Materiały źródłowe

• #1 Drug allergy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0289-y

  Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions with varying mechanisms and clinical presentations. […] Drug allergy is one type of unpredictable ADR that encompasses a spectrum of immunologically-mediated hypersensitivity reactions with varying mechanisms and clinical presentations. […] Immune-mediated allergic reactions to drugs are classified according to the Gell and Coombs classification system, which describes the predominant immune mechanisms involved in these reactions. This classification system includes: immediate-type reactions mediated by immunoglobulin E (IgE) antibodies (type I), cytotoxic reactions mediated by immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies (type II), immune-complex reactions (type III), and delayed-type hypersensitivity reactions mediated by cellular immune mechanisms, such as the recruitment and activation of T cells (type IV).

• #1 Drug allergy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-024-00936-1

  Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions (HSRs) with varying mechanisms and clinical presentations. […] A Drug allergy is an immunologically-mediated type B ADR (Table 1) that not only affects patient quality of life, but may also lead to delayed treatment, use of suboptimal alternate medications, unnecessary investigations, and increased morbidity and mortality. […] Immune-mediated allergic reactions to drugs are divided according to the Gell and Coombs classification system, which describes the predominant immune mechanisms involved in these reactions. This classification system includes: immediate-type reactions mediated by IgE antibodies (type I), cytotoxic reactions mediated by immunoglobulin G (IgG) or M (IgM) antibodies (type II), immune-complex reactions (type III), and delayed-type SRs mediated by cellular immune mechanisms, such as the recruitment and activation of T cells (type IV).

• #1 Pathogenesis of drug allergy–current concepts and recent insights – PubMed

  https://pubmed.ncbi.nlm.nih.gov/26172398/

  Drug hypersensitivity reactions (DHRs) may be caused by immunologic and non-immunologic mechanisms. According to the World Allergy Organization, drug allergy (DA) encompasses the subgroup of immunologic DHRs which are mediated either by specific antibodies or specific T lymphocytes. Due to the immunologic memory, DA reactions bear an increased risk for dramatically enhanced reactions on re-exposure. Some current concepts of DA were described decades ago. Drug allergies to soluble macromolecular protein drugs such as biopharmaceuticals are predominantly T cell-dependent drug-specific antibody responses leading to IgE-or IgG-mediated allergy. However, most drugs are too small to be directly recognized by specific B and T cells. Immune reactions to low-molecular drugs have been explained by the hapten model: a hapten drug can bind covalently to soluble autologous proteins (e.g. serum albumin). Resulting compounds may then be recognized by matching B cell receptors (BCRs) and induce a specific T cell-dependent IgE-or IgG-antibody production. Drug haptens may bind to extra- or intracellular proteins, which are processed and presented by various professional antigen-presenting cells (APCs). Depending on the APC, they may induce not only specific antibody production, but also non-immediate T cell-mediated DA. More recently, a supplementary effector mechanism for non-immediate DA to low-molecular drugs has been described, namely the pharmacological interaction of native low-molecular drugs with immune receptors (p-i-concept). Low-molecular drugs may directly and reversibly attach to immune receptors. These non-covalent interactions may modify the affinity between autologous major histocompatibility complex (MHC), presented peptides and specifically primed T cell receptors (TCRs) and thereby stimulate T cells. A special type of p-i-reaction has been recently described between the antiviral drug abacavir and the F pocket of HLA-B*57:01. This interaction causes an alteration of the MHC-presented self-peptide repertoire and may consecutively lead to a kind of auto-reactivity. Such types of reactions can explain the strong MHC-HLA associations which have been found for some T cell-mediated DHRs.

• #1 Drug Hypersensitivity – Immunology; Allergic Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/drug-hypersensitivity

  Some protein and large polypeptide medications (eg, insulin, therapeutic antibodies) can directly stimulate antibody production. However, most medications act as haptens, binding covalently to serum or cell-bound proteins, including peptides embedded in major histocompatibility complex (MHC) molecules. The binding makes the protein-medication complex immunogenic, stimulating anti-medication antibody production, T-cell responses against the medication, or both. Haptens may also bind directly to class II MHC molecules, directly activating T cells. Some medications act as prohaptens. When metabolized, prohaptens become haptens; eg, penicillin itself is not antigenic, but its main degradation product, benzylpenicilloic acid, can combine with tissue proteins to form benzylpenicilloyl (BPO), a major antigenic determinant. Some medications bind and stimulate T-cell receptors (TCR) directly; the clinical significance of nonhapten TCR binding is being determined.

• #1 Mechanisms of Drug-Induced Allergy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2664605/

  Type IV effector mechanisms have not been elucidated but may be explained by the hapten/prohapten concept and the pharmacological interactions of drugs with immune receptors (p-i) concept. […] According to the p-i concept, T cells must possess 3 properties to be activated. First, the T cells must express a TCR that can bind the drug and induce a stimulatory signal. Second, the T cells must have a low threshold for activation, which allows them to react to a minor signal such as the drug binding to its TCR. Antigen-experienced memory T cells (TEM) may have these properties. Third, an additional interaction of the TCR with the MHC on the APC must occur to enhance the response to the drug. Thus, a dense network of T cells and APCs favors such a reaction. […] Recent findings of preexisting sensitization in patients with cetuximab-induced or neuromuscular blocking agent-induced anaphylaxis or with hypersensitivity to iodinated contrast medium show that previous contact with the causative drug is not a prerequisite for drug allergy reactions and that these reactions may be explained by cross-reactivity. Therefore, an immune mechanism may also explain allergic reactions on primary exposure to a drug. Drug allergy due to cross-reactivity may occur in IgE-, IgG-, and T-cell-mediated reactions. The p-i concept and cross-reactivity provide an explanation for the predominant skin involvement in T-cell-mediated reactions to systemically applied drugs; skin tissue is particularly rich in memory T cells in close apposition to MHC-expressing dendritic cells.

• #1 Drug Allergy: Delayed Cutaneous Hypersensitivity Reactions to Drugs – EMJ

  https://www.emjreviews.com/allergy-immunology/article/drug-allergy-delayed-cutaneous-hypersensitivity-reactions-to-drugs/

  According to the hapten/prohapten hypothesis, the causative drug acts as either a hapten, prohapten, an antigen, a co-stimulatory agent, an immunogen, or a sensitogen. […] The drug acting as a hapten binds covalently to serum or cell-bound proteins, including peptides embedded in major histocompatibility complex (MHC) molecules. […] The p-i model was proposed by Pichler and is based on the direct binding of the parent drug to the T cell receptor or the human leukocyte antigen (HLA) which results in T cell activation and a subsequent immune response. […] The altered peptide repertoire hypothesis states that low-molecular-weight drugs bind non-covalently to parts of the HLA molecules within the antigen-binding cleft, thereby altering the shape of the cleft and the repertoire of peptides that are presented.

• #1 Drug allergy: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/drug-allergy-pathogenesis/print

  Drug allergy: Pathogenesis […] 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. […] Drugs can elicit drug-specific immune responses in two ways: 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. […] 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. 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.

• #1 Drug Allergy: Causes, Symptoms, Diagnosis & Treatment

  https://my.clevelandclinic.org/health/diseases/8621-medication-allergies

  Drug allergies are an allergic reaction to medications. Its when your bodys immune system overreacts to medications. Your body develops a sensitivity to one of the substances in the medication and remembers it as a harmful foreign invader, like bacteria or viruses. The next time you ingest that drug, your immune system releases antibodies to remove it from your body. […] If you have a drug allergy, your immune system responds by making immunoglobulin E (IgE) after your first exposure to the drug (sensitization). IgE is a type of antibody that helps remove harmful substances from your body. Your body makes many different IgE types, which target specific types of allergens. The IgE travels to cells that contain histamine (mast cells) in your mucus membranes, skin, gastrointestinal (GI) tract and airways. The next time you encounter the drug allergen, the IgE attaches to the allergen and tells the mast cells to release histamine and other chemicals. Histamine causes your immediate allergy symptoms they usually develop within minutes.

• #1 Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions

  https://www.mdpi.com/1422-0067/24/16/12577

  Most medications are small molecular weight compounds with simple chemical structures that are not easily recognized by the immune system so as to elicit a primary immune response involving specific T or B cells. Thus, most drugs are not effective immunogens. However, some drugs (or their metabolites) can become immunogenic after covalent binding to host proteins (e.g., albumin). The drug is then referred to as a hapten, the host protein as a carrier, and the complex or conjugate as hapten–carrier. Hapten–carrier conjugates are immunogenic for B cells (antibody responses) and for T cells. […] Various mechanisms and pathways can be involved in mast cell activation that lead to immediate hypersensitivity symptoms, including immunoglobulin-mediated and direct mast cell activation. Symptoms are similar, independent of the underlying mechanism involved and caused by the release of mediators such as histamine, tryptase, platelet-activating factor (PAF), and cysteinyl leukotrienes. Histamine induces smooth muscle constriction and increases vascular permeability, leading to flushing, pruritus, rhinorrhea, tachycardia, and bronchospasm.

• #1 Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions

  https://www.mdpi.com/1422-0067/24/16/12577

  Type IV hypersensitivity reactions are induced by activated T cells, with participation of both CD4+ and CD8+ T cells. Advances in the understanding of T cell functions led to a sub-classification of T cell-mediated hypersensitivity reactions into three subgroups (types IVa, IVb, IVc). A fourth subgroup, type IVd, was later added to sub-categorize type IV reactions into types IVa–IVd according to the dominant cytokines and to the contribution of certain subpopulations of leukocytes to skin inflammation and tissue damage. […] The lymphocyte transformation test (LTT) relies on the ability of drug-specific memory T cells to proliferate upon stimulation with the nominal antigen. This proliferation assay was initially named LTT because antigen-stimulated T cells undergo blastogenesis upon cell stimulation, and the old technique readouts for the assay relied on cell observation under the microscope. This test is indicated mainly in non-immediate allergic reactions, specifically in type IV T cell-mediated reactions. […] An increasing number of studies have shown an association between specific HLA alleles and the development of delayed drug hypersensitivity reactions.

• #1 Drug Allergies – Thong B, Vervloet D, Torres Jaen, MJ (Updated 2021)

  https://www.worldallergy.org/component/content/article/drug-allergies-thong-b-vervloet-d-torres-jaen-mj-updated-2021?catid=16&Itemid=101

  According to the more recent classification, the mechanism involved in each reaction could be determined by how drugs interact with the immune system. […] There are three main processes by which T cells are stimulated by drugs: Hapten concept, Pro-hapten concept, and Pi (pharmacologic interaction with immune receptors) concept. […] In toxic epidermal necrolysis (TEN), there is a specific drug hypersensitivity restricted to HLA class I antigens, resulting in clonal expansion of CD8+ cytotoxic T lymphocytes (CTLs). Cytotoxicity is mediated by CTL granzymes and possibly death receptor (DR) ligand (DR-L) and Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression.

• #1 Drug allergy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0289-y

  There are two theories to explain how a low molecular weight compound such as a drug is able to stimulate an immune response: (1) the hapten hypothesis and (2) the pharmacological-interaction (p-i) hypothesis. […] Unlike immune-mediated drug reactions, pseudoallergic reactions are not associated with the production of antibodies or sensitized T cells, but are often clinically indistinguishable from drug hypersensitivity reactions. […] Factors associated with an increased risk of developing a drug allergy include patient-related factors (e.g., age, gender, genetic polymorphisms, or infections with certain viruses) and drug-related factors (e.g., frequency of exposure, route of administration, or molecular weight). […] The diagnosis of drug allergy requires a thorough history and the identification of physical findings and symptoms that are compatible with the characteristics and timing of drug-induced allergic reactions.

• #1 Adverse Drug Reactions: Types and Treatment Options | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1101/p1781.html

  Pseudoallergic reactions are the result of direct mast cell activation and degranulation by drugs such as opiates, vancomycin, and radiocontrast media. These reactions may be clinically indistinguishable from Type I hypersensitivity, but do not involve drug-specific IgE. […] The most important drug-related risk factors for drug hypersensitivity concern the chemical properties and molecular weight of the drug. Larger drugs with greater structural complexity (e.g., nonhuman proteins) are more likely to be immunogenic. […] Another factor affecting the frequency of hypersensitivity drug reactions is the route of drug administration; topical, intramuscular, and intravenous administrations are more likely to cause hypersensitivity reactions. […] True hypersensitivity adverse drug reactions are great imitators of disease and may present with involvement of any organ system, including systemic reactions such as anaphylaxis.

• #1 Mechanisms of Drug-Induced Allergy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2664605/

  Drug allergies are type B reactions that are mediated by the adaptive immune system. In practice, it is often difficult to differentiate between immune- and non-immune-mediated reactions. Because clinical signs and symptoms of most immune reactions are observed only in the elicitation phase and not in the preceding sensitization phase, the dogma has been that allergic reactions to drugs are only observed on reexposure or longer-lasting exposure (at least 3 days) to the drug. However, more recent data show that previous contact with the causative drug is not a prerequisite for immune-mediated drug hypersensitivity. These findings indicate that the paradigm must be changed and that drug allergies might be best explained by cross-reactivity between the drug involved and other xenobiotics to which the affected patient may have been exposed beforehand.

• #1 Drug allergy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-024-00936-1

  Unlike immune-mediated drug reactions, non-allergic reactions (previously called pseudoallergic or anaphylactoid reactions) are not associated with the production of antibodies or sensitized T cells but are often clinically indistinguishable from immune-mediated drug HSRs. […] Certain patient- and drug-related factors are associated with an increased risk of developing drug allergy. […] Drug allergy typically occurs in young and middle-aged adults and is more common in women. […] The diagnosis of drug allergy requires a thorough history and the identification of physical findings and symptoms that are compatible with the characteristics and timing of drug-induced allergic reactions. […] The most effective strategy for the management of drug allergy is avoidance or discontinuation of the offending drug. […] If a particular drug to which the patient is allergic is indicated, induction of drug tolerance procedures may be considered to induce temporary tolerance to the drug.

• #1 Drug allergy – Review article – Karnataka Paediatric Journal

  https://iap-kpj.org/drug-allergy-review-article/

  Most of the drugs that elicit an immune response are multivalent by virtue of their large molecular weight with multiple repeating epitopes. […] Most medications have small molecular weights and they bind to host molecules (carrier) forming a complex called haptencarrier conjugate which elicits a drug-specific immune response. […] In this model, a chemically inert drug not capable of covalently binding to peptides or proteins activates the immune system by directly and reversibly binding to HLA molecule forming the HLA-drug complex which is capable of stimulating strong T-cell response. […] The threshold of activation of the immunological reactions can further be lowered due to certain virus infections EpsteinBarr virus (EBV), cytomegalovirus, Human Herpes Virus, Human immunodeficiency virus (HIV) and during exacerbation of autoimmune diseases.

• #1 Drug Allergy: Delayed Cutaneous Hypersensitivity Reactions to Drugs – EMJ

  https://www.emjreviews.com/allergy-immunology/article/drug-allergy-delayed-cutaneous-hypersensitivity-reactions-to-drugs/

  A study by Belln et al. supported the T cell-mediated hypothesis by identifying 85 genes that were differentially expressed during the acute phase of drug-induced hypersensitivity syndrome (DIHS). […] Associations have been discovered between HLA alleles and many of the serious cutaneous adverse reaction syndromes. […] The reaction to anticonvulsant medications, termed anticonvulsant hypersensitivity syndrome (AHS), has been linked to the presence of arene oxides. […] ADRs have been classified as Type A: those that are predictable and dose dependent reactions, including overdose, side effects, and drug interactions; and Type B, those that are unpredictable, more likely to be dose independent, and may include immunologically mediated drug hypersensitivity or non-immune mediated reactions, thus being considered allergic reactions.

• #1 Testing for drug allergy – Australian Prescriber

  https://australianprescriber.tg.org.au/articles/testing-for-drug-allergy.html

  Penicillin allergic patients have 10 times the risk of other people of reacting adversely to other antibiotics. […] Many patients are being recognised as having allergic reactions to a number of antigenically unrelated drugs, antibiotics in particular. […] General management principles for patients with a history of allergy to a specific drug are to obtain full clinical details of the reaction, use an alternative, non-cross-reacting drug if allergy is suspected, and know how to treat anaphylaxis.

• #1 Adverse drug reactions Allergy? Side-effect? Intolerance?

  https://www.racgp.org.au/afp/2013/january-february/adverse-drug-reactions

  The principles of the natural history of drug allergy reactions are shown in Table 4. Prior tolerance of a drug is not evidence against allergy to the drug, indeed, prior exposure is necessary for sensitisation. It is safest to assume that where an allergic reaction has occurred, it is most likely to occur again on subsequent exposure, and the severity of the reaction may be similar or worse. […] Cross-reactivity is when an immunological reaction develops specifically to drug 1, but because of similarity in molecular structure, the antibodies and/or T-cells also react against drug 2 (even without any previous exposure to drug 2). This allows some prediction of risk of reactivity to structurally related drugs. […] As the allergic reaction is mediated by a limited range of immunopathogenic mechanisms, diverse drugs can cause similar types of reactions, depending on which immunological effectors are activated. For example, an IgE-mediated anaphylactic reaction will be similar regardless of which drug triggers it. […] Tests are available for the diagnosis of drug allergy but they are limited. Specific IgE for some drugs can be detected on blood testing.

• #1 Drug Allergies | Reactions, Symptoms & Treatment | ACAAI Public Website

  https://acaai.org/allergies/allergic-conditions/drug-allergies/

  If a drug allergy is suspected, your allergist may also recommend an oral drug challenge, in which you will be supervised by medical staff as you take the drug suspected of triggering a reaction. […] Anaphylaxis is a severe, potentially life-threatening reaction that can simultaneously affect two or more organ systems (for instance, when there is both swelling and difficulty breathing, or vomiting and hives). […] If there is no suitable alternative to the antibiotic that you are allergic to, you will need to undergo drug desensitization. This involves taking the drug in increasing amounts until you can tolerate the needed dose with minimal side effects. […] Penicillin is the most common drug allergy. If you experience an allergic reaction after taking penicillin, you won’t necessarily have a similar reaction to related drugs such as amoxicillin. But it is more likely to happen. […] Those who have severe reactions to penicillin should seek emergency care, which may include an epinephrine injection and treatment to maintain blood pressure and normal breathing.

• #1

  https://link.springer.com/article/10.1007/s40521-015-0055-z

  The most highly studied model of DIA mediated by specific immunological mechanisms is that of penicillin. […] If a subject takes amoxicillin or another BL derivative and develops an anaphylactic response after an interval of over 1 h, we are likely dealing with an accelerated reaction for which the proposed mechanism is a T cell response. […] The situation is more complex for NSAIDs. […] In summary, when dealing with an NSAID reaction indicative of DIA, there are four potential mechanisms to consider: selective and cross-intolerance in subjects without any underlying disease, and immediate and accelerated reactions in subjects with chronic spontaneous urticaria. […] As stated above, the most highly studied model is that of BLs, where it has been shown that different penicillin structures can produce an epitope that induces selective or cross-reactive responses.

• #1 Drug hypersensitivity reactions – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/drug-hypersensitivity-reactions/

  Drug hypersensitivity reactions (DHR) are a group of adverse drug effects that resemble an allergy. […] Most DHRs are classified by either mechanism or clinical features; mixed DHRs are ones that do not fit into a single category. Mechanism: allergic DHR (i.e., drug allergy) or nonallergic DHR. […] Immediate DHRs often resemble viral infections; nonimmediate DHRs commonly manifest as drug-induced skin reactions but can cause a variety of syndromes. […] Management of DHRs varies depending on the underlying etiology and resulting syndrome. […] Incorrectly labeling a patient as having drug allergies can lead to avoidance of essential medications, use of less effective or overly broad alternative medications (e.g., antibiotics), and unnecessary desensitization procedures. […] DHR to contrast can be immediate (IgE-mediated or nonimmunologic) or nonimmediate (T-cell mediated). […] A group of four type IV DHRs associated with significant morbidity and mortality: DRESS, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP).

• #1 3. Drug hypersensitivity | The Medical Journal of Australiafacebookblueskylinkedinemailfacebookblueskylinkedinemailama-logo

  https://www.mja.com.au/journal/2006/185/6/3-drug-hypersensitivity

  Urticaria, angioedema, bronchospasm and anaphylaxis signify mast cell activation, and usually indicate an immune mechanism mediated by drug-specific IgE antibodies. […] Immediate reactions (occurring from several minutes to 1 hour after drug administration) suggest an IgE-mediated event caused by pre-formed IgE antibodies. […] Angioedema is a well recognised adverse reaction that affects 0.1%–0.5% of patients taking ACE inhibitors. […] The reaction involves a non-immune hypersensitivity mechanism caused by the accumulation of plasma kinins (such as bradykinin) as the result of inhibition (by ACE inhibitors) of the kininases that normally metabolise and inactivate bradykinin.

• #1 Drug allergy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-024-00936-1

  There are several theories to explain how a low molecular weight compound such as a drug is able to stimulate an immune response: (1) the hapten hypothesis; (2) the pharmacological-interaction (p-i) hypothesis; (3) the direct mast cell activation hypothesis and (4) the altered peptide repertoire model. […] The p-i hypothesis proposes that the drug binds to a cell-surface receptor, such as the major histocompatibility complex (MHC) or the T-cell receptor, and modifies its structure so that it is recognized by other cells of the adaptive immune system as foreign, thereby stimulating an immune response. […] High molecular weight therapeutic agents such as monoclonal antibodies (mAbs) often contain murine-derived structures which are recognized as foreign by the immune system, resulting in primarily type I (IgE and non-IgE mediated), cytokine release type, or type III (immune-complex-mediated) reactions.

• #1 Drug Allergy in Special Populations: From Pathogenesis to Practical Applications | AAAAI Education Center

  https://education.aaaai.org/drug-insect-allergy-and-vaccines/node/23365

  Session 1801 from the 2017 AAAAI Annual Meeting seeks to answer questions related to the prevalence, impact and underlying pathogenesis of drug allergy to commonly employed therapeutics in special and vulnerable populations and provides examples of drug allergy clinics in diverse settings. […] This session will also seek to provide a framework for understanding the causal mechanisms and approaches to different populations with key challenges in different drug allergy syndromes. […] What are the key mechanisms of delayed hypersensitivity and what has antiretroviral therapy taught us about this? […] What is known about the mechanisms of reactions associated chemotherapeutic agents and biologicals including immediate (IgE and non-IgE), injection site reactions and delayed reactions? […] Describe approaches to the prevention, diagnosis and management of delayed hypersensitivity reactions and lessons learned from antiretroviral drugs as a mechanistic model.

• #1 Drug allergy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0289-y

  Skin testing procedures, such as skin prick testing (SPT) and intradermal tests, are useful for the diagnosis of IgE-mediated (type I) reactions. […] The most effective strategy for the management of drug allergy is avoidance or discontinuation of the offending drug. […] If a particular drug to which the patient is allergic is indicated and there is no suitable alternative, induction of drug tolerance procedures may be considered to induce temporary tolerance to the drug.

• #1 Testing for drug allergy – Australian Prescriber

  https://australianprescriber.tg.org.au/articles/testing-for-drug-allergy.html

  Patients who report an allergic response may have had an adverse reaction to the drug. Adverse reactions to drugs are common and drug allergy represents only about 10% of them. […] Testing is primarily restricted to the detection of drug specific IgE antibodies. […] Immediate type skin tests are the most rapid, convenient and reproducible method of detecting drug-specific IgE antibodies. […] The tests are usually without risk, but anaphylaxis has occurred. […] Test doses can be used when there is an unconvincing history of drug allergy, but an IgE reaction is difficult to exclude. […] The most widely used is the radio allergosorbent test (RAST) which measures circulating drug specific IgE antibodies. […] Allergy to penicillin is the best studied drug reaction. Anaphylaxis most commonly occurs between the ages of 20 and 49 years, but children and the elderly are not exempt.

• #1 Drug allergy, why does it occur? – Genes Matter

  https://www.veritasint.com/blog/en/drug-allergies/

  When a drug triggers this process, it is because the immune system recognizes it as a harmful substance, so it generates specific antibodies against it. This may occur the first time a drug is taken, however, in most cases, drug allergy does not manifest itself until a second exposure has occurred. […] Anaphylactic shock is a severe, life-threatening anaphylactic (allergic) reaction to a drug. It is characterized by typical allergy symptoms (itching, rash, etc.) along with a severe drop in blood pressure, narrowing of the airways which prevents breathing extreme weakness and loss of consciousness. […] Diagnosis is essential for the treatment of a drug allergy. If your doctor thinks you may have one, he or she may order tests and refer you to an allergist to confirm the suspicion. […] Treatment of symptoms, in addition to abandoning the medication, includes: Antihistamines: Drugs to inhibit or block the effect of histamine, a molecule which, as we have said, is responsible for allergy symptoms. […] For cases of very severe reaction in which several body systems are affected and there is a risk of anaphylactic shock, the specialist usually prescribes an emergency solution: intramuscular adrenaline.

• #1 Drug allergies – UF Health

  https://ufhealth.org/conditions-and-treatments/drug-allergies

  The goal of treatment is to relieve symptoms and prevent a severe reaction. […] In some cases, a penicillin (or other drug) allergy responds to desensitization. This treatment involves being given very small doses at first, followed by larger and larger doses of a medicine to improve your tolerance of the drug. […] Most drug allergies respond to treatment. But sometimes, they can lead to severe asthma, anaphylaxis, or death. […] There is generally no way to prevent a drug allergy. […] In some cases, a provider may approve the use of a drug that causes an allergy if you are first treated with medicines that slow or block the immune response.

• #1 Identifying the mechanisms of drug hypersensitivity

  https://www.nature.com/collections/dieeehchgg

  Drug allergies are a significant medical problem, but their underlying pathogenesis is not well understood. […] Unravelling the genetics and mechanisms leading to adverse hypersensitivity to drugs is key to preventing these life-threatening events, and accelerating the development of better targeted diagnostic and therapeutic options. […] Identification of the dog orthologue of human MAS-related G protein coupled receptor X2 (MRGPRX2) essential for drug-induced pseudo-allergic reactions. […] Penicillin causes non-allergic anaphylaxis by activating the contact system.

• #1 A Modern View of the Pathogenesis of Allergy with Drug Etiology

  https://ideas.repec.org/a/aoj/lifscr/v3y2016i4p50-56id640.html

  Thus, considering the huge genetic polymorphism in systems of drug metabolism in the body and in the systems contributing immune response to the resulting products of conjugation of hapten-protein, evident is the need to further study the role of these systems in the occurrence of adverse reactions to drug therapy, in particular, in the development of allergic complications.

• #2 Drug allergy: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/drug-allergy-pathogenesis/print

  Drug allergy: Pathogenesis […] 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. […] Drugs can elicit drug-specific immune responses in two ways: 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. […] 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. 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.

• #2 Adverse Drug Reactions: Types and Treatment Options | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1101/p1781.html

  Drug hypersensitivity is a clinical diagnosis based on available data. Laboratory testing may be useful, with skin testing providing the greatest specificity. […] The terms drug allergy, drug hypersensitivity, and drug reaction are often used interchangeably. Drug hypersensitivity is defined as an immune-mediated response to a drug agent in a sensitized patient. Drug allergy is restricted specifically to a reaction mediated by IgE. […] Immune-mediated reactions account for 5 to 10 percent of all drug reactions and constitute true drug hypersensitivity, with IgE-mediated drug allergies falling into this category. […] The Gell and Coombs classification system describes the predominant immune mechanisms that lead to clinical symptoms of drug hypersensitivity. This classification system includes: Type I reactions (IgE-mediated); Type II reactions (cytotoxic); Type III reactions (immune complex); and Type IV reactions (delayed, cell-mediated). However, some drug hypersensitivity reactions are difficult to classify because of a lack of evidence supporting a predominant immunologic mechanism.

• #2 Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions

  https://www.mdpi.com/1422-0067/24/16/12577

  Drug hypersensitivity reactions (DHRs) are adverse effects of pharmaceutical formulations (including active drugs and excipients) that clinically resemble allergies. DHRs can be allergic or non-allergic in nature, with drug allergies being immunologically mediated DHRs. The term non-allergic hypersensitivity is preferred for those reactions in which the underlying pathogenic mechanisms do not involve a B cell-mediated or T cell-mediated drug-specific immune response, which have also been referred to as anaphylactoid or pseudoallergic by several authors. However, B and T cell-specific immune mechanisms are not always easily identified, even in allergic reactions. […] The classification of hypersensitivity reactions proposed by Gell and Coombs links the clinical phenotype to the immune mechanism involved. The immediate symptoms (urticaria, anaphylaxis) are categorized as type I hypersensitivity and are caused by allergen-specific IgE and mast cell degranulation. Delayed symptoms (e.g., exanthemas, hepatitis, Stevens-Johnson Syndrome/toxic epidermal necrolysis, DRESS) that are dependent on the activation of drug-specific T cells are classified as type IV hypersensitivity reactions. Some delayed reactions, such as hemolysis, thrombocytopenia, arthralgia, and vasculitis, could be due to drug-induced IgG/IgM antibodies (type II and type III hypersensitivity) and are less frequent.

• #2 Drug allergy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-024-00936-1

  There are several theories to explain how a low molecular weight compound such as a drug is able to stimulate an immune response: (1) the hapten hypothesis; (2) the pharmacological-interaction (p-i) hypothesis; (3) the direct mast cell activation hypothesis and (4) the altered peptide repertoire model. […] The p-i hypothesis proposes that the drug binds to a cell-surface receptor, such as the major histocompatibility complex (MHC) or the T-cell receptor, and modifies its structure so that it is recognized by other cells of the adaptive immune system as foreign, thereby stimulating an immune response. […] High molecular weight therapeutic agents such as monoclonal antibodies (mAbs) often contain murine-derived structures which are recognized as foreign by the immune system, resulting in primarily type I (IgE and non-IgE mediated), cytokine release type, or type III (immune-complex-mediated) reactions.

• #2 Drug Allergy: Delayed Cutaneous Hypersensitivity Reactions to Drugs – EMJ

  https://www.emjreviews.com/allergy-immunology/article/drug-allergy-delayed-cutaneous-hypersensitivity-reactions-to-drugs/

  Drug allergies, also termed adverse drug reactions (ADRs), are a problem for individuals of all ages, from paediatric to geriatric, and in all medical settings. They may be a predictable reaction to a specific drug (termed Type A) or particular to the individual (termed Type B). […] Drug allergies are one type of ADR and are defined by the Joint Task Force on Practice Parameters as an immunologically mediated response to a pharmaceutical and/or formulation (excipient) agent in a sensitized person. This definition implies that the reaction can have both immunoglobulin (Ig)E-mediated and non-IgE-mediated mechanisms. […] The pathophysiology of drug allergies is not fully understood; however, the cell-mediated immune reaction and the activation of T cells is proposed to occur through three different mechanisms: The hapten/prohapten hypothesis, The pharmacologic interaction with immune receptor (p-i) model, The altered peptide repertoire hypothesis.

• #2 Drug Allergies – Thong B, Vervloet D, Torres Jaen, MJ (Updated 2021)

  https://worldallergy.net/component/content/article/drug-allergies-thong-b-vervloet-d-torres-jaen-mj-updated-2021?catid=16&Itemid=101

  DHRs can be classified as allergic and non-allergic reactions based on the mechanism involved. According to the more recent classification, the mechanism involved in each reaction could be determined by how drugs interact with the immune system. There are three main processes by which T cells are stimulated by drugs: hapten concept, pro-hapten concept, and pharmacologic interaction with immune receptors (Pi concept). […] In toxic epidermal necrolysis (TEN), there is a specific drug hypersensitivity restricted to HLA class I antigens, resulting in clonal expansion of CD8+ cytotoxic T lymphocytes (CTLs). Cytotoxicity is mediated by CTL granzymes and possibly death receptor ligand and Fas ligand. […] The mechanisms involved in drug allergy include the hapten concept, where haptens bind to proteins/peptides and modify them covalently, stimulating the immune system. The pro-hapten concept involves compounds that must be metabolized into haptens to become reactive. The Pi concept describes how a chemically inert drug can activate immune cells specific for peptide antigens through reversible drug-receptor interactions. […] In summary, drug allergy pathogenesis involves complex interactions between drugs and the immune system, leading to various allergic and non-allergic reactions mediated by different immune mechanisms.

• #2 Drug Allergy: Delayed Cutaneous Hypersensitivity Reactions to Drugs – EMJ

  https://www.emjreviews.com/allergy-immunology/article/drug-allergy-delayed-cutaneous-hypersensitivity-reactions-to-drugs/

  According to the hapten/prohapten hypothesis, the causative drug acts as either a hapten, prohapten, an antigen, a co-stimulatory agent, an immunogen, or a sensitogen. […] The drug acting as a hapten binds covalently to serum or cell-bound proteins, including peptides embedded in major histocompatibility complex (MHC) molecules. […] The p-i model was proposed by Pichler and is based on the direct binding of the parent drug to the T cell receptor or the human leukocyte antigen (HLA) which results in T cell activation and a subsequent immune response. […] The altered peptide repertoire hypothesis states that low-molecular-weight drugs bind non-covalently to parts of the HLA molecules within the antigen-binding cleft, thereby altering the shape of the cleft and the repertoire of peptides that are presented.

• #2 Drug Allergies: Causes, Symptoms and Diagnosis | Live Science

  https://www.livescience.com/50750-drug-allergies.html

  Drug allergies are dangerous reactions to medicines or drugs that people take. These allergic reactions can lead to relatively mild problems, such as non-threatening rashes, or to more dangerous reactions, such as anaphylaxis and tissue damage. […] The first type, called Type I, is caused by immune system molecule, called immunoglobulin-E (Ig-E). […] Ig-E is an antibody, or a molecule made by the body whose jobs it is to identify specific parts of harmful substances or germs, called the antigen. But allergy-causing substances, called allergens, can occasionally co-opt this cellular process. In the case of drug allergies, a molecule in a drug may be mistaken for the antigen. When it binds to Ig-E molecules that are already attached to another cell type called mast cells, it „crosses the arms” of the Ig-E molecules.

• #2 Drug Allergy: Causes, Symptoms, Diagnosis & Treatment

  https://my.clevelandclinic.org/health/diseases/8621-medication-allergies

  Drug allergies are an allergic reaction to medications. Its when your bodys immune system overreacts to medications. Your body develops a sensitivity to one of the substances in the medication and remembers it as a harmful foreign invader, like bacteria or viruses. The next time you ingest that drug, your immune system releases antibodies to remove it from your body. […] If you have a drug allergy, your immune system responds by making immunoglobulin E (IgE) after your first exposure to the drug (sensitization). IgE is a type of antibody that helps remove harmful substances from your body. Your body makes many different IgE types, which target specific types of allergens. The IgE travels to cells that contain histamine (mast cells) in your mucus membranes, skin, gastrointestinal (GI) tract and airways. The next time you encounter the drug allergen, the IgE attaches to the allergen and tells the mast cells to release histamine and other chemicals. Histamine causes your immediate allergy symptoms they usually develop within minutes.

• #2 IgE and Drug Allergy: Antibody Recognition of ‘Small’ Molecules of Widely Varying Structures and Activities

  https://www.mdpi.com/2073-4468/3/1/56

  The variety of chemically diverse pharmacologically-active compounds administered to patients is large and seemingly forever growing, and, with every new drug released and administered, there is always the potential of an allergic reaction. The most commonly occurring allergic responses to drugs are the type I, or immediate hypersensitivity reactions mediated by IgE antibodies. These reactions may affect a single organ, such as the nasopharynx (allergic rhinitis), eyes (conjunctivitis), mucosa of mouth/throat/tongue (angioedema), bronchopulmonary tissue (asthma), gastrointestinal tract (gastroenteritis) and skin (urticaria, eczema), or multiple organs (anaphylaxis), causing symptoms ranging from minor itching and inflammation to death. […] It seems that almost every drug is capable of causing an immediate reaction and it is unusual to find a drug that has not provoked an anaphylactic response in at least one patient. These facts alone indicate the extraordinary breadth of recognition of IgE antibodies for drugs ranging from relatively simple structures, for example, aspirin, to complex molecules, such as the macrolide antibiotics composed of a large macrocyclic ring with attached deoxy sugars. This wide recognition profile is borne out at the molecular level by results of quantitative immunochemical studies where hapten inhibition investigations have identified structural determinants complementary to IgE antibodies in the sera of allergic subjects. Allergenic determinants have been identified on a variety of drugs including neuromuscular blockers, penicillins, cephalosporins, opioids, thiopentone, sulfonamides, trimethoprim, quinolones, chlorhexidine and the non-steroidal anti-inflammatory drug aspirin. […] It is already clear that IgE can distinguish fine structural differences on a wide variety of molecules, determinants may be at least as small as an amino group or encompass the whole molecule, and individual drugs may demonstrate allergenic heterogeneity.

• #2 Adverse drug reactions Allergy? Side-effect? Intolerance?

  https://www.racgp.org.au/afp/2013/january-february/adverse-drug-reactions

  Adverse drug reactions (ADRs) vary from life-threatening anaphylaxis to minor common side-effects. The mechanism of the ADR may be helpful in risk assessment. Drug allergy has immunological mechanisms: it may be severe, tends to be reproducible and may cross-react with structurally related drugs. […] Allergic ADRs are a distinct subgroup because the mechanisms (if not the reason for their occurrence) are well understood. The classic system of Gell and Coombs still provides a good basis for understanding drug hypersensitivity reactions, although the vast majority of reactions fall into either type 1 (acute IgE mediated: urticaria or anaphylaxis) or type 4 (cell mediated: delayed rash or organ pathology). Type 4 has recently been divided into four subtypes according to the dominant effector cells: broadly, 4a macrophage, 4b eosinophil, 4c cytotoxic T-cell and 4d neutrophil. Each of these can be represented by a specific cutaneous drug allergy reaction.

• #2 Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions

  https://www.mdpi.com/1422-0067/24/16/12577

  Type IV hypersensitivity reactions are induced by activated T cells, with participation of both CD4+ and CD8+ T cells. Advances in the understanding of T cell functions led to a sub-classification of T cell-mediated hypersensitivity reactions into three subgroups (types IVa, IVb, IVc). A fourth subgroup, type IVd, was later added to sub-categorize type IV reactions into types IVa–IVd according to the dominant cytokines and to the contribution of certain subpopulations of leukocytes to skin inflammation and tissue damage. […] The lymphocyte transformation test (LTT) relies on the ability of drug-specific memory T cells to proliferate upon stimulation with the nominal antigen. This proliferation assay was initially named LTT because antigen-stimulated T cells undergo blastogenesis upon cell stimulation, and the old technique readouts for the assay relied on cell observation under the microscope. This test is indicated mainly in non-immediate allergic reactions, specifically in type IV T cell-mediated reactions. […] An increasing number of studies have shown an association between specific HLA alleles and the development of delayed drug hypersensitivity reactions.

• #2 Drug allergy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-024-00936-1

  Unlike immune-mediated drug reactions, non-allergic reactions (previously called pseudoallergic or anaphylactoid reactions) are not associated with the production of antibodies or sensitized T cells but are often clinically indistinguishable from immune-mediated drug HSRs. […] Certain patient- and drug-related factors are associated with an increased risk of developing drug allergy. […] Drug allergy typically occurs in young and middle-aged adults and is more common in women. […] The diagnosis of drug allergy requires a thorough history and the identification of physical findings and symptoms that are compatible with the characteristics and timing of drug-induced allergic reactions. […] The most effective strategy for the management of drug allergy is avoidance or discontinuation of the offending drug. […] If a particular drug to which the patient is allergic is indicated, induction of drug tolerance procedures may be considered to induce temporary tolerance to the drug.

• #2 Drug Allergies – Thong B, Vervloet D, Torres Jaen, MJ (Updated 2021)

  https://www.worldallergy.org/component/content/article/drug-allergies-thong-b-vervloet-d-torres-jaen-mj-updated-2021?catid=16&Itemid=101

  Allergic reactions are mediated by a specific immune response to a drug acting as hapten that can lead to all types of Coombs and Gell-mediated immune reactions: types I (IgE-mediated, produced by B cells), type II (IgG/IgM-mediated cytotoxicity), type III (immunocomplex) and IV (T cell-mediated). The most common are type I and IV, involved in IRs and NIRs, respectively. […] Non-allergic reactions include all other IRs without an underlying demonstrated immune mechanism. They are clinically indistinguishable from allergic reactions and they are produced after drug interaction with inflammatory cells as mast cells, basophils, and neutrophils through mechanisms based on (i) over-inhibition of specific enzymes such as the COX-1 inhibition (pharmacological effect) in non-steroidal anti-inflammatory drugs reactions or (ii) the off-target occupation of receptors by drugs (direct stimulation) such as the Mas-related G-protein receptor (MRGPRX2) on mast cells by neuromuscular blocking agent (NMBAs) and fluoroquinolones.

• #2 3. Drug hypersensitivity | The Medical Journal of Australiafacebookblueskylinkedinemailfacebookblueskylinkedinemailama-logo

  https://www.mja.com.au/journal/2006/185/6/3-drug-hypersensitivity

  Urticaria, angioedema, bronchospasm and anaphylaxis signify mast cell activation, and usually indicate an immune mechanism mediated by drug-specific IgE antibodies. […] Immediate reactions (occurring from several minutes to 1 hour after drug administration) suggest an IgE-mediated event caused by pre-formed IgE antibodies. […] Angioedema is a well recognised adverse reaction that affects 0.1%–0.5% of patients taking ACE inhibitors. […] The reaction involves a non-immune hypersensitivity mechanism caused by the accumulation of plasma kinins (such as bradykinin) as the result of inhibition (by ACE inhibitors) of the kininases that normally metabolise and inactivate bradykinin.

• #2 A Modern View of the Pathogenesis of Allergy with Drug Etiology

  https://ideas.repec.org/a/aoj/lifscr/v3y2016i4p50-56id640.html

  Nowadays many diseases are associated with a high risk of drug allergy, and this risk can vary greatly depending on the type of disease. […] In HIV-infected patients, there is the high risk of developing allergies in the form of skin rashes and temperature, and severe skin syndromes Stevens-Jones (SJS) and toxic epidermal necrolysis (TEN) in 6%-10% of cases. […] Studies on the antigenicity of antibiotics demonstrated the potential relevance of both categories of drug allergy: hapten and p-i models. […] In patients with allergic reaction to piperacillin, this medication acts as the hapten, with the formation of the immunogenic conjugate piperacillin – albumin, which stimulates the drug-responsive T-cells. […] Immunogenetic factors have been identified as risk indicators for the development of hypersensitivity reactions to the representatives of many classes of drugs, such as Abacavir and Nevirapine, Carbamazepine and Allopurinol, etc.

• #2

  https://asianonlinejournals.com/index.php/Lifsc/article/view/640

  Nowadays many diseases are associated with a high risk of drug allergy, and this risk can vary greatly depending on the type of disease. […] In HIV-infected patients, there is the high risk of developing allergies in the form of skin rashes and temperature, and severe skin syndromes Stevens-Jones (SJS) and toxic epidermal necrolysis (TEN) in 6%-10% of cases. […] Studies on the antigenicity of antibiotics demonstrated the potential relevance of both categories of drug allergy: hapten and p-i models. […] Immunogenetic factors have been identified as risk indicators for the development of hypersensitivity reactions to the representatives of many classes of drugs, such as Abacavir and Nevirapine, Carbamazepine and Allopurinol, etc. […] Thus, considering the huge genetic polymorphism in systems of drug metabolism in the body and in the systems contributing immune response to the resulting products of conjugation of hapten-protein, evident is the need to further study the role of these systems in the occurrence of adverse reactions to drug therapy, in particular, in the development of allergic complications.

• #2 Multiple drug hypersensivity: insight into the underlying mechanism and correlation with autoimmune diseases – European Annals of Allergy and Clinical Immunology

  https://www.eurannallergyimm.com/multiple-drug-hypersensivity-insight-into-the-underlying-mechanism-and-correlation-with-autoimmune-diseases/

  Subjects with drug hypersensitivity are sometimes simultaneously reactive to several drugs. This nosological entity is defined as multiple drug hypersensivity (MDH). Urticaria and angioedema are the commonest clinical manifestations of hypersensitivity drug reactions (HDR). These clinical signs are also pathognomonic of chronic idiopathic urticaria (CIU), whose pathogenetic mechanisms are still largely unknown. […] In patients with MDH, ASST proved to be frequently positive, as previously described for multiple NSAIDs intolerance. In ASST-positive subjects, the activity of several drugs appears to add up FceRIspecific autoantibodies in the induction of the release of allergic mediators.

• #2 Adverse drug reactions Allergy? Side-effect? Intolerance?

  https://www.racgp.org.au/afp/2013/january-february/adverse-drug-reactions

  The principles of the natural history of drug allergy reactions are shown in Table 4. Prior tolerance of a drug is not evidence against allergy to the drug, indeed, prior exposure is necessary for sensitisation. It is safest to assume that where an allergic reaction has occurred, it is most likely to occur again on subsequent exposure, and the severity of the reaction may be similar or worse. […] Cross-reactivity is when an immunological reaction develops specifically to drug 1, but because of similarity in molecular structure, the antibodies and/or T-cells also react against drug 2 (even without any previous exposure to drug 2). This allows some prediction of risk of reactivity to structurally related drugs. […] As the allergic reaction is mediated by a limited range of immunopathogenic mechanisms, diverse drugs can cause similar types of reactions, depending on which immunological effectors are activated. For example, an IgE-mediated anaphylactic reaction will be similar regardless of which drug triggers it. […] Tests are available for the diagnosis of drug allergy but they are limited. Specific IgE for some drugs can be detected on blood testing.

• #2 Drug Hypersensitivity – Immunology; Allergic Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/drug-hypersensitivity

  How primary sensitization occurs and how the immune system is initially involved is unclear, but once a medication stimulates an immune response, cross-reactions with other medications within and between medication classes can occur. For example, patients who are penicillin-sensitive are highly likely to react to semisynthetic penicillins (eg, amoxicillin, carbenicillin, ticarcillin). […] In early, poorly designed studies, about 10% of patients who had a vague history of penicillin sensitivity reacted to cephalosporins, which have a similar beta-lactam structure; this finding has been cited as evidence of cross-reactivity between these medication classes. However, in better-designed studies, only about 2% of patients with a penicillin allergy detected during skin testing react to cephalosporins; about the same percentage of patients react to structurally unrelated antibiotics (eg, sulfa medications). Sometimes this and other apparent cross-reactions (eg, between sulfonamide antibiotics and nonantibiotics) are due to a predisposition to allergic reactions rather than to specific immune cross-reactivity.

• #2

  https://link.springer.com/article/10.1007/s40521-015-0055-z

  The most highly studied model of DIA mediated by specific immunological mechanisms is that of penicillin. […] If a subject takes amoxicillin or another BL derivative and develops an anaphylactic response after an interval of over 1 h, we are likely dealing with an accelerated reaction for which the proposed mechanism is a T cell response. […] The situation is more complex for NSAIDs. […] In summary, when dealing with an NSAID reaction indicative of DIA, there are four potential mechanisms to consider: selective and cross-intolerance in subjects without any underlying disease, and immediate and accelerated reactions in subjects with chronic spontaneous urticaria. […] As stated above, the most highly studied model is that of BLs, where it has been shown that different penicillin structures can produce an epitope that induces selective or cross-reactive responses.

• #2 Adverse Drug Reactions: Types and Treatment Options | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1101/p1781.html

  Pseudoallergic reactions are the result of direct mast cell activation and degranulation by drugs such as opiates, vancomycin, and radiocontrast media. These reactions may be clinically indistinguishable from Type I hypersensitivity, but do not involve drug-specific IgE. […] The most important drug-related risk factors for drug hypersensitivity concern the chemical properties and molecular weight of the drug. Larger drugs with greater structural complexity (e.g., nonhuman proteins) are more likely to be immunogenic. […] Another factor affecting the frequency of hypersensitivity drug reactions is the route of drug administration; topical, intramuscular, and intravenous administrations are more likely to cause hypersensitivity reactions. […] True hypersensitivity adverse drug reactions are great imitators of disease and may present with involvement of any organ system, including systemic reactions such as anaphylaxis.

• #2 Mechanisms of Drug-Induced Allergy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2664605/

  We identified English-language publications on hypersensitivity reactions to xenobiotics through the PubMed database, using the search terms drug and/or xenobiotic, hypersensitivity reaction, mechanism, and immune mediated. We analyzed articles pertaining to the mechanism and the role of T cells. Immune hypersensitivity reactions to drugs are mediated predominantly by IgE antibodies or T cells. The mechanism of IgE-mediated reactions is well investigated, but the mechanisms of T-cell-mediated drug hypersensitivity are not well understood. The literature describes 2 concepts: the hapten/prohapten concept and the concept of pharmacological interactions of drugs with immune receptors. In T-cell-mediated allergic drug reactions, the specificity of the T-cell receptor that is stimulated by the drug may often be directed to a cross-reactive major histocompatibility complex-peptide compound. Thus, previous contact with the causative drug is not obligatory, and an immune mechanism should be considered as the cause of hypersensitivity, even in reactions that occur on primary exposure. Indeed, immune-mediated reactions to xenobiotics in patients without prior exposure to the agent have been described recently for radiocontrast media and neuromuscular blocking agents. Thus, the allergenic potential of a drug under development should be evaluated not only by screening its haptenlike characteristics but also by assessing its direct immunostimulatory potential.

• #2 Drug Allergy: Delayed Cutaneous Hypersensitivity Reactions to Drugs – EMJ

  https://www.emjreviews.com/allergy-immunology/article/drug-allergy-delayed-cutaneous-hypersensitivity-reactions-to-drugs/

  A study by Belln et al. supported the T cell-mediated hypothesis by identifying 85 genes that were differentially expressed during the acute phase of drug-induced hypersensitivity syndrome (DIHS). […] Associations have been discovered between HLA alleles and many of the serious cutaneous adverse reaction syndromes. […] The reaction to anticonvulsant medications, termed anticonvulsant hypersensitivity syndrome (AHS), has been linked to the presence of arene oxides. […] ADRs have been classified as Type A: those that are predictable and dose dependent reactions, including overdose, side effects, and drug interactions; and Type B, those that are unpredictable, more likely to be dose independent, and may include immunologically mediated drug hypersensitivity or non-immune mediated reactions, thus being considered allergic reactions.

• #2 Drug Hypersensitivity – Immunology; Allergic Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/drug-hypersensitivity

  Immune checkpoint inhibitors, a commonly used class of cancer immunotherapy, can have immune-related adverse effects. These effects result from nonspecific immune activation and can affect almost any organ system; however, they most commonly affect the skin, liver, gastrointestinal tract, heart, and endocrine system.

• #2 Adverse Drug Reactions: Types and Treatment Options | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/1101/p1781.html

  A diagnosis of drug hypersensitivity depends on identifying symptoms and physical findings that are compatible with an immune drug reaction. […] The goal of diagnostic testing is to evaluate biochemical or immunologic markers that confirm activation of a particular immunopathologic pathway to explain the suspected adverse drug effect. […] Confirmation of suspected Type I hypersensitivity reactions require the detection of antigen-specific IgE. Skin testing is a useful diagnostic procedure in these patients. […] Laboratory tests measuring mast cell activation may be helpful if obtained within four hours of onset of the suspected allergic reaction. […] The diagnosis of drug hypersensitivity is usually based on clinical judgment, because definitive, confirmatory drug-specific testing is often difficult. […] Immune-mediated drug hypersensitivity reactions typically pose a predictable, more serious health risk with re-exposure to a drug. Nonimmune drug reactions tend to be less severe and less reproducible.

• #2 Drug Allergies | Reactions, Symptoms & Treatment | ACAAI Public Website

  https://acaai.org/allergies/allergic-conditions/drug-allergies/

  If you develop a rash, hives or difficulty breathing after taking certain medications, you may have a drug allergy. […] As with other allergic reactions, these symptoms can occur when your body’s immune system becomes sensitized to a substance in the medication, perceives it as a foreign invader and releases chemicals to defend against it. […] While you may not experience allergic symptoms the first time you take a drug, your body could be producing antibodies to it. As a result, the next time you take the drug, your immune system may see it as an invader, and you’ll develop symptoms as your body releases chemicals to defend against it. […] Drug allergies can be hard to diagnose. An allergy to penicillin-type drugs is the only one that can be definitively diagnosed through a skin test.

• #2 The Role of Corticosteroids in the Management of Drug Allergy: A Narrative Literature Review | Bioscientia Medicina : Journal of Biomedicine and Translational Research

  https://www.bioscmed.com/index.php/bsm/article/view/773

  Drug allergy is an adverse drug reaction that occurs through an immune reaction that occurs through IgE or a rapid hypersensitivity reaction with various mechanisms and clinical presentations. […] In allergic processes, corticosteroids can suppress the production and effects of humoral factors involved in the inflammatory response, inhibit the migration of leukocytes to sites of inflammation, and interfere with the function of endothelial cells, granulocytes, mast cells, and fibroblasts. […] Corticosteroids inhibit the synthesis of a number of cytokines, such as the interleukins IL-1 to IL-6, tumor necrosis factor- (TNF-), and granulocyte-macrophage colony-stimulating factor (GM-CSF). […] In conclusion, corticosteroids are one of the therapeutic modalities in various manifestations of drug allergies. Every drug allergy gets the anti-inflammatory effects of corticosteroids with different choices, routes, and doses for each manifestation.

• #2

  https://link.springer.com/article/10.1007/s40521-015-0055-z

  In daily practice, a controlled challenge is often necessary to assess tolerance and confirm diagnosis, due to the low sensitivity and availability of many of the above-mentioned diagnostic tests. […] The aim of desensitisation is to achieve the situation where basophils and mast cells become unresponsive to the drug. […] Desensitisation in DIA is indicated when the drug is crucial to the patient and no alternatives are available.

• #2 Mechanisms and manifestations of drug hypersensitivities

  https://tales.nmc.unibas.ch/de/allergies-when-the-immune-system-backfires-41/eczemas-and-drug-hypersensitivity-220/mechanisms-and-manifestations-of-drug-hypersensitivities-1233

  Drug hypersensitivity reactions are among the most complex phenomena in clinical allergology. […] Drugs, on the other hand, are very heterogeneous. They include mostly haptens (eg antibiotics and pain medications), hormones (eg corticosteroids), as well as proteins (eg insulin and biological drugs). […] Type B or drug hypersensitivity reactions encompass specific immune mechanisms (ie drug allergies in a narrower sense) or pseudoallergic mechanisms. […] However, in many drug hypersensitivities, non-immunologic, pseudoallergic mechanisms are involved. […] In a given patient usually just one mechanism and manifestation to one molecule is present remember the immune system is efficient but also highly specific. […] We have now recognized why drug hypersensitivities are the most challenging issue in allergology: different drugs may cause manifold clinical manifestations through highly heterogeneous mechanisms.

• #2 Drug Allergy in Special Populations: From Pathogenesis to Practical Applications | AAAAI Education Center

  https://education.aaaai.org/drug-insect-allergy-and-vaccines/node/23365

  Session 1801 from the 2017 AAAAI Annual Meeting seeks to answer questions related to the prevalence, impact and underlying pathogenesis of drug allergy to commonly employed therapeutics in special and vulnerable populations and provides examples of drug allergy clinics in diverse settings. […] This session will also seek to provide a framework for understanding the causal mechanisms and approaches to different populations with key challenges in different drug allergy syndromes. […] What are the key mechanisms of delayed hypersensitivity and what has antiretroviral therapy taught us about this? […] What is known about the mechanisms of reactions associated chemotherapeutic agents and biologicals including immediate (IgE and non-IgE), injection site reactions and delayed reactions? […] Describe approaches to the prevention, diagnosis and management of delayed hypersensitivity reactions and lessons learned from antiretroviral drugs as a mechanistic model.

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