T cell counts as well as active immune suppression as into four types: antibody-dependent type I, II and III reactions
a result of antiretroviral therapy are thought to increase the risk and T cell–mediated type IV reactions. More recently, in the
of reactions. light of developments in T-cell biology and to take account of