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Immune-mediated adverse reactions to vaccines.
Stone CA, Rukasin CRF, Beachkofsky TM, Phillips EJ
(2019) Br J Clin Pharmacol 85: 2694-2706
MeSH Terms: Guillain-Barre Syndrome, Humans, Hypersensitivity, Delayed, Hypersensitivity, Immediate, Immunocompromised Host, Immunoglobulin E, Skin Tests, T-Lymphocytes, Vaccination, Vaccine Excipients, Vaccines
Show Abstract · Added March 30, 2020
Vaccination continues to be the single most important and successful public health intervention, due to its prevention of morbidity and mortality from prevalent infectious diseases. Severe immunologically mediated reactions are rare and less common with the vaccine than the true infection. However, these events can cause public fearfulness and loss of confidence in the safety of vaccination. In this paper, we perform a systematic literature search and narrative review of immune-mediated vaccine adverse events and their known and proposed mechanisms, and outline directions for future research. Improving our knowledge base of severe immunologically mediated vaccine reactions and their management drives better vaccine safety and efficacy outcomes.
© 2019 The British Pharmacological Society.
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11 MeSH Terms
The safety of antibiotic skin testing in severe T-cell-mediated hypersensitivity of immunocompetent and immunocompromised hosts.
Trubiano JA, Douglas AP, Goh M, Slavin MA, Phillips EJ
(2019) J Allergy Clin Immunol Pract 7: 1341-1343.e1
MeSH Terms: Aged, Allergens, Anti-Bacterial Agents, Drug Hypersensitivity, Female, Humans, Hypersensitivity, Delayed, Immunocompetence, Immunocompromised Host, Male, Middle Aged, Practice Guidelines as Topic, Skin Tests, T-Lymphocytes
Added March 30, 2020
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14 MeSH Terms
Antibiotic allergy testing improves antibiotic appropriateness in patients with cancer.
Trubiano JA, Grayson ML, Phillips EJ, Stewardson AJ, Thursky KA, Slavin MA
(2018) J Antimicrob Chemother 73: 3209-3211
MeSH Terms: Adult, Aged, Anti-Bacterial Agents, Clinical Laboratory Techniques, Drug Hypersensitivity, Female, Humans, Hypersensitivity, Delayed, Male, Middle Aged, Neoplasms, Penicillins, Prospective Studies
Added March 30, 2020
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Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice.
Peter JG, Lehloenya R, Dlamini S, Risma K, White KD, Konvinse KC, Phillips EJ
(2017) J Allergy Clin Immunol Pract 5: 547-563
MeSH Terms: Alleles, Animals, Drug Hypersensitivity, Genetic Predisposition to Disease, HLA Antigens, Humans, Hypersensitivity, Delayed, Immunoglobulin E, Risk, Skin, Stevens-Johnson Syndrome, T-Lymphocytes
Show Abstract · Added March 30, 2020
Most immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCARs) are an uncommon, potentially life-threatening, and challenging subgroup of IM-ADRs with diverse clinical phenotypes, mechanisms, and offending drugs. T-cell-mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis, although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short- and long-term morbidity/mortality and the potential need to treat ongoing comorbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive, diagnostic, treatment, and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying comorbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management.
Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Old dog begging for new tricks: current practices and future directions in the diagnosis of delayed antimicrobial hypersensitivity.
Konvinse KC, Phillips EJ, White KD, Trubiano JA
(2016) Curr Opin Infect Dis 29: 561-576
MeSH Terms: Anti-Bacterial Agents, Cross Reactions, Drug Hypersensitivity, Drug-Related Side Effects and Adverse Reactions, Enzyme-Linked Immunospot Assay, Forecasting, Humans, Hypersensitivity, Delayed, Metaphor, T-Lymphocytes
Show Abstract · Added March 30, 2020
PURPOSE OF REVIEW - Antimicrobials are a leading cause of severe T cell-mediated adverse drug reactions (ADRs). The purpose of this review is to address the current understanding of antimicrobial cross-reactivity and the ready availability of and evidence for in-vitro, in-vivo, and ex-vivo diagnostics for T cell-mediated ADRs.
RECENT FINDINGS - Recent literature has evaluated the efficacy of traditional antibiotic allergy management, including patch testing, skin prick testing, intradermal testing, and oral challenge. Although patch and intradermal testing are specific for the diagnosis of immune-mediated ADRs, they suffer from drug-specific limitations in sensitivity. The use of ex-vivo diagnostics, especially enzyme-linked immunospot, has been highlighted as a promising new approach to assigning causality. Knowledge of true rates of antimicrobial cross-reactivity aids empirical antibiotic choice in the setting of previous immune-mediated ADRs.
SUMMARY - In an era of increasing antimicrobial resistance and use of broad-spectrum antimicrobial therapy, ensuring patients are assigned the correct 'allergy label' is essential. Re-exposure to implicated antimicrobials, especially in the setting of severe adverse cutaneous reaction, is associated with significant morbidity and mortality. The process through which an antibiotic label gets assigned, acted on and maintained is still imprecise. Predicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines.
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Return to sender: the need to re-address patient antibiotic allergy labels in Australia and New Zealand.
Trubiano JA, Worth LJ, Urbancic K, Brown TM, Paterson DL, Australasian Society for Infectious Diseases Clinical Research Network, Lucas M, Australasian Society of Clinical Immunology and Allergy, Phillips E
(2016) Intern Med J 46: 1311-1317
MeSH Terms: Anti-Bacterial Agents, Australia, Clinical Competence, Cross Reactions, Demography, Drug Hypersensitivity, Health Knowledge, Attitudes, Practice, Humans, Hypersensitivity, Delayed, Hypersensitivity, Immediate, New Zealand, Pharmacists, Physicians, Referral and Consultation, Skin Tests
Show Abstract · Added March 30, 2020
BACKGROUND/AIM - Antibiotic allergies are frequently reported and have significant impacts upon appropriate prescribing and clinical outcomes. We surveyed infectious diseases physicians, allergists, clinical immunologists and hospital pharmacists to evaluate antibiotic allergy knowledge and service delivery in Australia and New Zealand.
METHODS - An online multi-choice questionnaire was developed and endorsed by representatives of the Australasian Society of Clinical Immunology and Allergy (ASCIA) and the Australasian Society of Infectious Diseases (ASID). The 37-item survey was distributed in April 2015 to members of ASCIA, ASID, the Society of Hospital Pharmacists of Australia and the Royal Australasian College of Physicians.
RESULTS - Of 277 respondents, 94% currently use or would utilise antibiotic allergy testing (AAT) and reported seeing up to 10 patients/week labelled as antibiotic-allergic. Forty-two per cent were not aware of or did not have AAT available. Most felt that AAT would aid antibiotic selection, antibiotic appropriateness and antimicrobial stewardship (79, 69 and 61% respectively). Patients with the histories of immediate hypersensitivity were more likely to be referred than those with delayed hypersensitivities (76 vs 41%, P = 0.0001). Lack of specialist physicians (20%) and personal experience (17%) were barriers to service delivery. A multidisciplinary approach was a preferred AAT model (53%). Knowledge gaps were identified, with the majority overestimating rates of penicillin/cephalosporin (78%), penicillin/carbapenem (57%) and penicillin/monobactam (39%) cross-reactivity.
CONCLUSIONS - A high burden of antibiotic allergy labelling and demand for AAT is complicated by a relative lack availability or awareness of AAT services in Australia and New Zealand. Antibiotic allergy education and deployment of AAT, accessible to community and hospital-based clinicians, may improve clinical decisions and reduce antibiotic allergy impacts. A collaborative approach involving infectious diseases physicians, pharmacists and allergists/immunologists is required.
© 2016 Royal Australasian College of Physicians.
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T cell-mediated hypersensitivity reactions to drugs.
Pavlos R, Mallal S, Ostrov D, Buus S, Metushi I, Peters B, Phillips E
(2015) Annu Rev Med 66: 439-54
MeSH Terms: Drug Hypersensitivity, Drug Hypersensitivity Syndrome, HLA Antigens, Humans, Hypersensitivity, Delayed, Stevens-Johnson Syndrome, T-Lymphocytes
Show Abstract · Added March 30, 2020
The immunological mechanisms driving delayed hypersensitivity reactions (HSRs) to drugs mediated by drug-reactive T lymphocytes are exemplified by several key examples and their human leukocyte antigen (HLA) associations: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02, allo-purinol and HLA-B*58:01, and both amoxicillin-clavulanate and nevirapine with multiple class I and II alleles. For HLA-restricted drug HSRs, specific class I and/or II HLA alleles are necessary but not sufficient for tissue specificity and the clinical syndrome. Several models have been proposed to explain the immunopathogenesis of severe T cell-mediated drug HSRs, and our increased understanding of the risk factors and mechanisms involved in the development of these reactions will further the development of sensitive and specific strategies for preclinical screening that will lead to safer and more cost-effective drug design.
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Inhibition of local immune responses by the frog-killing fungus Batrachochytrium dendrobatidis.
Fites JS, Reinert LK, Chappell TM, Rollins-Smith LA
(2014) Infect Immun 82: 4698-706
MeSH Terms: Adaptive Immunity, Animals, Chytridiomycota, Dermatomycoses, Female, Hypersensitivity, Delayed, Immunity, Innate, Phytohemagglutinins, Xenopus laevis
Show Abstract · Added February 12, 2015
Amphibians are suffering unprecedented global declines. A leading cause is the infectious disease chytridiomycosis caused by the chytrid fungus Batrachochytrium dendrobatidis. Chytridiomycosis is a skin disease which disrupts transport of essential ions leading to death. Soluble factors produced by B. dendrobatidis impair amphibian and mammalian lymphocytes in vitro, but previous studies have not shown the effects of these inhibitory factors in vivo. To demonstrate in vivo inhibition of immunity by B. dendrobatidis, a modified delayed-type-hypersensitivity (DTH) protocol was developed to induce innate and adaptive inflammatory swelling in the feet of Xenopus laevis by injection of killed bacteria or phytohemagglutinin (PHA). Compared to previous protocols for PHA injection in amphibians, this method induced up to 20-fold greater inflammatory swelling. Using this new protocol, we measured DTH responses induced by killed bacteria or PHA in the presence of B. dendrobatidis supernatants. Swelling induced by single injection of PHA or killed bacteria was not significantly affected by B. dendrobatidis supernatants. However, swelling caused by a secondary injection of PHA, was significantly reduced by B. dendrobatidis supernatants. As previously described in vitro, factors from B. dendrobatidis appear to inhibit lymphocyte-mediated inflammatory swelling but not swelling caused by an inducer of innate leukocytes. This suggests that B. dendrobatidis is capable of inhibiting lymphocytes in a localized response to prevent adaptive immune responses in the skin. The modified protocol used to induce inflammatory swelling in the present study may be more effective than previous methods to investigate amphibian immune competence, particularly in nonmodel species.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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9 MeSH Terms
Clindamycin skin testing has limited diagnostic potential.
Notman MJ, Phillips EJ, Knowles SR, Weber EA, Shear NH
(2005) Contact Dermatitis 53: 335-8
MeSH Terms: Administration, Oral, Adolescent, Adult, Aged, Anti-Bacterial Agents, Clindamycin, Drug Eruptions, Female, Humans, Hypersensitivity, Delayed, Injections, Intradermal, Male, Middle Aged, Predictive Value of Tests, Retrospective Studies, Sensitivity and Specificity, Skin Tests
Show Abstract · Added March 30, 2020
We examined the role of clindamycin prick and intradermal skin testing in a tertiary care clinic population. Experience with diagnostic modalities such as prick and intradermal testing has been limited with clindamycin. A retrospective chart review was conducted for patients with immunologic reactions temporally associated with clindamycin who were referred to the Drug Safety Clinic (Toronto, Ontario). A total of 31 patients were identified who had undergone prick and intradermal skin testing. All 31 negative immediate prick and intradermal tests were followed by a 150 mg oral dose of clindamycin. 10/31 (32%) subjects had significant reactions to the oral clindamycin provocation. 2 patients reported delayed reactions at the clindamycin intradermal test sites. Our experience suggests that prick and intradermal skin testing is not adequate in identifying patients with previous allergic reactions associated with clindamycin. Oral provocation tests can be used in patients with histories of clindamycin adverse reactions; however, it should be offered on a risk-benefit basis.
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Induction of specific T cell immunity in patients with prostate cancer by vaccination with PSA146-154 peptide.
Perambakam S, Hallmeyer S, Reddy S, Mahmud N, Bressler L, DeChristopher P, Mahmud D, Nunez R, Sosman JA, Peace DJ
(2006) Cancer Immunol Immunother 55: 1033-42
MeSH Terms: Aged, Aged, 80 and over, Amino Acid Sequence, Cancer Vaccines, Dendritic Cells, Epitopes, Humans, Hypersensitivity, Delayed, Immunity, Cellular, Immunotherapy, Active, Male, Middle Aged, Molecular Sequence Data, Peptide Fragments, Peptides, Prostate-Specific Antigen, Prostatic Neoplasms, T-Lymphocyte Subsets, T-Lymphocytes, Cytotoxic, Transplantation, Autologous
Show Abstract · Added March 5, 2014
T cell immunotherapy of prostate cancer (CaP) offers the potential for less toxic, more effective outcomes. A clinical trial was conducted in 28 patients with locally advanced or metastatic CaP to determine whether an HLA-A2 binding epitope of prostate-specific antigen, PSA146-154 (PSA-peptide), can induce specific T cell immunity. Patients were vaccinated either by intradermal injection of PSA-peptide and GM-CSF or by intravenous administration of autologous dendritic cells pulsed with PSA-peptide at weeks 1, 4 and 10. Delayed-type hypersensitivity (DTH) skin testing was performed at weeks 4, 14, 26 and 52. Fifty percent of the patients developed positive DTH responses to PSA-peptide. The size of the DTH induration progressively increased over time in the majority of responding patients. Skin biopsies from seven DTH-positive patients were available and T cells that developed in situ were also characterized. The phenotype of recovered T cells demonstrated variable proportions of CD4+CD8-, CD4-CD8+ and CD4+CD8+ T cell populations. Cytokine analysis of PSA-peptide stimulated T cells per bead array assay exhibited specific IFN-gamma and TNF-alpha response in six of seven patients. Specific IL-4 response was observed in five patients, while IL-10 response was detected in one patient. Purified CD4-CD8+ T cells isolated from four patients demonstrated specific cytolytic activity per chromium release assay. In conclusion, immunization with PSA-peptide induced specific T cell immunity in one-half of the patients with locally advanced and hormone-sensitive, metastatic CaP. DTH-derived T cells exhibited PSA-peptide-specific cytolytic activity and predominantly expressed a type-1 cytokine profile.
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20 MeSH Terms