Current Pharmaceutical Design - Volume 22, Issue 45, 2016

Our knowledge of genetic predisposing factors of drug hypersensitivity reactions (DHRs) is still scarce. The analysis of the genetic basis of these reactions may contribute to dissect the underlying mechanisms. We will outline current knowledge of the genetic predictors of most common DHRs, including reactions to betalactam antibiotics (BLs), nonsteroidal anti-inflammatory drugs (NSAIDs) and biological agents. The predictors of DHRs to BLs are mostly linked to IgE-class switching, IgE pathway and atopy (IL4R, NOD2, LGALS3) in replicated candidate gene studies, and to antigen presentation (HLA-DRA) in the single replicated GWAS performed so far. The HLA-DRA variants are predictors of allergy to penicillins, but not to cephalosporins and they influence also the sensitization against prevalent allergens. The predictors of DHRs against NSAIDs are mostly linked to metabolism of eicosanoids (ALOX5, ALOX5AP, TBXAS1, PTGDR, CYSLTR1). Single nucleotide polymorphisms (SNPs) in genes involved in histamine biosynthesis and antigen presentation, HLA, could also have a role in DHRs against NSAIDs. The intriguing association of DHRs to NSAIDs with atopy should deserve further attention. Predictors of DHRs against asparaginase and other biological agents relate to antigen presentation (HLA-DRB1 and HLA-A alleles, respectively). The potential relationship of genetic predictors of DHRs with pathomechanisms also involved in environmental exposure and atopy highlights the need to perform GWAS in contrasted populations, taking into account world-wide variations of allele frequencies and contrasted situations of environmental exposure.

Drug hypersensitivity reactions (DHRs) are adverse drug reactions that may be divided into several categories; namely pharmacologic intolerance, idiosyncratic reactions, pseudo-allergic reactions and allergic reactions. Drug allergic reactions are those DHRs that are mediated by either antibodies or drug-specific T cells. They vary in terms of severity, time-to-onset of clinical manifestations and target organ. Skin is most commonly implicated in drug hypersensitivity reactions; however, it is now apparent that reactions targeting internal organs fall under the definition of drug hypersensitivity. Multiple hypotheses have been proposed to explain the diverse immune mechanisms involved and the heterogeneous clinical presentation. The discovery of human leukocyte antigen (HLA) risk alleles for some DHRs has provided insights in the pathogenesis of these reactions. In this review we summarize immune cells involved in DHRs, discuss the possible immunological mechanisms of DHRs, with an emphasis on the IgE-mediated immediate reactions and T cell-dependent delayed type reactions.

Drug hypersensitivity reactions result from the activation of the immune system by drugs or their metabolites. The clinical presentations of drug hypersensitivity can range from relatively mild local manifestations to severe systemic syndromes that can be lifethreatening. As in other allergic reactions, the causes are multifactorial as genetic, metabolic and concomitant factors may influence the occurrence of drug hypersensitivity. Formation of drug protein adducts is considered a key step in drug adverse reactions, and in particular in the immunological recognition in drug hypersensitivity reactions. Nevertheless, noncovalent interactions of drugs with receptors in immune cells or with MHC clefts and/or exposed peptides can also play an important role. In recent years, development of proteomic approaches has allowed the identification and characterization of the protein targets for modification by drugs in vivo and in vitro, the nature of peptides exposed on MHC molecules, the changes in protein levels induced by drug treatment, and the concomitant modifications induced by danger signals, thus providing insight into context factors. Nevertheless, given the complexity and multifactorial nature of drug hypersensitivity reactions, understanding the underlying mechanisms also requires the integration of knowledge from genomic, metabolomic and clinical studies.

Allergic drug reactions are currently a major public health problem affecting patient health and increasing healthcare costs. They are caused by interactions between a drug and the human immune system and result in symptoms ranging from urticaria or angioedema to those more serious such as anaphylaxis or anaphylactic shock. The most commonly accepted mechanism for immunological activation is based on the hapten hypothesis. Drugs are low molecular weight substances that cannot cause an immune response on their own. However, they can act as haptens and form covalent adducts with proteins. The resulting hapten-carrier (drug-protein) conjugate can induce the production of IgE antibodies or T cells. An epitope, or antigenic determinant, is the part of the drug-protein antigen that is specifically recognized by the immune system. This may involve not only the drug derivative but also part of the carrier protein. Understanding the way in which drugs are metabolized after protein conjugation is vital in order to make progresses in the diagnosis of clinical allergy. In this review, recent advances in the identification of the chemical structures of antigenic determinants involved in immediate allergic reactions to drugs are presented. We have focused on drugs that most commonly elicit these reactions: betalactam and quinolone antibiotics and the non-steroidal anti-inflamatory drug pyrazolone. This will be discussed from a chemical point of view, relating our understanding of drug structure, chemical reactivity and immune recognition.

The diagnosis of drug hypersensitivity reactions (DHR) is complex, with many potential pitfalls. Although the use of clinical history and skin testing can be valuable, drug provocation testing (DPT) remains the gold standard for many DHR. However, DPT carries some potential risk and should not be performed for severe reactions. There is therefore a general consensus on the need to improve in vitro tests to achieve safe and accurate diagnosis of DHR. A range of in vitro approaches can be applied depending on the type of reaction and the immunological mechanism involved, i.e. IgE- or T-cell-mediated. However, commercially available tests only exist for a handful of drugs, and only for drugs that provoke IgEmediated DHR. Of the cellular tests that focus on the identification of the culprit drug, the best validated is the basophil activation test used for evaluating IgE-mediated reactions. For T-cell-mediated DHR, the lymphocyte transformation test and enzyme-linked immunosorbent spot appear to be the most promising. However, these tests often show low sensitivity. Despite their current drawbacks, in vitro tests can complement in vivo testing and further work in this area will be crucial to improve our current arsenal of tools for the detection and assessment of DHR. For this, the use of appropriate and relevant drug metabolites as well as other factors that can amplify the cell response as well as the use of multiple tests in concert key to improving in vitro diagnosis. Such improvements will be crucial to diagnose patients with severe reactions for whom DPT cannot be performed.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the leading causes of hypersensitivity reactions to drugs, and they are classified in two groups: those induced by nonspecific immunological mechanisms (non-allergic or cross-intolerance (CI) reactions), or by specific immunological mechanisms (allergic or selective reactions (SR)). The pathogenesis of CI is associated with their pharmacological activity (COX-1 inhibition), with symptoms due to an imbalance in the arachidonic acid pathway, independently of their chemical structure. SRs are mediated by specific IgE- or by a T-cell response and can be induced by a single NSAID or a class of chemically related NSAIDs, with patients tolerating chemically unrelated compounds. NSAIDs hypersensitivity reactions have been classified in five main groups: i) NSAIDs-exacerbated respiratory disease (NERD); ii) NSAIDs-exacerbated cutaneous disease (NECD); iii) NSAIDs-induced urticaria/angioedema (NIUA); iv) Single NSAID–induced urticaria/angioedema or anaphylaxis (SNIUAA); v) Single NSAID–induced delayed reactions (SNIDRs). Although this classification described above is widely accepted by most authors some phenotypes such as blended reactions do not fit. Therefore more research is needed in this topic.

Hypersensitivity reactions to β-lactam antibiotics are commonly reported. They can be classified as immediate or non-immediate according to the time interval between the last drug administration and their onset. Immediate reactions occur within one hour after the last drug administration and are manifested clinically by urticaria and/or angioedema, rhinitis, bronchospasm, and anaphylactic shock; they may be mediated by specific IgEantibodies. Non-immediate reactions occur more than one hour after the last drug administration. The most common manifestations are maculopapular exanthemas; specific T lymphocytes may be involved in this type of manifestation. In the diagnostic evaluation of hypersensitivity reactions to β -lactam antibiotics, the patient’s history is fundamental. The allergy examination is based on in vitro and in vivo tests selected on the basis of the clinical features and the type of reaction, immediate or non-immediate. Immediate reactions can be assessed in vitro by serum specific IgE assays and basophil activation tests and in vivo by immediate-reading skin tests and, in selected cases, drug provocation tests (DPTs). Non-immediate reactions can be evaluated mainly by delayed-reading skin tests, patch tests, and DPTs.

Perioperative hypersensitivity reactions are rare, often life-threatening events, and subsequent investigations to identify the culprit are important to avoid re-exposure. All exposures in the perioperative setting may potentially be the cause of a hypersensitivity reaction, but drugs administered intravenously such as neuromuscular blocking agents (NMBA), induction agents and antibiotics have traditionally been reported to be implicated most commonly. It has recently become apparent that there are geographical differences in sensitization patterns related to variation in exposures, referral patterns and performance and interpretation of investigations. Differences in sensitization to NMBAs are partly explained by cross sensitization to pholcodine, an ingredient in cough-medicines available in some countries. While NMBAs are the most common causes of perioperative hypersensitivity in some countries, this may not necessarily be the case in all countries. New and hidden allergens have emerged as causes of perioperative hypersensitivity such as blue dyes, chlorhexidine and excipients. Detailed knowledge of the events at the time of reaction is necessary to identify potential culprits including rare and hidden allergens. Cooperation between allergists and anaesthetists, or other staff present perioperatively, is often needed to identify hidden or even undocumented exposures. The objectives of this review are to provide an overview of the history of investigation of perioperative hypersensitivity, to describe the differences in causes of perioperative hypersensitivity emerging over time and to increase awareness about the “hidden allergens” in the perioperative setting. Some practical advice on how to approach the patient testing negative on all initial investigations is also included.

Systemic hypersensitivity (HS) to corticosteroids (CS) is paradoxical but does exist. Some patients with a previous contact allergy to topical CS may develop a systemic contact dermatitis (SCD) while receiving CS orally or intravenously. However, a previous contact sensitization is not mandatory for developing a systemic HS to CS. Acute or delayed urticaria can occur in immediate HS. Immediate HS can be due to excipients, mainly carboxymethylcellulose or to CS themselves. Delayed reactions, mainly maculopapular rash and acute generalized exanthematous pustulosis can occur. Skin tests with systemic CS have to be standardized. It is necessary to determine if IDT with CS frequently induce skin atrophy or not and if such skin atrophy is transient by doing prospective studies using an standardized method and a limited injected volume (0.02 ml). Patch tests can be done in delayed HS, with readings at day 2, 4 and 7. In SCD, the Baeck’s classification of CS in 3 chemical groups could explain cross reactivity between systemic CS. However, this classification is not applicable to explain cross-reactions between in systemic HS. According to the literature, 52/79 patients had a HS reaction to a group confirmed by a positive allergological investigations, but had a negative provocation test with another CS belonging to the same group. In case of non-severe cutaneous adverse reactions and when skin tests are negative, provocation tests have to be performed to find an alternative CS, even if it belongs to the same chemical group as those responsible for the initial reaction.

Suspicion for drug hypersensitivity (DH) is a common reason for children’s referral to an allergy department, with β-lactam antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) as the most frequently involved drugs. The prevalence of DH in children remains not well defined as epidemiologic studies in children are lacking, and the most of those take into account adverse drug reactions (ADR) without a systematic allergy work-up to confirm or exclude hypersensitivity. The clinical history is mandatory in order to classify the reaction as being immediate or non-immediate and then to subsequently adapt the allergy work-up. Mainly due to the lack of studies, the same guidelines used for diagnosis of drug allergy in adults are generally used in the pediatric population, and the diagnosis is based mainly on in vivo tests (i.e. skin tests and/or drug provocation test) and rarely on in vitro tests. However, specific aspects of management of DH in children have been recently highlighted.

Severe cutaneous adverse reactions (SCAR) are known for a high morbidity and mortality. They may be life-threatening for the affected patient and difficult to accomplish for the patient’s family and the treating physician. Such conditions include not only bullous reactions like toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), but also acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Since clinical pattern, etiology, prognosis and treatment differ among these severe skin reactions, a clear diagnosis based on a comprehensive clinical examination, skin biopsy, and specific laboratory tests is necessary. Because most of these reactions are caused by drug intake, a thorough history of medication use has to be obtained. However, there are cases with an infectious or idiopathic cause. In any case it is crucial to identify the most likely cause and rapidly discontinue the inducing agent, if a drug cause is suspected. This is associated with the patient`s prognosis which is often poor for bullous reaction. In addition, patient`s age, underlying conditions, and the extent of skin detachment play a major role in terms of prognosis. Severe cutaneous adverse reactions are T-cell-mediated reactions, and certain alleles of human leukocyte antigens (HLA) are involved in the activation of T-cells with cytotoxic effect. The therapeutic options depend on the clinical diagnosis. For all reactions a symptomatic and adequate supportive therapy is necessary, in some cases a systemic immunomodulating therapy can be useful.

Mastocytosis is a clonal disease characterized by proliferation and accumulation of mast cells (MC) in different tissues, preferentially skin and bone marrow, leading to a wide variety of clinical manifestations, mainly caused by the inappropriate release of MC mediators. As a consequence, patients with mastocytosis may experience symptoms due to massive MC activation and release of mediators. Anaphylaxis is the most frequent manifestation of this phenomenon. Drugs are possible triggers of anaphylaxis in patients with mastocytosis, even though the association between mastocytosis and drug anaphylaxis does not appear to be as strong as anaphylaxis after hymenoptera sting; nevertheless, MC disorders might be ruled out in cases of severe systemic reactions to drugs. Moreover, the risk of perioperative anaphylaxis in adults appears high, mainly in patients with indolent systemic mastocytosis regardless of skin involvement. Such risk is probably lower in patients who have never experienced anaphylaxis and/or have tolerated previous general anaesthesia. However, data published about drug anaphylaxis in patients with MC disorders are scanty and currently it is not possible to provide clear recommendations.

Chemotherapies drugs and monoclonal antibodies are key components of the treatment of cancer patients and patients with chronic inflammatory conditions to provide increase in life expectancy and quality of life. Their increased use has lead to an increase in drugs hypersensitivity reactions (DHR) worldwide. DHR to those agents prevented their use and promoted the use of second line therapies to protect patients’ hypersensitive reactions and anaphylaxis. Second line medications may not fully address the patients’ medical condition and it is desirable to keep patients on first line therapy. Drug hypersensitivity symptoms can range from mild cutaneous reactions to life-threatening anaphylaxis. Rapid drug desensitization (RDD) is a novel approach to the management of drug hypersensitivity reactions which are IgE and non-IgE mediated. Through the diferent desensitization protocols patients can receive the full dose of the medications that they have presented a hypersensitive reaction and been protected against anaphylaxis. This review looks at the current literature on hypersensitivity reactions (HSR) to chemotherapy drugs and monoclonal antibodies and the potential use of RDD for their management.