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Clinical Reviews in Allergy & Immunology Jun 2022Confirming drug imputability is an important step in the management of cutaneous adverse drug reactions (CADR). Re-challenge is inconvenient and in many cases life... (Review)
Review
Confirming drug imputability is an important step in the management of cutaneous adverse drug reactions (CADR). Re-challenge is inconvenient and in many cases life threatening. We review the literature on ideal patch testing technique for specific CADRs. Testing should be performed approximately 3 months after the resolution of the eruption using standard patch testing techniques. Commercially available patch test preparations are available for a minority of drugs, so in most cases, testing should be performed with the drug at various recommended concentrations and in different vehicles. Testing to all known excipients, such as dyes, vehicles and preservatives is also important. Immunosuppressive medications should be discontinued or down titrated to the lowest tolerable dose to decrease the risk of false negative reactions. We provide an overview of expert recommendations and extant evidence on the utility of patch testing for identifying the culprit drug in common CADRs and for specific drug or drug classes. Overall, there appears to be significant variability in the patch test positivity of different drugs, which is likely the result of factors intrinsic to the drug such as dermal absorption (as a function of lipophilicity and molecular size) and whether the drug itself or a downstream metabolite is implicated in the immune reaction. Drugs with high patch test positivity rates include beta-lactam antibiotics, aromatic anticonvulsants, phenytoin, and corticosteroids, among others. Patch testing positivity varies both as a function of the drug and type of CADR. The sum of the evidence suggests that patch testing in the setting of morbilliform eruptions, fixed drug eruption, acute generalized exanthematous pustulosis, and possibly also drug-induced hypersensitivity syndrome, photoallergic and eczematous reactions may be worthwhile, although utility of testing may vary on the specific drug in question for the eruption. It appears to be of limited utility and is not recommended in the setting of other complex CADR, such as SJS/TEN and leukocytoclastic vasculitis.
Topics: Anticonvulsants; Drug Eruptions; Drug Hypersensitivity; Exanthema; Humans; Hypersensitivity, Delayed; Patch Tests
PubMed: 35113364
DOI: 10.1007/s12016-022-08924-2 -
Allergy May 2021Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well established in inducing adaptive reactions of the immune system to small... (Review)
Review
Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well established in inducing adaptive reactions of the immune system to small molecules like drugs. The role of hapten-carrier adducts in re-challenge reactions leading to mast cell degranulation and anaphylaxis is unclear. Based on clinical observations, the speed of adduct formation, skin and in vitro tests to inert drug molecules, a different explanation of IgE-mediated reactions to drugs is proposed: These are (a) A natural role of reduced mast cell (MC) reactivity in developing IgE-mediated reactions to drugs. This MC unresponsiveness is antigen-specific and covers the serum drug concentrations, but allows reactivity to locally higher concentrations. (b) Some non-covalent drug-protein complexes rely on rather affine bindings and have a similar appearance as covalent hapten-protein adducts. Such drug-protein complexes represent so-called "fake antigens," as they are unable to induce immunity, but may react with and cross-link preformed drug-specific IgE. As they are formed very rapidly and in high concentrations, they may cause fulminant MC degranulation and anaphylaxis. (c) The generation of covalent hapten-protein adducts requires hours, either because the formation of covalent bonds requires time or because first a metabolic step for forming a reactive metabolite is required. This slow process of stable adduct formation has the advantage that it may give time to desensitize mast cells, even in already sensitized individuals. The consequences of this new interpretation of IgE-mediated reactions to drugs are potentially wide-reaching for IgE-mediated drug allergy but also allergy in general.
Topics: Anaphylaxis; Animals; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Humans; Immunoglobulin E; Mast Cells; Pharmaceutical Preparations
PubMed: 32780486
DOI: 10.1111/all.14554 -
International Archives of Allergy and... 2020Drug hypersensitivity is one of the most frequent causes of anaphylaxis, particularly in adults and in hospitalized patients. Drug-induced anaphylaxis (DIA) is also... (Review)
Review
Drug hypersensitivity is one of the most frequent causes of anaphylaxis, particularly in adults and in hospitalized patients. Drug-induced anaphylaxis (DIA) is also associated with more severe outcomes than other anaphylaxis triggers, and drugs are responsible for the majority of deaths due to anaphylaxis. We here review the current knowledge on the incidence, prevalence, drugs involved, mortality, and mortality risk factors for DIA. The incidence of both anaphylaxis and DIA seems to be increasing worldwide. Antibiotics and analgesics are the most frequently reported triggers of DIA. However, the importance of other drug groups should be taken into account, especially in particular settings (e.g., peri-operative and oncology). The identification of risk factors, geographical variables, and drugs associated with higher risk for DIA may improve the outcomes of this entity.
Topics: Anaphylaxis; Drug Hypersensitivity; Humans; Incidence; Prevalence
PubMed: 32396909
DOI: 10.1159/000507445 -
International Journal of Molecular... Jul 2023In recent years, there has been a noticeable development in oncological treatment, including chemotherapy and biological treatment. Despite their significant... (Review)
Review
In recent years, there has been a noticeable development in oncological treatment, including chemotherapy and biological treatment. Despite their significant effectiveness, they are not free from side effects, such as allergic and dermatological reactions. These reactions can vary in severity and outcome, including potential death. Examples, among others, are type I-IV hypersensitivity reactions of various origins and skin reactions including rashes, itching and redness, but also severe cutaneous syndromes. Due to the therapy used, these may include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis. In some cases, it is necessary to interrupt therapy, which may result in a poorer outcome and shorten the patient's survival. This paper reviews various types of research documents published since 2016. It aims to systematize the latest knowledge and highlight the need for further research into ways to avoid adverse reactions.
Topics: Humans; Skin; Stevens-Johnson Syndrome; Acute Generalized Exanthematous Pustulosis; Drug Hypersensitivity Syndrome; Eosinophilia
PubMed: 37511017
DOI: 10.3390/ijms241411257 -
Allergy Apr 2022
Topics: Anti-Bacterial Agents; Drug Hypersensitivity; Humans; beta-Lactams
PubMed: 35344217
DOI: 10.1111/all.15135 -
Allergy Jan 2023The diagnosis of allergic reactions to penicillins (AR-PEN) is very complex as there is a loss of sensitization over time, which leads to negative skin tests (STs) and...
BACKGROUND
The diagnosis of allergic reactions to penicillins (AR-PEN) is very complex as there is a loss of sensitization over time, which leads to negative skin tests (STs) and specific IgE in serum, and even to tolerance to the drug involved. However, STs may become positive after subsequent exposure to the culprit drug (resensitization), with the risk of inducing potentially severe reactions. The exact rate of resensitization to penicillins is unknown, ranging from 0% to 27.9% in published studies.
OBJECTIVES
To analyze the rate of resensitization in patients with suggestive AR-PEN by repeating STs (retest) after an initial evaluation (IE).
MATERIAL AND METHODS
Patients with suspected AR-PEN were prospectively evaluated between 2017 and 2020. They underwent STs, and a randomized group also underwent a drug provocation test (DPT) with the culprit. Only patients with negative STs and/or DPT were included. All included cases were retested by STs at 2-8 weeks.
RESULTS
A total of 545 patients were included: 296 reporting immediate reactions (IRs) and 249 non-immediate reactions (NIRs). Eighty (14.7%) cases had positive results in retest (RT+): 63 (21.3%) IRs and 17 (6.8%) NIRs (p < 0.0001). The rate of RT+ was higher in anaphylaxis compared with all other reactions (45.8% vs 9.1%, p < 0.0001). The risk of RT+ was higher from the fifth week after IE (OR: 4.64, CI: 2.1-11.6; p < 0.001) and increased with the patient's age (OR: 1.02; CI: 1.01-1.04; p = 0.009).
CONCLUSIONS
Due to the high rate of resensitization, retest should be included in the diagnostic algorithm of IRs to penicillins after an initial negative study, especially in anaphylaxis, to avoid potentially severe reactions after subsequent prescriptions of these drugs.
Topics: Humans; Anaphylaxis; Skin Tests; Immunoglobulin E; Penicillins; Drug Hypersensitivity; Sodium Tetradecyl Sulfate; Anti-Bacterial Agents
PubMed: 36067012
DOI: 10.1111/all.15508 -
Frontiers in Immunology 2021The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant... (Review)
Review
The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.
Topics: Animals; Biomarkers; Costimulatory and Inhibitory T-Cell Receptors; Cytokines; Diagnosis, Differential; Disease Susceptibility; Drug Hypersensitivity; Gene Expression Regulation; Humans; Immunomodulation; Severity of Illness Index; Signal Transduction; T-Lymphocyte Subsets
PubMed: 33717075
DOI: 10.3389/fimmu.2021.597761 -
International Journal of Occupational... Nov 2023On average about 10% of parents report hypersensitivity to at least 1 drug in their children. After diagnosis process a few of these reactions are being confirmed as...
OBJECTIVES
On average about 10% of parents report hypersensitivity to at least 1 drug in their children. After diagnosis process a few of these reactions are being confirmed as drug hypersensitivity reactions. The aim of the study was to assess the real-life prevalence of drug hypersensitivity in children based on drug provocation tests.
MATERIAL AND METHODS
The authors included 113 children, aged 4-18 years, referred to Pediatrics and Allergy Clinic in Łódź, Poland, due to incidence of adverse reaction during treatment. Medical history regarding allergies to drugs was taken in accordance to the form developed by the United States Food and Drug Administration Adverse Event Reporting System. Skin prick tests, intradermal test and drug provocation test were performed in all patients.
RESULTS
In all 113 patients suspected of drug allergy, after all diagnostic procedures, the authors proved IgE-mediated allergy to β-lactams, nonsteroid anti-inflammatory drugs, local anesthetics in 19 patients (16.8%). Previous history of allergy was a risk factor for drug allergy in studied patients (p = 0.001). The most frequent symptoms of allergy were urticaria and erythematous papular rash.
CONCLUSIONS
Drug allergy is a difficult problem in the practice of a doctor and is difficult to diagnose, especially in the pediatric population. It seems that too often isolated symptoms reported during infection or disease are taken as a symptom of drug allergy, and not as a symptom resulting from the course of the disease. Int J Occup Med Environ Health. 2023;36(5):632-42.
Topics: Child; Humans; Drug Hypersensitivity; Hypersensitivity; Skin Tests; beta-Lactams; Risk Factors; Anti-Bacterial Agents
PubMed: 37750429
DOI: 10.13075/ijomeh.1896.02227 -
Immunity, Inflammation and Disease Sep 2020β-Lactam allergy is over-reported and this leads to greater healthcare costs. Allergy testing has inherent risks, yet patients who test negative may continue avoiding...
BACKGROUND
β-Lactam allergy is over-reported and this leads to greater healthcare costs. Allergy testing has inherent risks, yet patients who test negative may continue avoiding β-lactams.
OBJECTIVE
To evaluate the safety and diagnostic value of β-lactams allergy testing locally and usage of antibiotics following negative testing.
METHODS
We performed a retrospective medical record review and follow-up survey of patients who underwent β-lactam testing between 2010 and 2016 at the National Skin Centre, Singapore.
RESULTS
We reviewed the records of 166 patients, with a total of 173 β-lactam allergy labels. Eighty (46.2%) labels were to penicillin, 75 (43.1%) to amoxicillin/amoxicillin-clavulanic acid, 11 (6.4%) to cephalexin, and 5 (2.9%) to others. Skin tests were performed in 142 patients and drug provocation tests (DPTs) in 141 patients. Eleven (6.6%) patients defaulted DPTs after skin testing. Out of 166 patients, 22 (13.3%) patients were proven allergic by either skin tests (16) or DPTs (6). Patients who tested positive had nonsevere reactions. Out of 155 patients who were conclusively evaluated, 133 (85.8%) were not allergic. Of these patients, 30 (22.6%) used the tested β-lactam subsequently, with one reporting a mild reaction. Fifty-one (38.3%) patients were uncontactable or uncertain if they consumed a β-lactam since testing negative. Fifty-two (39.1%) patients had no re-exposure (35 had no indication, 17 were fearful of reactions).
CONCLUSION
Drug allergy testing was safe and removed inappropriate labels.
CLINICAL IMPLICATION
Allergy testing is efficacious, but fears of subsequent rechallenge should be addressed to maximize the effectiveness of allergy delabeling.
Topics: Adolescent; Adult; Aged; Drug Hypersensitivity; Female; HIV Infections; Humans; Male; Middle Aged; Retrospective Studies; Singapore; Skin Tests; Young Adult; beta-Lactams
PubMed: 32506796
DOI: 10.1002/iid3.318 -
Pediatric Allergy, Immunology, and... Jun 2022Previous studies reported that the prevalence of drug allergy is higher in patients with cystic fibrosis (CF) than in the general population. It is important to exclude...
Previous studies reported that the prevalence of drug allergy is higher in patients with cystic fibrosis (CF) than in the general population. It is important to exclude or confirm the drug allergy diagnosis with detailed allergic evaluation for preventing drug allergy overdiagnosis. Our study aims to determine the actual frequency of drug allergy proven by diagnostic tests in children with CF and to compare it with the control group. Patients diagnosed with CF who were followed up in the Pediatric Pulmonology Clinic were included in the study group. Children with similar gender and age characteristics who did not have any chronic diseases and who applied to the Pediatric Polyclinics were included in the control group. We reviewed the medical data of patients with CF. Also, we evaluated the parents of the patients via phone conversation and/or during the control of the outpatient clinic and questioned them in terms of drug allergy. In addition, we assessed those with suspected drug allergies in the pediatric allergy clinic for diagnostic tests and compared it to the control group. CF patients ( = 44) and control group ( = 100) were included in the study. Only 1 patient (2.2%) out of the 44 patients in the study group had a suspicion of drug-related hypersensitivity history. In the control group, 1 patient had a history of rash, provocation test was performed to rule out drug hypersensitivity reaction, and it was evaluated as a negative result. The result of our study showed that the frequency of drug allergy in children diagnosed with CF was not different from the control group. However, it will be useful to confirm the data of pediatric patients with CF in larger groups. In the presence of suspicion of drug allergy, a diagnostic evaluation can prevent unnecessary drug allergy diagnoses.
Topics: Child; Cystic Fibrosis; Drug Hypersensitivity; Exanthema; Humans; Prevalence; Skin Tests
PubMed: 35588286
DOI: 10.1089/ped.2021.0165