Classification of Adverse Drug Reactions

Drug hypersensitivity

Drug Hypersensitivity affect approximately 10-20% of hospitalized patients and can manifest in many different clinical symptoms, which can even be fatal. Drug hypersensitivity reactions are increasing with the increasing number of therapeutic agents. Allergic reactions to first line therapy after repeated exposure/ cross reactivity with environmental allergens (Wedi, 2010). The most common reaction is an allergic one that occurs in the skin and occurs in 2-3% of hospitalized patients (Pichler, 2007). The simplest classification of adverse drug reactions is Type A, which can occur in anyone and is predictable side effects causes by the pharmacological action of the drug (Pichler, 2007), and Type B. Type B is unpredictable and affects only susceptible people. However, it has been thought that not all adverse drug reactions fall into one or the other category and that some reactions could be classified as both Type A and Type B, so it has been suggested by Edwards et al. that ADR’s can be classified into six types. Type A is dose-related and is linked to the pharmacological action of the drug. It can be treated by reducing the dose. Type B is dose-independent, unpredictable and idiosyncratic. The management is to withdraw and withhold the drug. Type C is dose- and time-related and has chronic effects. Type D is time-related and has delayed effects. Type E is due to withdrawal of a drug and has end-of-use effects. And finally Type F is the unexpected failure of the therapy. Drug Hypersensitivity can be divided into immunological and non-immunological reactions and the immunological reactions can be further broken down by the Gell and Coombs classification.

Type I-IgE-mediated reactions mainly causing urticarial, angioedema, anaphylaxis and asthma

Type II- Immunoglobulin mediated cytotoxic, mainly cytopenias

Type III- immune complex mediated, causing vasculitis

Type IV- T-cell mediated reactions causing so-called delayed hypersensitivity reactions (Wedi, 2010). For non-immunological reactions the mechanisms are unknown so can’t be further classified. Due to the more recent availability of the analysis of T-cell subsets and functions Type IV reactions can be sub classified from Type IVa-d.

Type I

Type I reactions are mediated by IgE antibodies that are drug specific. These IgE antibodies are produced after the first exposure to the drug antigen after presentation to T_H2 cells. Then it binds to high-affinity Fc-IgE receptors on mast cells or basophils (Actor, 2012). Upon the second exposure to the antigen cross linking between IgE bound antigen on mast cells leads to activation of the mast cells, which causes the immediate release of the pre-formed mediator, Histamine. This is followed by a rapid production of arachidonic acid, leading to the release of other mediators such as leukotrienes and prostaglandins. IgE mediated reactions cause immediate symptoms ranging from mild to very severe (Pichler, 2007)The more severe reactions are known as anaphylaxis and is a response to the systemic circulation of an allergen and the IgE cross-linking in the peri-vascular tissue. The increased circulation of histamine caused by the degranulation of the mast cells causes vasodilation. The symptoms occur rapidly and can be fatal if not treated quickly due to the swelling and restriction of the airways. Type I hypersensitivity can be displayed by skin testing where the allergen is introduced by an intradermal injection and a reaction can be observed very quickly by wheal/flare at the site of the injection.

Type II

Type II hypersensitivity reactions are caused by immune-mediated damage by IgG or IgM.  The IgG/IgM antibodies bind to antigens on the cells surface and cause cell destruction or sequestration. This can be done by a couple of mechanisms, the first of which is the activation of the complement pathway. This can cause damage to the target cells by either forming a membrane attack complex which forms pores in the membrane of the target cells leading to cell bursting due to the increases influx of water and electrolytes. Or by opsonization and phagocytosis. An alternative mechanism of type II hypersensitivity is anthibody-dependant cell mediated cytotoxicity (ADCC). This occurs when the cells are too large for phagocytosis. The foreign cells are tagged with the IgG or IgM antibodies which attracts phagocytes. These phagocytes bind to the cell bound antibodies and releases hydrolytic enzymes, perforins and tumor necrosis factors. Examples of diseases caused by type II hypersensitivity are hemolytic anemia, production of antibodies to red blood cell antigens, Myasthenia gravis, production of antibodies or acetylcholine receptor and Goodpasture syndrome, production of antibodies against certain proteins in the glomeruli and alveoli.

Type III

Type III hypersensitivity reactions are also known as immune-complex reactions. Like Type II reactions Type III also involves IgG and IgM antibodies. The antibodies bind with the antigens extracellularly and forms and antibody-antigen complex (Ag-Ab). This occurs in normal immune responses however in hypersensitivity reactions the Ag-Ab complexes are not removed and lead to deposits in blood vessels and tissues (Sheldon et al., 2014). Activation of the complement cascade leads to chemoattractant factors to be released and attract neutrophils as well as enzymes that destroy proteins and collagen (Nussenblatt, 2010). This results in an inflammation reaction and tissue damage. The clinical symptoms of type III reactions are fever, urticaria and arthritis.

Type IVa-d

Type IV hypersensitivity is delayed reactions mediated by T-cells and occurs at least 48 hours after exposure. In Type IVa reactions large amounts of IFN- are secreted by the Th1 type T cells causing the activation of macrophages (Wedi, 2010). Type IVb is mast cell and eosinophil activation and macrophage deactivation due to the release of IL-4 and IL-5 cytokines from Th2 T-cells. The activation of eosinophils causes an inflammatory reaction (Adam et al., 2011).  Type IVc involves the T cell function as effector cells as the emigrate to the tissue and can destroy tissue cells such as keratinocytes and hepatocytes (Wedi, 2010). Type IVc reactions are present in bullous skin conditions such as Steven’s Johnsons Syndrome (SJS) and Toxic Epidermal necrolysis (TEN). Finally, Type IVd involves T cells driven by and antigen can cause sterile neutrophilic inflammation.

T-Cells

There are currently two theories of the mechanism of T-cell mediated drug hypersensitivity. There are two theories as to how the T-cells are stimulated. These are the hapten concept and the p-i concept. The hapten concept involves the formation of a hapten-carrier complex from a drug binding covalently to a large protein or peptide to create an immune response. The p-i concept involves the binding of a drug to an off-target immune receptor, especially HLA and TCRs (Pichler and Hausmann, 2016).

In the hapten concept a drug with a small molecular weight of <1,000 Daltons is not immunogenic however it is chemically active. They produce an immune response by binding covalently to a large protein or peptide, forming a hapten-carrier complex. In order for this to occur the drug must be sufficiently chemically reactive in order to bind to the protein/peptide spontaneously (Yun et al., 2016).  These hapten-carrier complexes activate the innate immune system by presentation to HLA molecules which is recognized by TCR and leads to T-cell stimulation (Chen et al., 2018).

There are drugs, however, that are not chemically reactive but are able to elicit an immune response due to the formation of a reactive metabolite formed by metabolism.

HLA table

Drug	HLA Association	Disease Phenotype	Population	Reference
Abacavir	B*5701	Hypersensitivity	European, African	(Profaizer and Eckels, 2012)
Allopurinol	B*5801	SJS/TEN/DRESS	Predominately Asian	(Dean, 2012)
Amoxicillin-Clavulanate	DRB1*1501	DILI		(Alfirevic and Pirmohamed, 2011)
Carbamazepine	B*1502, A*3101	SJS/TEN/DRESS	Han Chinese	(Ferrell and McLeod, 2008)
Clozapine	DQB1*0502, B (158T), DQB1, B*5901	Agranulocytosis	European	(Redwood et al., 2018)
Co-trimoxazole	B*1502, C*0602, C*0801	SJS/TEN	Thai	(Kongpan et al., 2015)
Flucloxacillin	B*5701	DILI	European	(Illing et al., 2016)
Lamotrigene	B*38	SJS/TEN		(Usui and Naisbitt, 2017)
Lapatinib	DRB1*0701, DQA1*0201	DILI	European, Han Chinese	(Parham et al., 2016)
Levamisole	B*27	Agranulocytosis	European	(Hodinka et al., 1981)
Lumiracoxib	DRB1*1501, DQB1*0602, DRB5*0101, DQA1*0102	DILI	European	(Singer et al., 2010)
Methazolamide	B*59, B*5901	SJS/TEN	Han Chinese	(Yang et al., 2016)
Nevirapine	C*04, B*35, DRBQ*01	cARDs	Thai, European	(Cornejo Castro et al., 2015)
Phenytoin	B*1502	SJS/TEN	Malaysian, Han Chinese, Thai	(Li et al., 2014)
Sulfonamide	A*29, B*29, DR*7	TEN	European	(Mannis and Holland, 2016)
Ticlopidine	A*3303	DILI	Japanese	(Hirata et al., 2008)
Ximelagatran	DRB1*0701, DQA1*0201	DILI	European	(Alfirevic et al., 2012)

References

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Chen, C.-B., Abe, R., Pan, R.-Y., and Wang, C.-W. (2018). Review Article An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity. J. Immunol. Res. 2018: 1–22.

Cornejo Castro, E.M., Carr, D.F., Jorgensen, A.L., Alfirevic, A., and Pirmohamed, M. (2015). HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity: A systematic review of the literature and meta-analysis. Pharmacogenet. Genomics 25: 186–198.

Dean, L. (2012). Allopurinol Therapy and HLA-B*58:01 Genotype (National Center for Biotechnology Information (US)).

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Usui, T., and Naisbitt, D.J. (2017). Human leukocyte antigen and idiosyncratic adverse drug reactions. Drug Metab. Pharmacokinet. 32: 21–30.

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Yang, F., Xuan, J., Chen, J., Zhong, H., Luo, H., Zhou, P., et al. (2016). HLA-B∗59:01: A marker for Stevens-Johnson syndrome/toxic epidermal necrolysis caused by methazolamide in Han Chinese. Pharmacogenomics J. 16: 83–87.

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