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A Rapid Allele-Specific Assay for HLA-A*32:01 to Identify Patients at Risk for Vancomycin-Induced Drug Reaction with Eosinophilia and Systemic Symptoms.
Rwandamuriye FX, Chopra A, Konvinse KC, Choo L, Trubiano JA, Shaffer CM, Watson M, Mallal SA, Phillips EJ
(2019) J Mol Diagn 21: 782-789
MeSH Terms: Alleles, Anti-Bacterial Agents, Base Sequence, Drug Hypersensitivity Syndrome, Eosinophilia, Genetic Testing, HLA-A Antigens, Humans, Polymerase Chain Reaction, Sequence Homology, Vancomycin
Show Abstract · Added March 30, 2020
Human leukocyte antigen (HLA) alleles have been implicated as risk factors for immune-mediated adverse drug reactions. The authors recently reported a strong association between HLA-A*32:01 and vancomycin-induced drug reaction with eosinophilia and systemic symptoms. Identification of individuals with the risk allele before or shortly after the initiation of vancomycin therapy is of great clinical importance to prevent morbidity and mortality, and improve drug safety and antibiotic treatment options. A prerequisite to the success of pharmacogenetic screening tests is the development of simple, robust, cost-effective single HLA allele test that can be implemented in routine diagnostic laboratories. In this study, the authors developed a simple, real-time allele-specific PCR for typing the HLA-A*32:01 allele. Four-hundred and fifty-eight DNA samples including 30 HLA-A*32:01-positive samples were typed by allele-specific PCR. Compared with American Society for Histocompatibility and Immunogenetics-accredited, sequence-based, high-resolution, full-allelic HLA typing, this assay demonstrates 100% accuracy, 100% sensitivity (95% CI, 88.43% to 100%), and 100% specificity (95% CI, 99.14% to 100%). The lowest limit of detection of this assay using PowerUp SYBR Green is 10 ng of template DNA. The assay demonstrates a sensitivity and specificity to differentiate the HLA-A*32:01 allele from closely related non-HLA-A*32 alleles and may be used in clinical settings to identify individuals with the risk allele before or during the course of vancomycin therapy.
Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
The Innate Immune Protein S100A9 Protects from T-Helper Cell Type 2-mediated Allergic Airway Inflammation.
Palmer LD, Maloney KN, Boyd KL, Goleniewska AK, Toki S, Maxwell CN, Chazin WJ, Peebles RS, Newcomb DC, Skaar EP
(2019) Am J Respir Cell Mol Biol 61: 459-468
MeSH Terms: Adaptive Immunity, Allergens, Alternaria, Alveolitis, Extrinsic Allergic, Animals, Bronchial Hyperreactivity, Bronchoalveolar Lavage Fluid, Calgranulin A, Calgranulin B, Cytokines, Forkhead Transcription Factors, Immunoglobulin E, Inflammation, Leukocyte L1 Antigen Complex, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pulmonary Eosinophilia, Specific Pathogen-Free Organisms, T-Lymphocytes, Regulatory, Th2 Cells
Show Abstract · Added April 7, 2019
Calprotectin is a heterodimer of the proteins S100A8 and S100A9, and it is an abundant innate immune protein associated with inflammation. In humans, calprotectin transcription and protein abundance are associated with asthma and disease severity. However, mechanistic studies in experimental asthma models have been inconclusive, identifying both protective and pathogenic effects of calprotectin. To clarify the role of calprotectin in asthma, calprotectin-deficient and wild-type (WT) C57BL/6 mice were compared in a murine model of allergic airway inflammation. Mice were intranasally challenged with extracts of the clinically relevant allergen, (Alt Ext), or PBS every third day over 9 days. On Day 10, BAL fluid and lung tissue homogenates were harvested and allergic airway inflammation was assessed. Alt Ext challenge induced release of S100A8/S100A9 to the alveolar space and increased protein expression in the alveolar epithelium of WT mice. Compared with WT mice, mice displayed significantly enhanced allergic airway inflammation, including production of IL-13, CCL11, CCL24, serum IgE, eosinophil recruitment, and airway resistance and elastance. In response to Alt Ext, mice accumulated significantly more IL-13IL-5CD4 T-helper type 2 cells. mice also accumulated a significantly lower proportion of CD4 T regulatory (Treg) cells in the lung that had significantly lower expression of CD25. Calprotectin enhanced WT Treg cell suppressive activity . Therefore, this study identifies a role for the innate immune protein, S100A9, in protection from CD4 T-helper type 2 cell hyperinflammation in response to Alt Ext. This protection is mediated, at least in part, by CD4 Treg cell function.
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23 MeSH Terms
Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell cytokine production in vivo.
Toki S, Goleniewska K, Reiss S, Zhang J, Bloodworth MH, Stier MT, Zhou W, Newcomb DC, Ware LB, Stanwood GD, Galli A, Boyd KL, Niswender KD, Peebles RS
(2018) J Allergy Clin Immunol 142: 1515-1528.e8
MeSH Terms: Allergens, Alternaria, Animals, Asthma, Cytokines, Dermatophagoides pteronyssinus, Eosinophilia, Female, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Immunity, Innate, Interleukin-33, Lung, Lymphocytes, Mice, Inbred BALB C, Mice, Transgenic, Mucus, Signal Transduction
Show Abstract · Added April 10, 2018
BACKGROUND - IL-33 is one of the most consistently associated gene candidates for asthma identified by using a genome-wide association study. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type 2 cytokine production from both group 2 innate lymphoid cells (ILC2s) and T2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells.
OBJECTIVE - We sought to determine the effect of glucagon-like peptide 1 receptor (GLP-1R) signaling on aeroallergen-induced airway IL-33 production and release and on innate type 2 airway inflammation.
METHODS - BALB/c mice were challenged intranasally with Alternaria extract for 4 consecutive days. GLP-1R agonist or vehicle was administered starting either 2 days before the first Alternaria extract challenge or 1 day after the first Alternaria extract challenge.
RESULTS - GLP-1R agonist treatment starting 2 days before the first Alternaria extract challenge decreased IL-33 release in the bronchoalveolar lavage fluid and dual oxidase 1 (Duox1) mRNA expression 1 hour after the first Alternaria extract challenge and IL-33 expression in lung epithelial cells 24 hours after the last Alternaria extract challenge. Furthermore, GLP-1R agonist significantly decreased the number of ILC2s expressing IL-5 and IL-13, lung protein expression of type 2 cytokines and chemokines, the number of perivascular eosinophils, mucus production, and airway responsiveness compared with vehicle treatment. GLP-1R agonist treatment starting 1 day after the first Alternaria extract challenge also significantly decreased eosinophilia and type 2 cytokine and chemokine expression in the airway after 4 days of Alternaria extract challenge.
CONCLUSION - These results reveal that GLP-1R signaling might be a therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria.
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Eosinophilic Laryngitis in Children with Aerodigestive Dysfunction.
Yawn RJ, Acra S, Goudy SL, Flores R, Wootten CT
(2015) Otolaryngol Head Neck Surg 153: 124-9
MeSH Terms: Adolescent, Child, Child, Preschool, Chronic Disease, Digestive System Diseases, Eosinophilia, Eosinophilic Esophagitis, Female, Humans, Infant, Laryngitis, Male, Respiration Disorders, Retrospective Studies, Risk Factors
Show Abstract · Added October 8, 2015
OBJECTIVE - To describe the presence of laryngeal eosinophils and associated symptomatology in patients with aerodigestive dysfunction.
STUDY DESIGN - Case series with chart review.
SETTING - Single tertiary pediatric referral center.
SUBJECTS - Eighty-one consecutive pediatric patients referred to a multidisciplinary aerodigestive clinic with upper airway concerns.
METHODS - Microlaryngoscopy and posterior arytenoid biopsy, flexible bronchoscopy, esophagogastroduodenoscopy and esophageal biopsy, and impedance probe testing were performed as indicated by clinical symptoms. Positive versus negative posterior arytenoid biopsy for eosinophils and the presence or absence of concomitant histopathological laryngitis and/or esophagitis were measured.
RESULTS - Nine of 81 (11%) patients had positive laryngeal biopsy for eosinophils (range, 1-29 eosinophils/high-powered field [HPF]). Three of these 9 patients also had concurrent biopsy-proven eosinophilic esophagitis, while 8 of 81 total patients had biopsy-proven eosinophilic esophagitis. The frequency of biopsy-proven eosinophilic esophagitis was higher in patients with posterior arytenoid eosinophils versus patients without laryngeal eosinophils (33% versus 6.9%, P = .0408).
CONCLUSIONS - Eosinophilic inflammation in the larynx has not been described in children with complex aerodigestive complaints. Posterior arytenoid eosinophils may serve as a marker of chronic laryngeal inflammation in children with aerodigestive dysfunction, although their exact role in this inflammation remains unclear. In our population, >15 eosinophils/HPF within posterior arytenoid biopsies was associated with concomitant eosinophilic esophagitis.
© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.
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15 MeSH Terms
Endoscopic Mucosal Impedance Measurements Correlate With Eosinophilia and Dilation of Intercellular Spaces in Patients With Eosinophilic Esophagitis.
Katzka DA, Ravi K, Geno DM, Smyrk TC, Iyer PG, Alexander JA, Mabary JE, Camilleri M, Vaezi MF
(2015) Clin Gastroenterol Hepatol 13: 1242-1248.e1
MeSH Terms: Adolescent, Adult, Animals, Electric Impedance, Endoscopy, Eosinophilia, Eosinophilic Esophagitis, Extracellular Space, Female, Histocytochemistry, Humans, Male, Middle Aged, Mucous Membrane, Young Adult
Show Abstract · Added September 28, 2015
BACKGROUND & AIMS - Penetration of the esophageal epithelium by food antigens is an early event in the pathogenesis of eosinophilic esophagitis (EoE), but the precise relationship among eosinophilia, dilated intercellular spaces (DIS), and decreased barrier function is unclear. We investigated the correlation between site-specific mucosal impedance (MI) measurements of ion flux and esophageal histology, and whether MI measurements can be used to distinguish between patients with active and inactive EoE.
METHODS - MI was measured (in Ω) in 10 patients with active EoE (>15 eosinophils [eos]/high-power field [HPF]) and in 10 with inactive EoE (<15 eos/HPF, as a result of treatment), and mucosal biopsy specimens were collected from 4 esophageal sites (2, 5, 10, and 15 cm above the Z-line). MI also was measured in 10 individuals without esophageal symptoms (controls). MI measurements, eos/HPF, and DIS grade were compared among patients with EoE and controls.
RESULTS - The esophageal MI values were significantly lower in patients with active EoE (1909 Ω) compared with inactive EoE (4349 Ω) or controls (5530 Ω) (P < .001). Biopsy specimens from 4 patients with active EoE contained fewer than 15 eos/HPF and lower-grade DIS than in patients with active disease. There were significant inverse correlations between MI and eos/HPF (rs = -.584), as well as between MI and DIS (rs = -.531; P < .001). The MI cut-off value of 2300 Ω identified patients with active EoE with 90% sensitivity and 91% specificity, and high-grade DIS with 89% sensitivity and 82% specificity.
CONCLUSIONS - In patients with EoE, eosinophilia and DIS correlate with MI measurements of ion flux. Endoscopic MI measurement in the esophagus is safe and easy to perform, and can be used to assess activity of diseases such as EoE.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms
A mouse model for Betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant.
Agnihothram S, Yount BL, Donaldson EF, Huynh J, Menachery VD, Gralinski LE, Graham RL, Becker MM, Tomar S, Scobey TD, Osswald HL, Whitmore A, Gopal R, Ghosh AK, Mesecar A, Zambon M, Heise M, Denison MR, Baric RS
(2014) mBio 5: e00047-14
MeSH Terms: Animals, Chiroptera, Coronavirus, Coronavirus Infections, Disease Models, Animal, Drug Carriers, Encephalitis Virus, Venezuelan Equine, Eosinophilia, Genetic Vectors, Mice, Mice, Inbred BALB C, Respiratory System, Vaccines, Synthetic, Viral Vaccines
Show Abstract · Added February 19, 2015
Cross-species transmission of zoonotic coronaviruses (CoVs) can result in pandemic disease outbreaks. Middle East respiratory syndrome CoV (MERS-CoV), identified in 2012, has caused 182 cases to date, with ~43% mortality, and no small animal model has been reported. MERS-CoV and Pipistrellus bat coronavirus (BtCoV) strain HKU5 of Betacoronavirus (β-CoV) subgroup 2c share >65% identity at the amino acid level in several regions, including nonstructural protein 5 (nsp5) and the nucleocapsid (N) protein, which are significant drug and vaccine targets. BtCoV HKU5 has been described in silico but has not been shown to replicate in culture, thus hampering drug and vaccine studies against subgroup 2c β-CoVs. We report the synthetic reconstruction and testing of BtCoV HKU5 containing the severe acute respiratory syndrome (SARS)-CoV spike (S) glycoprotein ectodomain (BtCoV HKU5-SE). This virus replicates efficiently in cell culture and in young and aged mice, where the virus targets airway and alveolar epithelial cells. Unlike some subgroup 2b SARS-CoV vaccines that elicit a strong eosinophilia following challenge, we demonstrate that BtCoV HKU5 and MERS-CoV N-expressing Venezuelan equine encephalitis virus replicon particle (VRP) vaccines do not cause extensive eosinophilia following BtCoV HKU5-SE challenge. Passage of BtCoV HKU5-SE in young mice resulted in enhanced virulence, causing 20% weight loss, diffuse alveolar damage, and hyaline membrane formation in aged mice. Passaged virus was characterized by mutations in the nsp13, nsp14, open reading frame 5 (ORF5) and M genes. Finally, we identified an inhibitor active against the nsp5 proteases of subgroup 2c β-CoVs. Synthetic-genome platforms capable of reconstituting emerging zoonotic viral pathogens or their phylogenetic relatives provide new strategies for identifying broad-based therapeutics, evaluating vaccine outcomes, and studying viral pathogenesis. IMPORTANCE The 2012 outbreak of MERS-CoV raises the specter of another global epidemic, similar to the 2003 SARS-CoV epidemic. MERS-CoV is related to BtCoV HKU5 in target regions that are essential for drug and vaccine testing. Because no small animal model exists to evaluate MERS-CoV pathogenesis or to test vaccines, we constructed a recombinant BtCoV HKU5 that expressed a region of the SARS-CoV spike (S) glycoprotein, thereby allowing the recombinant virus to grow in cell culture and in mice. We show that this recombinant virus targets airway epithelial cells and causes disease in aged mice. We use this platform to (i) identify a broad-spectrum antiviral that can potentially inhibit viruses closely related to MERS-CoV, (ii) demonstrate the absence of increased eosinophilic immune pathology for MERS-CoV N protein-based vaccines, and (iii) mouse adapt this virus to identify viral genetic determinants of cross-species transmission and virulence. This study holds significance as a strategy to control newly emerging viruses.
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14 MeSH Terms
Successful re-exposure to clozapine after eosinophilia and clinically suspected myocarditis.
Granja-Ingram NM, James J, Clark N, Stovall J, Heckers S
(2013) Braz J Psychiatry 35: 95-6
MeSH Terms: Antipsychotic Agents, Clozapine, Eosinophilia, Humans, Male, Myocarditis, Schizophrenia, Paranoid, Time Factors, Treatment Outcome, Young Adult
Added February 12, 2015
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10 MeSH Terms
Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation.
Liu T, Laidlaw TM, Feng C, Xing W, Shen S, Milne GL, Boyce JA
(2012) Proc Natl Acad Sci U S A 109: 12692-7
MeSH Terms: Allergens, Animals, Antigens, Dermatophagoides, Asthma, Dinoprostone, Intercellular Adhesion Molecule-1, Intramolecular Oxidoreductases, Male, Mice, Mice, Knockout, Pneumonia, Prostaglandin-E Synthases, Pulmonary Eosinophilia, Receptors, Prostaglandin E, EP1 Subtype, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Thromboxane, Signal Transduction, Thromboxane A2, Up-Regulation
Show Abstract · Added March 26, 2014
Prostaglandin E(2) (PGE(2)) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE(2) generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE(2)-deficient ptges(-/-) mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smooth-muscle hyperplasia compared with PGE(2)-sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE(2) deficiency depend on thromboxane A(2) and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges(-/-) mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP)(1) and EP(2) receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE(2) deficiency. Thus, PGE(2) controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.
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19 MeSH Terms
Drug hypersensitivity: pharmacogenetics and clinical syndromes.
Phillips EJ, Chung WH, Mockenhaupt M, Roujeau JC, Mallal SA
(2011) J Allergy Clin Immunol 127: S60-6
MeSH Terms: Anticonvulsants, Clinical Trials as Topic, Drug Hypersensitivity, Enzyme Inhibitors, Eosinophilia, Female, Genetic Testing, HLA-B Antigens, Humans, Male, Skin Diseases
Show Abstract · Added March 30, 2020
Severe cutaneous adverse reactions include syndromes such as drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). An important advance has been the discovery of associations between HLA alleles and many of these syndromes, including abacavir-associated hypersensitivity reaction, allopurinol-associated DRESS/DIHS and SJS/TEN, and SJS/TEN associated with aromatic amine anticonvulsants. These HLA associations have created the promise for prevention through screening and have additionally shed further light on the immunopathogenesis of severe cutaneous adverse reactions. The rollout of HLA-B∗5701 into routine clinical practice as a genetic screening test to prevent abacavir hypersensitivity provides a translational roadmap for other drugs. Numerous hurdles exist in the widespread translation of several other drugs, such as carbamazepine, in which the positive predictive value of HLA-B∗1502 is low and the negative predictive value of HLA-B∗1502 for SJS/TEN might not be 100% in all ethnic groups. International collaborative consortia have been formed with the goal of developing phenotypic standardization and undertaking HLA and genome-wide analyses in diverse populations with these syndromes.
Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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MeSH Terms
Peripheral blood eosinophilia as a clue to the diagnosis of an occult Coccidioides infection.
Simons CM, Stratton CW, Kim AS
(2011) Hum Pathol 42: 449-53
MeSH Terms: Aged, Antifungal Agents, Antigens, Fungal, Coccidioides, Coccidioidomycosis, DNA, Fungal, Eosinophilia, Fluconazole, Humans, Lung Diseases, Fungal, Male, Radiography, Thoracic, Treatment Outcome
Show Abstract · Added May 28, 2014
A marked peripheral blood eosinophilia is an uncommon finding in a complete blood count (CBC). According to Wardlaw and Kay (Eosinophils and Their Disorders. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, editors. Williams Hematology. 6(th) ed. New York: McGraw-Hill, 2001. p. 790-93), the most common causes are infection by helminthic parasites, atopic disease, and, less commonly, primary hypereosinophilic syndromes. Therefore, when eosinophilia is seen in a CBC, it can provide an important clue to the correct diagnosis. We present a case of a patient with a finding of pulmonary nodules in the setting of cancer and a CBC finding of profound peripheral blood eosinophilia. As a result of the high level of clinical suspicion for Coccidioides infection due in part to the eosinophilia, adequate steps were taken in the clinical laboratory not only to correctly diagnosis the patient, but also to protect the laboratory staff from work-related exposure to this easily aerosolizable infectious agent.
Copyright © 2011 Elsevier Inc. All rights reserved.
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13 MeSH Terms