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Frontiers in Medicine 2023
PubMed: 37942420
DOI: 10.3389/fmed.2023.1305765 -
Clinical and Experimental Allergy :... Jan 2024Vancomycin, a glycopeptide antibiotic used for Gram-positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in...
BACKGROUND
Vancomycin, a glycopeptide antibiotic used for Gram-positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA-A*32:01-expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug-reactive T-cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug-specific T-cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug-reactive T-cell clones (TCCs) generated from healthy donors and vancomycin-hypersensitive patients.
METHODS
CD4+ and CD8+ vancomycin-responsive TCCs were generated by serial dilution. The Seahorse XFe Analyzer was used to measure the extracellular acidification rate (ECAR) as an indicator of glycolytic function. Additionally, T-cell proliferation and cytokine release (IFN-γ) assay were utilised to correlate the bioenergetic characteristics of T-cell activation with in vitro assays.
RESULTS
Model T-cell stimulants induced non-specific T-cell activation, characterised by immediate augmentation of ECAR and rate of ATP production (JATPglyc). There was a dose-dependent and drug-specific glycolytic shift when vancomycin-reactive TCCs were exposed to the drug. Vancomycin-reactive TCCs did not exhibit T-cell cross-reactivity with structurally similar compounds within proliferative and cytokine readouts. However, cross-reactivity was observed when analysing energetic responses; TCCs with prior specificity for vancomycin were also found to exhibit glycolytic switching after exposure to teicoplanin. Glycolytic activation of TCC was HLA restricted, as exposure to HLA blockade attenuated the glycolytic induction.
CONCLUSION
These studies describe the glycolytic shift of CD4+ and CD8+ T cells following vancomycin exposure. Since similar glycolytic switching is observed with teicoplanin, which did not activate T cells, it is possible the master switch for T-cell activation is located upstream of metabolic signalling.
Topics: Humans; Vancomycin; Teicoplanin; CD8-Positive T-Lymphocytes; Lymphocyte Activation; Cytokines; Glycolysis
PubMed: 38177093
DOI: 10.1111/cea.14423 -
JAMA Network Open May 2024β-lactam (BL) allergies are the most common drug allergy worldwide, but most are reported in error. BL allergies are also well-established risk factors for adverse drug...
IMPORTANCE
β-lactam (BL) allergies are the most common drug allergy worldwide, but most are reported in error. BL allergies are also well-established risk factors for adverse drug events and antibiotic-resistant infections during inpatient health care encounters, but the understanding of the long-term outcomes of patients with BL allergies remains limited.
OBJECTIVE
To evaluate the long-term clinical outcomes of patients with BL allergies.
DESIGN, SETTING, AND PARTICIPANTS
This longitudinal retrospective cohort study was conducted at a single regional health care system in western Pennsylvania. Electronic health records were analyzed for patients who had an index encounter with a diagnosis of sepsis, pneumonia, or urinary tract infection between 2007 and 2008. Patients were followed-up until death or the end of 2018. Data analysis was performed from January 2022 to January 2024.
EXPOSURE
The presence of any BL class antibiotic in the allergy section of a patient's electronic health record, evaluated at the earliest occurring observed health care encounter.
MAIN OUTCOMES AND MEASURES
The primary outcome was all-cause mortality, derived from the Social Security Death Index. Secondary outcomes were defined using laboratory and microbiology results and included infection with methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, or vancomycin-resistant Enterococcus (VRE) and severity and occurrence of acute kidney injury (AKI). Generalized estimating equations with a patient-level panel variable and time exposure offset were used to evaluate the odds of occurrence of each outcome between allergy groups.
RESULTS
A total of 20 092 patients (mean [SD] age, 62.9 [19.7] years; 12 231 female [60.9%]), of whom 4211 (21.0%) had BL documented allergy and 15 881 (79.0%) did not, met the inclusion criteria. A total of 3513 patients (17.5%) were Black, 15 358 (76.4%) were White, and 1221 (6.0%) were another race. Using generalized estimating equations, documented BL allergies were not significantly associated with the odds of mortality (odds ratio [OR], 1.02; 95% CI, 0.96-1.09). BL allergies were associated with increased odds of MRSA infection (OR, 1.44; 95% CI, 1.36-1.53), VRE infection (OR, 1.18; 95% CI, 1.05-1.32), and the pooled rate of the 3 evaluated antibiotic-resistant infections (OR, 1.33; 95% CI, 1.30-1.36) but were not associated with C difficile infection (OR, 1.04; 95% CI, 0.94-1.16), stage 2 and 3 AKI (OR, 1.02; 95% CI, 0.96-1.10), or stage 3 AKI (OR, 1.06; 95% CI, 0.98-1.14).
CONCLUSIONS AND RELEVANCE
Documented BL allergies were not associated with the long-term odds of mortality but were associated with antibiotic-resistant infections. Health systems should emphasize accurate allergy documentation and reduce unnecessary BL avoidance.
Topics: Humans; Drug Hypersensitivity; Female; Male; beta-Lactams; Retrospective Studies; Middle Aged; Aged; Anti-Bacterial Agents; Longitudinal Studies; Pennsylvania; Adult; Urinary Tract Infections; Risk Factors; Electronic Health Records
PubMed: 38758551
DOI: 10.1001/jamanetworkopen.2024.12313 -
Mucosal Immunology Aug 2023Obesity and type 2 diabetes (T2D) have been found to be associated with abnormalities in several organs, including the intestine. These conditions can lead to changes in...
Obesity and type 2 diabetes (T2D) have been found to be associated with abnormalities in several organs, including the intestine. These conditions can lead to changes in gut homeostasis, compromising tolerance to luminal antigens and increasing susceptibility to food allergies. The underlying mechanisms for this phenomenon are not yet fully understood. In this study, we investigated changes in the intestinal mucosa of diet-induced obese mice and found that they exhibited increased gut permeability and reduced Treg cells frequency. Upon oral treatment with ovalbumin (OVA), obese mice failed to develop oral tolerance. However, hyperglycemia treatment improved intestinal permeability and oral tolerance induction in mice. Furthermore, we observed that obese mice exhibited a more severe food allergy to OVA, and this allergy was alleviated after treatment with a hypoglycemic drug. Importantly, our findings were translated to obese humans. Individuals with T2D had higher serum IgE levels and downregulated genes related to gut homeostasis. Taken together, our results suggest that obesity-induced hyperglycemia can lead to a failure in oral tolerance and to exacerbation of food allergy. These findings shed light on the mechanisms underlying the relationship among obesity, T2D, and gut mucosal immunity, which could inform the development of new therapeutic approaches.
Topics: Humans; Mice; Animals; Diabetes Mellitus, Type 2; Mice, Obese; Food Hypersensitivity; Obesity; Immune Tolerance; Allergens; Administration, Oral; Ovalbumin; Mice, Inbred BALB C
PubMed: 37302712
DOI: 10.1016/j.mucimm.2023.05.008 -
Respirology (Carlton, Vic.) Aug 2023
Topics: Humans; Adult; Immunity, Innate; Lymphocytes; Asthma; Pulmonary Eosinophilia; Cell Proliferation; Anti-Asthmatic Agents; Eosinophils
PubMed: 37164907
DOI: 10.1111/resp.14517 -
Acta Pharmaceutica Sinica. B Aug 2023Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of...
Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.
PubMed: 37655331
DOI: 10.1016/j.apsb.2023.05.010 -
Asia Pacific Allergy Sep 2023Given the deficits in allergists and testing capacity, the diagnosis of drug allergy is largely dependent on the clinician's and pharmacist's judgment. The ability to...
BACKGROUND
Given the deficits in allergists and testing capacity, the diagnosis of drug allergy is largely dependent on the clinician's and pharmacist's judgment. The ability to recognize drug allergies and respond appropriately is crucial to patient safety. Currently, there is a void in the evidence that limits the ability to recommend comprehensive and swift improvements on this front.
OBJECTIVE
This study thus aimed to evaluate the knowledge, attitude, and practice toward drug allergy among doctors and pharmacists working in public healthcare facilities in Sabah, Malaysia.
METHODS
This cross-sectional study was conducted in 24 hospitals and 11 clinics in Sabah. A validated Drug Allergy Knowledge, Attitude, and Practice Questionnaire was adapted from a published study and developed on an online survey platform. The questionnaire was distributed to all listed eligible respondents via email and personal messenger service.
RESULTS
A total of 549 doctors and pharmacists responded, with an overall response rate of 18.2%. The total mean knowledge, attitude, and practice scores were 8.3 (SD, 1.98), 18.9 (SD, 2.55), and 17.3 (SD, 4.4), respectively. It was found that pharmacists performed significantly poorer than both medical officers (mean score difference = -0.5; = 0.006) and specialists (mean score difference = -0.9; = 0.020) in the knowledge domain. As the time in service doubles, the knowledge score increases significantly by 0.3 ( = 0.015).
CONCLUSION
Knowledge, attitude, and practice on drug allergy among doctors and pharmacists in Sabah were poor. It is thus timely for advanced educational programs on drug allergy to be formalized and implemented.
PubMed: 37744958
DOI: 10.5415/apallergy.0000000000000115 -
International Journal of Molecular... Aug 2023Drug hypersensitivity reactions are a serious concern in clinical practice because they can be severe and result in lifelong sequelae. An accurate diagnosis and... (Review)
Review
Drug hypersensitivity reactions are a serious concern in clinical practice because they can be severe and result in lifelong sequelae. An accurate diagnosis and identification of the culprit drug is essential to prevent future reactions as well as for the identification of safe treatment alternatives. Nonetheless, the diagnosis can be challenging. In vivo and in vitro tests can be helpful, although none are conclusive; therefore, the tests are not usually performed in isolation but as part of a diagnostic algorithm. In addition, some in vitro tests are only available in research laboratories, and standardization has not been fully accomplished. Collaborating research is needed to improve drug hypersensitivity reaction diagnosis. In this review, we update the current available in vivo and in vitro tools with their pros and cons and propose an algorithm to integrate them into clinical practice.
Topics: Humans; Algorithms; Causality; Disease Progression; Drug Hypersensitivity; Hypersensitivity
PubMed: 37628756
DOI: 10.3390/ijms241612577 -
The Journal of Allergy and Clinical... Nov 2023Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D, and low levels of prostaglandin E. Further,...
BACKGROUND
Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D, and low levels of prostaglandin E. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown.
OBJECTIVE
We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD.
METHODS
Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis.
RESULTS
Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081).
CONCLUSION
Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.
Topics: Humans; Immunity, Innate; Lymphocytes; Asthma, Aspirin-Induced; Hydroxyeicosatetraenoic Acids; Cyclooxygenase Inhibitors; Sinusitis; Nasal Mucosa; Prostaglandins; Eicosanoids; Aspirin; Nasal Polyps
PubMed: 37543185
DOI: 10.1016/j.jaci.2023.06.028 -
Diagnostics (Basel, Switzerland) Jan 2024Mastocytosis is a myeloproliferative neoplasm characterized by abnormal proliferation and activation of clonal mast cells typically bearing the KITD816V mutation.... (Review)
Review
Mastocytosis is a myeloproliferative neoplasm characterized by abnormal proliferation and activation of clonal mast cells typically bearing the KITD816V mutation. Symptoms manifest due to the release of bioactive mediators and the tissue infiltration by neoplastic mast cells. Mast cell activation symptoms include flushing, pruritus, urticaria, abdominal cramping, diarrhea, wheezing, neuropsychiatric symptoms, and anaphylaxis. Up to 50% of patients with mastocytosis report a history of provoked and unprovoked anaphylaxis, with Hymenoptera venom and drugs the most common culprits. NSAIDs, antibiotics, vaccines, perioperative medications, and radiocontrast media are often empirically avoided without evidence of reactions, depriving patients of needed medications and placing them at risk for unfavorable outcomes. The purpose of this review is to highlight the most common agents responsible for adverse drug reactions in patients with mastocytosis, with a review of current epidemiology, diagnosis, and management of drug hypersensitivity and Hymenoptera venom allergy.
PubMed: 38247999
DOI: 10.3390/diagnostics14020123