-
Frontiers in Immunology 2022Allergic drug reaction or drug allergy is an immunologically mediated drug hypersensitivity reaction (DHR). G-protein coupled receptors (GPCRs) are common drug targets...
BACKGROUND
Allergic drug reaction or drug allergy is an immunologically mediated drug hypersensitivity reaction (DHR). G-protein coupled receptors (GPCRs) are common drug targets and communicate extracellular signals that initiate cellular responses. Recent evidence shows that GPCR MRGPRX2 is of major importance in IgE-independent pseudo-allergic DHRs based on the suspected interactions between many FDA-approved peptidergic compounds and MRGPRX2.
OBJECTIVE
Our aim was to uncover novel MRGPRX2-selective and -potent agonists as drug candidates responsible for clinical features of pseudo-allergic DHRs.
METHODS
We conducted a primary high-throughput screening (HTS), coupled with mutagenesis targeting the MRGPRX2 N62S mutation, on a panel of 3,456 library compounds. We discovered pharmacologically active hit compounds as agonists of the MRGPRX2 protein according to high degrees of potency evaluated by the calcium response and validated by the degranulation assay. Using the molecular tool Forge, we also characterized the structure-activity relationship shared by identified hit compounds.
RESULTS
The alternative allele of single nucleotide polymorphism rs10833049 (N62S) in MRGPRX2 demonstrated property in response to substance P and antineoplastic agent daunorubicin hydrochloride. We applied a unique assay system targeting the N62S mutation to the HTS and identified 84 MRGPRX2-selective active hit compounds representing diverse classes according to primary drug indications. The top five highly represented groups included fluoroquinolone and non-fluoroquinolone antibiotics; antidepressive/antipsychotic; antihistaminic and antineoplastic agents. We classified hit compounds into 14 clusters representing a variety of chemical and drug classes beyond those reported, such as opioids, neuromuscular blocking agents, and fluoroquinolones. We further demonstrated MRGPRX2-dependent degranulation in the human mast cell line LAD2 cells induced by three novel agonists representing the non-fluoroquinolone antibiotics (bacitracin A), anti-allergic agents (brompheniramine maleate) and tyrosine-kinase inhibitors (imatinib mesylate).
CONCLUSION
Our findings could facilitate the development of interventions for personalized prevention and treatment of DHRs, as well as future pharmacogenetic investigations of MRGPRX2 in relevant disease cohorts.
Topics: Humans; Receptors, Neuropeptide; Cell Degranulation; Mast Cells; Nerve Tissue Proteins; Receptors, G-Protein-Coupled; Drug Hypersensitivity; Anti-Bacterial Agents
PubMed: 36341461
DOI: 10.3389/fimmu.2022.997389 -
Journal of Immunological Methods Jun 2021Drug-induced hypersensitivity reactions encompass a variety of different clinical phenotypes ranging from harmless rashes to fatal reactions. They can be classified into... (Review)
Review
Drug-induced hypersensitivity reactions encompass a variety of different clinical phenotypes ranging from harmless rashes to fatal reactions. They can be classified into allergic (i.e. drug allergy) and non-allergic reactions (i.e. non-allergic hypersensitivity). Drug allergies in turn can either be antibody (e.g. IgE) or T cell-mediated. One of the diagnostic tools for the in vitro detection of drug allergy is the lymphocyte transformation test (LTT) which is based on the activation and expansion of the drug-specific memory T cells following co-incubation of the patient's peripheral mononuclear cells (PMBC) with the suspected drug in vitro. The read-out parameter in the classical LTT is T cell proliferation which can be measured as counts per minute following the addition of radiolabeled thymidine to the cell culture. However, in the course of time different modifications of the classical LTT with regard to the read-out parameters and methods have been proposed. Likewise, variations of the LTT platform itself have been described in the literature. This review article describes the development of the classical LTT and its use in the context of drug allergy detection and summarizes the modifications which have been published over time.
Topics: Drug Hypersensitivity; Humans; Immunologic Tests; Lymphocyte Activation; Lymphocytes
PubMed: 33745950
DOI: 10.1016/j.jim.2021.113036 -
Current Allergy and Asthma Reports Feb 2021The coronavirus disease 2019 (COVID-19) has challenged healthcare system capacities and safety for health care workers, reshaping doctor-patient interaction favoring... (Review)
Review
PURPOSE OF REVIEW
The coronavirus disease 2019 (COVID-19) has challenged healthcare system capacities and safety for health care workers, reshaping doctor-patient interaction favoring e-Health or telemedicine. The pandemic situation may make difficult to prioritize patients with allergies diseases (AD), face-to-face evaluation, and moreover concern about the possible COVID-19 diagnosis, since COVID-19 shared many symptoms in common with AD. Being COVID-19 a novel disease, everyone is susceptible; there are some advances on vaccine and specific treatment. We evaluate existing literature on allergic diseases (AD): allergic rhinitis, asthma, food allergy, drug allergy, and skin allergy, and potential underlying mechanisms for any interrelationship between AD and COVID-19.
RECENT FINDINGS
There is inconclusive and controversial evidence of the association between AD and the risk of adverse clinical outcomes of COVID-19. AD patients should minimize hospital and face-to-face visits, and those who have used biologics and allergen immunotherapy should continue the treatment. It is essential to wear personal protective equipment for the protection of health care workers. Social distancing, rational use of facemasks, eye protection, and hand disinfection for health care workers and patients deserve further attention and promotion. Teleconsultation during COVID-19 times for AD patients is very encouraging and telemedicine platform can provide a reliable service in patient care.
Topics: Asthma; Biological Products; COVID-19; Dermatitis, Allergic Contact; Dermatitis, Atopic; Desensitization, Immunologic; Disease Management; Disease Outbreaks; Drug Hypersensitivity; Food Hypersensitivity; Health Personnel; Humans; Infection Control; Pandemics; Personal Protective Equipment; Physical Distancing; Rhinitis, Allergic; SARS-CoV-2; Telemedicine
PubMed: 33560451
DOI: 10.1007/s11882-021-00989-x -
The Journal of Allergy and Clinical... Aug 2019Many notable advances in drug allergy, urticaria, angioedema, and anaphylaxis were reported in 2018. Broad-spectrum antibiotic use and, consequently, antibiotic... (Review)
Review
Many notable advances in drug allergy, urticaria, angioedema, and anaphylaxis were reported in 2018. Broad-spectrum antibiotic use and, consequently, antibiotic resistance are widespread, and algorithms to clarify β-lactam allergy and optimize antibiotic use were described. Meaningful data emerged on the pathogenesis of delayed drug hypersensitivity reactions. Progress not only in defining biomarkers but also in understanding the effect on quality of life and developing better treatments has been made for patients with chronic idiopathic urticaria. Patients with hereditary angioedema (HAE) have gained additional access to highly efficacious therapies, with associated improvements in quality of life, and some progress was made in our understanding of recurrent angioedema in patients with normal laboratory results. Guidelines have defined clear goals to help providers optimize therapies in patients with HAE. The epidemiology and triggers of anaphylaxis and the mechanisms underlying anaphylaxis were elucidated further. In summary, these disorders (and labels) cause substantial burdens for individual persons and even society. Fortunately, publications in 2018 have informed on advancements in diagnosis and management and have provided better understanding of mechanisms that potentially could yield new therapies. This progress should lead to better health outcomes and paths forward in patients with drug allergy, urticaria, HAE, and anaphylaxis.
Topics: Anaphylaxis; Angioedema; Drug Hypersensitivity; Humans; Hypersensitivity, Delayed; Quality of Life; Urticaria; beta-Lactams
PubMed: 31247266
DOI: 10.1016/j.jaci.2019.06.010 -
Allergy Dec 2019Drug hypersensitivity reactions (DHRs) are nowadays the third cause of allergy after rhinitis and asthma with a significant increase in prevalence in both adults and... (Review)
Review
Drug hypersensitivity reactions (DHRs) are nowadays the third cause of allergy after rhinitis and asthma with a significant increase in prevalence in both adults and paediatric population with new drugs included as culprit. For this, DHRs represent not only a health problem but also a significant financial burden for affected individuals and health systems. Mislabelling DHRs is showing to be a relevant problem for both, false label of drug allergic and false label of nonallergic. All this reinforces the need to improve accurate diagnostic approaches that allow an appropriate management. Moreover, there is a need for training both, nonallergist stakeholders and patients to improve the reaction identification and therefore decrease the mislabelling. The use of allergy cards has shown to be relevant to avoid the induction of DHRs due to the prescription of wrong medication. Recent developments over the last 2 years and highlights about risk factors, diagnostic approaches, mechanisms involved as well as prevention actions, and management have been reviewed. In these papers, it has been outlined the need for correct diagnosis and de-labelling of patients previously false-reported as allergic, which will improve the management and treatment of patients with DHRs.
Topics: Cost of Illness; Disease Management; Disease Susceptibility; Drug Hypersensitivity; Drug Labeling; Humans; Incidence; Risk Assessment; Risk Factors
PubMed: 31557314
DOI: 10.1111/all.14061 -
Frontiers in Immunology 2021Allergic reactions to drugs and chemicals are mediated by an adaptive immune response involving specific T cells. During thymic selection, T cells that have not yet... (Review)
Review
Allergic reactions to drugs and chemicals are mediated by an adaptive immune response involving specific T cells. During thymic selection, T cells that have not yet encountered their cognate antigen are considered naive T cells. Due to the artificial nature of drug/chemical-T-cell epitopes, it is not clear whether thymic selection of drug/chemical-specific T cells is a common phenomenon or remains limited to few donors or simply does not exist, suggesting T-cell receptor (TCR) cross-reactivity with other antigens. Selection of drug/chemical-specific T cells could be a relatively rare event accounting for the low occurrence of drug allergy. On the other hand, a large T-cell repertoire found in multiple donors would underline the potential of a drug/chemical to be recognized by many donors. Recent observations raise the hypothesis that not only the drug/chemical, but also parts of the haptenated protein or peptides may constitute the important structural determinants for antigen recognition by the TCR. These observations may also suggest that in the case of drug/chemical allergy, the T-cell repertoire results from particular properties of certain TCR to recognize hapten-modified peptides without need for previous thymic selection. The aim of this review is to address the existence and the role of a naive T-cell repertoire in drug and chemical allergy. Understanding this role has the potential to reveal efficient strategies not only for allergy diagnosis but also for prediction of the immunogenic potential of new chemicals.
Topics: Cross Reactions; Dermatitis, Contact; Drug Hypersensitivity; Epitopes, T-Lymphocyte; Haptens; Humans; Peptides; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 34267746
DOI: 10.3389/fimmu.2021.653102 -
Medicina (Kaunas, Lithuania) May 2020Biologic drugs are widely used in pediatric medicine. Monoclonal antibodies (mAbs) in particular are a therapeutic option for rheumatic, autoinflammatory and oncologic... (Review)
Review
Biologic drugs are widely used in pediatric medicine. Monoclonal antibodies (mAbs) in particular are a therapeutic option for rheumatic, autoinflammatory and oncologic diseases. Adverse drug reactions and hypersensitivity reactions (HSR) to mAbs may occur in children. Clinical presentation of HSRs to mAbs can be classified according to phenotypes in infusion-related reactions, cytokine release syndrome, both alpha type reactions and type I (IgE/non-IgE), type III, and type IV reactions, all beta-type reactions. The aim of this review is to focus on HSRs associated with the most frequent mAbs in childhood, with particular attention to beta-type reactions. When a reaction to mAbs is suspected a diagnostic work-up including in-vivo and in-vitro testing should be performed. A drug provocation test is recommended only when no alternative drugs are available. In selected patients with immediate IgE-mediated drug allergy a desensitization protocol is indicated. Despite the heavy use of mAbs in childhood, studies evaluating the reliability of diagnostic test are lacking. Although desensitization may be effective in reducing the risk of reactions in children, standardized pediatric protocols are still not available.
Topics: Adolescent; Antibodies, Monoclonal; Biological Products; Child; Cytokine Release Syndrome; Drug Hypersensitivity; Female; Humans; Immunologic Factors; Male
PubMed: 32408641
DOI: 10.3390/medicina56050232 -
European Review For Medical and... Oct 2020H2 receptors' antagonists (H2RA) are widely used drugs and they are generally well-tolerated. Ranitidine hypersensitivity reactions (HR) are rarely reported. The article... (Review)
Review
H2 receptors' antagonists (H2RA) are widely used drugs and they are generally well-tolerated. Ranitidine hypersensitivity reactions (HR) are rarely reported. The article emphasizes the importance of recognizing ranitidine as a cause of anaphylaxis and the advantages and limits of allergological evaluation to establish a positive diagnose. We reviewed a series of published cases of ranitidine-induced hypersensitivity reactions, starting from a clinical case presentation. Moreover, we analyzed the ranitidine related adverse events in the Eudravigilance European database of adverse reactions. Most of the allergic reactions induced by ranitidine are type I HR with immediate onset after exposure, with variable clinical presentation. But in a few cases, there were also described delayed reactions, some after occupational exposure. The article underlines the importance of allergy evaluation to avoid future contact with the drug to reduce the risk of more severe reactions. The suspected reactions should be reported, allowing pharmacovigilance systems to analyse them and to establish further recommendations for clinicians.
Topics: Drug Hypersensitivity; Histamine H2 Antagonists; Humans; Ranitidine; Rhinitis, Allergic; Skin Tests
PubMed: 33155242
DOI: 10.26355/eurrev_202010_23443 -
International Journal of Medical... Mar 2022Drug allergy alert systems (DAAS), have been considered an effective strategy to reduce preventable adverse drug events (ADEs), improving patient's safety. To date, no... (Review)
Review
BACKGROUND AND OBJECTIVE
Drug allergy alert systems (DAAS), have been considered an effective strategy to reduce preventable adverse drug events (ADEs), improving patient's safety. To date, no review has been conducted analyzing characteristics of DAAS in the hospital setting. Therefore, the aim of this study is to identify, describe and summarize the DAAS used in hospitals. The secondary objectives are to analyse drug allergy alerts (DAA) characteristics, the override rate (OvR) and the clinical consequences of alert overrides.
METHODS
Searches were conducted in Medline and Cochrane Library to identify studies describing DAAS. Systems characteristics, generated alerts, DAA, OvR, and its clinical consequences were extracted and analyzed.
RESULTS
Twenty-eight articles were included in the review. Seventeen different electronic DAAS were identified, of which 53% were commercially available. Systems differed in drug allergy information and rules for generating alerts. DAA were generally interruptive, triggered by non-exact match at drug prescribing and when ignored, an override reason was mandatory. The OvR ranged from 43.7% to 97%. The main override reason given by providers was that 'patient had previously tolerated or had taken the drug without allergic reaction'. Clinical consequences of overriding DAA were only analyzed in four studies, with an ADE incidence between 0% and 6%.
CONCLUSIONS
Different DAAS are used in hospitals with some degree of heterogeneity. Accurate and updated drug allergy information is important to generate only high value alerts. A regular review of DAAS and a standardization of alert rules, alert information and override reasons are necessary to optimize systems. Future studies should evaluate the impact of the DAAS aspects on preventing ADEs.
Topics: Decision Support Systems, Clinical; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Medical Order Entry Systems; Medication Systems
PubMed: 34990941
DOI: 10.1016/j.ijmedinf.2021.104673 -
Current Allergy and Asthma Reports Jan 2023The purpose of this literature review was to review the latest advancements with biologics in rapid drug desensitization. Our methodology was to highlight both... (Review)
Review
PURPOSE OF REVIEW
The purpose of this literature review was to review the latest advancements with biologics in rapid drug desensitization. Our methodology was to highlight both desensitization to biologics themselves and the use of biologics in desensitization to both biologic and nonbiologic drugs.
RECENT FINDINGS
Biologics are a vast category of drugs that include monoclonal antibodies, nanobodies, modern vaccinations, and even hormones. Desensitization to biologics can be safely performed through standardized procedure. Biomarkers are used both in vitro and in vivo to help identify and classify hypersensitivity reactions. Hypersensitivity reactions to the mRNA vaccinations against SARS-CoV-2 present their own unique challenges to management. There are specific excipients in monoclonal antibodies that are thought to be responsible for many of their hypersensitivity reactions. Certain biologics can even be used to assist in desensitization to other drugs. Rapid drug desensitization is a standardized procedure that may be able to help many patients who have experienced hypersensitivity reactions to biologics and would best be treated with them to continue to receive them. Biologic drugs have opened a new era in medicine for the prevention and treatment of infectious diseases, cancer, and inflammatory diseases. Hypersensitivity reactions to biologics are quite common. This literature review presents the latest advancements in our understanding of hypersensitivity reactions to biologics, how rapid drug desensitization can be used to continue therapy despite history of hypersensitivity, and how biologics themselves can be used to aid in desensitization itself.
Topics: Humans; Drug Hypersensitivity; COVID-19; SARS-CoV-2; Antibodies, Monoclonal; Desensitization, Immunologic; Anaphylaxis; Biological Products
PubMed: 36445652
DOI: 10.1007/s11882-022-01052-z