Publications by authors named "Larry Borish"

141 Publications

Recent discoveries regarding the pathogenesis of chronic rhinosinusitis and their implications for future therapies.

Ann Allergy Asthma Immunol 2021 02;126(2):107-108

Department of Medicine and Microbiology, University of Virginia Health System, Charlottesville, Virginia.

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http://dx.doi.org/10.1016/j.anai.2020.11.006DOI Listing
February 2021

The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: A Work Group Report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.

J Allergy Clin Immunol 2021 Mar 9;147(3):827-844. Epub 2020 Dec 9.

Division of Allergy, Asthma, and Immunology, Scripps Clinic, San Diego, Calif.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and an intolerance to medications that inhibit the cycloxgenase-1 enzyme. Patients with AERD on average have more severe respiratory disease compared with patients with chronic rhinosinusitis with nasal polyps and/or asthma alone. Although patients with AERD traditionally develop significant upper and lower respiratory tract symptoms on ingestion of cycloxgenase-1 inhibitors, most of these same patients report clinical benefit when desensitized to aspirin and maintained on daily aspirin therapy. This Work Group Report provides a comprehensive review of aspirin challenges, aspirin desensitizations, and maintenance aspirin therapy in patients with AERD. Identification of appropriate candidates, indications and contraindications, medical and surgical optimization strategies, protocols, medical management during the desensitization, and recommendations for maintenance aspirin therapy following desensitization are reviewed. Also included is a summary of studies evaluating the clinical efficacy of aspirin therapy after desensitization as well as a discussion on the possible cellular and molecular mechanisms explaining how this therapy provides unique benefit to patients with AERD.
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http://dx.doi.org/10.1016/j.jaci.2020.10.043DOI Listing
March 2021

α-Gal on Crotalidae-polyvalent Fab antivenom (CroFab): Investigating the relevance to immediate hypersensitivity reactions.

J Allergy Clin Immunol Pract 2021 Feb 27;9(2):1015-1017.e1. Epub 2020 Oct 27.

Division of Allergy and Clinical Immunology, University of Virginia Health System, Charlottesville, Va. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870545PMC
February 2021

Biologics for the Treatment of Allergic Rhinitis, Chronic Rhinosinusitis, and Nasal Polyposis.

Immunol Allergy Clin North Am 2020 11 9;40(4):539-547. Epub 2020 Sep 9.

Department of Medicine, Asthma and Allergic Disease Center, University of Virginia Health Systems, Charlottesville, VA 22908-1355, USA; Department of Microbiology, Asthma and Allergic Disease Center, University of Virginia Health Systems, Charlottesville, VA 22908-1355, USA. Electronic address:

Allergic rhinitis (AR), most presentations of nasal polyposis (NP), and many presentations of chronic rhinosinusitis are type 2 disorders characterized by expression of interleukin (IL)-4, IL-5, and IL-13. Neutralization of IgE with anti-IgE (omalizumab) has proven efficacy in AR. Similarly, in addition to anti-IgE, blockade of IL-5/IL-5 (mepolizumab, reslizumab, benralizumab) and dual blockade of IL-4 and IL-13 with anti-IL-4R (dupilumab) have demonstrated efficacy in NP. However, these agents are expensive and future studies are essential to evaluate cost effectiveness in comparison with current medical and surgical therapies. This article reviews biologics as potential interventions in AR, chronic rhinosinusitis, and NP.
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http://dx.doi.org/10.1016/j.iac.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539135PMC
November 2020

Insights into how innocuous foods or proteins deserving of immune ignorance can become allergens.

Authors:
Larry Borish

J Clin Invest 2020 10;130(10):5118-5120

Allergic disorders include food allergy, allergic rhinitis, and certain forms of asthma resulting from the inappropriate development of immune responses to otherwise innocuous aeroallergens and foods. In this issue of the JCI, Thouvenot and Roitel et al. explore transcription infidelity as a mechanism that underlies the ability of these benign proteins to become allergens. Some foods and bioaerosols that produce allergies have RNA polymerase with a propensity to generate RNA gaps, thereby causing translational frameshifts. These frameshifts often create cationic carboxy-terminus residues that replace hydrophobic amino acids and have enhanced MHC binding, resulting in the tendency to provoke immune responses. IgE antibody responses initiated by these variant transcripts can later lead to IgE against the native molecule and also explain how anaphylaxis may occur in individuals who lacked specific IgE when tested using native protein reagents. This study has the potential to transform the diagnosis and treatment of allergic disorders.
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http://dx.doi.org/10.1172/JCI141950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524461PMC
October 2020

Bronchoalveolar lavage cytokine patterns in children with severe neutrophilic and paucigranulocytic asthma.

J Allergy Clin Immunol 2021 Feb 9;147(2):686-693.e3. Epub 2020 Jun 9.

Division of Allergy and Immunology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Va; Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Va; Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Va. Electronic address:

Background: Asthma is a complex heterogeneous disease occurring in adults and children that is characterized by distinct inflammatory patterns. While numerous studies have been performed in adults, little is known regarding the heterogeneity of severe asthma in children, particularly inflammatory signatures involving the air spaces.

Objective: We sought to determine the relationship of bronchoalveolar lavage (BAL) cytokine/chemokine expression patterns in children with severe therapy-resistant asthma stratified according to neutrophilic versus nonneutrophilic BAL inflammatory cell patterns.

Methods: Children with severe asthma with inadequate symptom control despite therapy underwent diagnostic bronchoscopy and BAL. Inflammatory cytokine/chemokine concentrations were determined using a multiplex protein bead assay.

Results: Analysis of BAL constituents with an unbiased clustering approach revealed distinct cytokine/chemokine patterns, and these aligned with pathways associated with type 2 innate lymphoid cells, monocytes, neutrophil trafficking, and T effector cells. All cytokines examined (n = 27) with 1 exception (vascular endothelial growth factor) were overexpressed with BAL neutrophilia compared with nonneutrophilic asthma, and this was confirmed in a cross-validation analysis. Cytokines specifically responsible for T17 (IL-17, IL-6, G-CSF) and T1 differentiation and expression (IL-12, TNF-α, IFN-γ) were enhanced in the neutrophilic cohorts. Neutrophilic groups were also characterized by higher prevalence of bacterial and viral pathogens; however, cytokine expression patterns manifested independently of pathogen expression.

Conclusions: The results demonstrate that children with refractory asthma and neutrophilic inflammation had a BAL cytokine pattern consistent with a mixed T17/T1/T2 response. In contrast, nonneutrophilic asthma presented independently of cytokine overexpression.
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http://dx.doi.org/10.1016/j.jaci.2020.05.039DOI Listing
February 2021

Our evolving understanding of the pathogenesis and presentations of chronic rhinosinusitis: Implications for therapeutic options.

Ann Allergy Asthma Immunol 2020 04;124(4):303-304

Department of Medicine, Asthma and Allergic Disease Center, University of Virginia Health Systems, Charlottesville, Virginia; Department of Microbiology, Asthma and Allergic Disease Center, University of Virginia Health Systems, Charlottesville, Virginia. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2020.02.005DOI Listing
April 2020

The Rationale for Multidisciplinary Management of Chronic Rhinosinusitis with Nasal Polyposis.

J Allergy Clin Immunol Pract 2020 05 12;8(5):1565-1566. Epub 2020 Mar 12.

Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic, Scottsdale, AZ. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.03.001DOI Listing
May 2020

Clinical Research Needs for the Management of Chronic Rhinosinusitis with Nasal Polyps in the New Era of Biologics: A National Institute of Allergy and Infectious Diseases Workshop.

J Allergy Clin Immunol Pract 2020 05 4;8(5):1532-1549.e1. Epub 2020 Mar 4.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address:

The development of biologics targeting various aspects of type 2 inflammation for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) will provide clinicians with powerful tools to help treat these patients. However, other therapies are also available, and positioning of biologics in a management algorithm will require comparative trials. In November 2019, the National Institute of Allergy and Infectious Diseases convened a workshop to consider potential future trial designs. Workshop participants represented a wide spectrum of clinical specialties, including otolaryngology, allergy, and pulmonary medicine, as well as expertise in CRSwNP pathophysiology and in trial methodology and statistics. The workshop discussed the current state of knowledge in CRSwNP and considered the advantages and disadvantages of various clinical trial or observational study designs and various clinical outcomes. The output from this workshop, which is presented in this report, will hopefully provide investigators with adequate information and ideas to design future studies and answer critical clinical questions. It will also help clinicians understand the current state of the management of CRSwNP and its gaps and be more able to interpret the new information to come.
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http://dx.doi.org/10.1016/j.jaip.2020.02.023DOI Listing
May 2020

Understanding the asthmatic response to an experimental rhinovirus infection: Exploring the effects of blocking IgE.

J Allergy Clin Immunol 2020 09 1;146(3):545-554. Epub 2020 Feb 1.

Department of Pediatric Infectious Diseases, University of Virginia, Charlottsville, Va.

Background: Rhinovirus frequently causes asthma exacerbations among children and young adults who are allergic. The interaction between allergen and rhinovirus-induced symptoms and inflammation over time is unclear.

Objective: Our aim was to compare the response to an experimental inoculation with rhinovirus-16 in allergic asthmatics with the response in healthy controls and to evaluate the effects of administrating omalizumab before and during the infection.

Methods: Two clinical trials were run in parallel. In one of these trials, the response to an experimental inoculation with rhinovirus-16 among asthmatics with high levels of total IgE was compared to the response in healthy controls. The other trial compared the effects of administering omalizumab versus placebo to asthmatics in a randomized, double-blind placebo-controlled investigation. The primary outcome for both trials compared lower respiratory tract symptoms (LRTSs) between study groups over the first 4 days of infection.

Results: Frequent comparisons of symptoms, lung function, and blood eosinophil counts revealed differences that were more pronounced among allergic asthmatics than among controls by days 2 and 3 after virus inoculation. Additionally, an augmentation of upper respiratory tract symptom scores and LRTS scores occurred among the atopic asthmatics versus the controls during the resolution of symptoms (P < .01 for upper respiratory symptom tract scores and P < .001 for LRTS scores). The beneficial effects of administering omalizumab on reducing LRTSs and improving lung function were strongest over the first 4 days.

Conclusions: LRTSs and blood eosinophil counts were augmented and lung function was reduced among allergic asthmatics early after rhinovirus inoculation but increased late in the infection during symptom resolution. The effect of administering omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection.
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http://dx.doi.org/10.1016/j.jaci.2020.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733370PMC
September 2020

T-bet+ Memory B Cells Link to Local Cross-Reactive IgG upon Human Rhinovirus Infection.

Cell Rep 2020 01;30(2):351-366.e7

Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Electronic address:

Human rhinoviruses cause the common cold and exacerbate chronic respiratory diseases. Although infection elicits neutralizing antibodies, these do not persist or cross-protect across multiple rhinovirus strains. To analyze rhinovirus-specific B cell responses in humans, we developed techniques using intact RV-A16 and RV-A39 for high-throughput high-dimensional single-cell analysis, with parallel assessment of antibody isotypes in an experimental infection model. Our approach identified T-bet+ B cells binding both viruses that account for ∼5% of CXCR5- memory B cells. These B cells infiltrate nasal tissue and expand in the blood after infection. Their rapid secretion of heterotypic immunoglobulin G (IgG) in vitro, but not IgA, matches the nasal antibody profile post-infection. By contrast, CXCR5+ memory B cells binding a single virus are clonally distinct, absent in nasal tissue, and secrete homotypic IgG and IgA, mirroring the systemic response. Temporal and spatial functions of dichotomous memory B cells might explain the ability to resolve infection while rendering the host susceptible to re-infection.
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http://dx.doi.org/10.1016/j.celrep.2019.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994188PMC
January 2020

Use of mepolizumab in adult patients with cystic fibrosis and an eosinophilic phenotype: case series.

Allergy Asthma Clin Immunol 2020 6;16. Epub 2020 Jan 6.

2Department of Medicine, University of Virginia School of Medicine, PO Box 800546, Charlottesville, VA 22908 USA.

Background: Cystic fibrosis (CF) is characterized by inflammation, progressive lung disease, and respiratory failure. Although the relationship is not well understood, patients with CF are thought to have a higher prevalence of asthma than the general population. CF Foundation (CFF) annual registry data in 2017 reported a prevalence of asthma in CF of 32%. It is difficult to differentiate asthma from CF given similarities in symptoms and reversible obstructive lung function in both diseases. However, a specific asthma phenotype (type 2 inflammatory signature), is often identified in CF patients and this would suggest potential responsiveness to biologics targeting this asthma phenotype. A type 2 inflammatory condition is defined by the presence of an interleukin (IL)-4, IL-5, IL-13 state and is suggested by the presence of an elevated total IgE, specific IgE sensitization, or an elevated absolute eosinophil count (AEC). In this manuscript we report the effects of using mepolizumab in patients with CF and type 2 inflammation.

Results: We present three patients with CF (63, 34 and 24 year of age) and personal history of asthma, who displayed significant eosinophilic inflammation and high total serum IgE concentrations (type 2 inflammation) who were treated with mepolizumab. All three patients were colonized with multiple organisms including and and tested positive for specific IgE to multiple allergens. We examined the effect of mepolizumab on patients' lung function (FEV1), blood markers of type 2 inflammation, systemic corticosteroid use and frequency of CF exacerbations. One patient had a substantial increase in lung function after starting mepolizumab and all three patients had a substantial benefit in regards to reduced oral CCS use. While none of the patients showed significant changes in the exacerbation rates there was markedly reduced requirements for oral CCS with exacerbations. In addition, mepolizumab had a positive effect on type 2 inflammatory markers, reducing markers of allergic inflammation in all 3 patients.

Conclusions: Mepolizumab appears to have a positive effect on clinical course in patients with CF presenting with a type 2 phenotype characterized by allergic sensitization and hyper-eosinophilia.
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http://dx.doi.org/10.1186/s13223-019-0397-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945791PMC
January 2020

Endotype-Phenotype Correlation in Chronic Rhinosinusitis: Is It Time to Think Beyond Polyposis?

J Allergy Clin Immunol Pract 2019 Nov - Dec;7(8):2821-2822

Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

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http://dx.doi.org/10.1016/j.jaip.2019.07.024DOI Listing
May 2020

Suppression of aspirin-mediated eosinophil activation by prostaglandin E: Relevance to aspirin and nonsteroidal anti-inflammatory drug hypersensitivity.

Ann Allergy Asthma Immunol 2019 11 9;123(5):503-506. Epub 2019 Sep 9.

Departments of Medicine, University of Virginia Health System, Charlottesville, Virginia.

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by severe, sometimes life-threatening reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). Mechanisms driving the disease include overproduction of leukotrienes and loss of anti-inflammatory prostaglandin E (PGE) production. Many cell types contribute to the disease; however, eosinophils are markedly elevated and are important drivers of pathologic findings.

Objective: To investigate the capacity of aspirin and NSAIDs to drive eosinophil activation and the ability of PGE to inhibit this activation.

Methods: Eosinophils were purified from blood of healthy individuals without AERD and stimulated with lysine aspirin, ketorolac, or sodium salicylate. The role of PGE in altering activation was determined by incubating eosinophils with increasing doses of PGE before lysine aspirin stimulation. Specific PGE receptor use was determined by incubating eosinophils with receptor agonists and antagonists before aspirin stimulation. Cysteinyl leukotrienes (CysLTs), leukotriene B (LTB), and eosinophil-derived neurotoxin (EDN) were quantified by enzyme-linked immunosorbent assay.

Results: Stimulation of eosinophils with lysine aspirin, ketorolac, or sodium salicylate resulted in secretion of CysLTs and LTB in the absence of EDN release. Low doses of PGE inhibited LTB and CysLT release, an effect lost at higher PGE concentrations. Use of butaprost, an EP receptor agonist, suppressed lysine aspirin stimulation. This mechanism was supported by blocking activity of the EP and EP receptors.

Conclusion: Eosinophils can be directly activated by NSAIDs via cyclooxygenase-independent pathways to produce CysLTs and LTB. This effect can be inhibited by PGE acting through the EP receptor. The recognized loss of EP receptor expression combined with low PGE levels explains in part the sensitivity to NSAIDs.
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http://dx.doi.org/10.1016/j.anai.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825585PMC
November 2019

Nasal polyposis and future risk of sinonasal malignancy.

J Allergy Clin Immunol 2019 10 28;144(4):933-934. Epub 2019 Aug 28.

Medicine and Microbiology, University of Virginia Health System, Charlottesville, Va. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.08.015DOI Listing
October 2019

Expression of IL-5 receptor alpha by murine and human lung neutrophils.

PLoS One 2019 15;14(8):e0221113. Epub 2019 Aug 15.

Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States of America.

The role of eosinophilia in atopic diseases, including asthma, is well established, as is the well-known role of IL-5 as a major eosinophilopoeitin and chemoattractant. Following influenza A virus infection of mice, type 2 innate lymphoid cells are recruited to the respiratory tract and produce large quantities of IL-5, which contributes to the recruitment of eosinophils into the infected lungs during the recovery phase of infection. We demonstrate here that while IL-5 is required for optimal recovery from influenza A virus infection in BALB/c and C57BL/6 mice, the protective effect of IL-5 is independent of eosinophils, suggesting an alternative cellular target. We describe the unexpected finding of IL-5 receptor alpha (CD125) expression on neutrophils infiltrating the inflamed mouse lungs, as well as on neutrophils at other anatomic sites. We extend this finding of neutrophil CD125 expression to humans, specifically to neutrophils found in the bronchoalveolar lavage fluid from the inflamed lungs of children with treatment-refractory asthma. We further demonstrate that the IL-5 receptor on neutrophils is capable of signal transduction. Our data provide further evidence that neutrophils can play a role bridging atopic type 2 and innate anti-microbial immunity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221113PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695150PMC
March 2020

Rhinovirus and Asthma Exacerbations.

Immunol Allergy Clin North Am 2019 08 15;39(3):335-344. Epub 2019 May 15.

Department of Medicine, University of Virginia Health Systems, MR4 Building Room 5041, 409 Lane Road, Charlottesville, VA 22903, USA; Department of Microbiology, University of Virginia Health Systems, MR4 Building Room 5041, 409 Lane Road, Charlottesville, VA 22903, USA; Carter Immunology Center, University of Virginia Health Systems, MR4 Building Room 5041, 409 Lane Road, Charlottesville, VA 22903, USA.

Rhinovirus (RV) is ubiquitous and typically causes only minor upper respiratory symptoms. However, especially in children and adolescent asthmatics, RV is responsible for most exacerbations. This ability of RV to drive exacerbations typically requires the concomitant presence of exposure to a bystander allergen. Susceptibility to RV-mediated exacerbations is also related to the genetic background of the host, which contributes to greater infectivity, more severe infections, altered immune responses, and to greater inflammation and loss of asthma control. Given these responses, there are several treatments available or being developed that should improve the control of exacerbations related to RV infection.
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http://dx.doi.org/10.1016/j.iac.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625523PMC
August 2019

Differential Expression of Extracellular Matrix Components in Nasal Polyp Endotypes.

Am J Rhinol Allergy 2019 Nov 25;33(6):665-670. Epub 2019 Jun 25.

Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, Virginia.

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http://dx.doi.org/10.1177/1945892419860634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843742PMC
November 2019

Low Serum IgG: A Novel Predictor of Virus-Induced Asthma Exacerbations?

J Allergy Clin Immunol Pract 2019 May - Jun;7(5):1514-1515

Division of Allergy, Asthma, Immunology, Department of Medicine, Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Va; Departments of Medicine and Microbiology, University of Virginia School of Medicine, Charlottesville, Va.

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http://dx.doi.org/10.1016/j.jaip.2019.03.003DOI Listing
May 2020

Aspirin-exacerbated Respiratory Disease: A Syndrome of Mast Cell-mediated PgD2 Overproduction.

Authors:
Larry Borish

Am J Respir Crit Care Med 2019 Sep;200(6):651-652

Professor of Medicine and MicrobiologyUniversity of Virginia Health SystemsCharlottesville, Virginia.

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http://dx.doi.org/10.1164/rccm.201904-0716EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775875PMC
September 2019

Nasal IgE production in allergic rhinitis: Impact of rhinovirus infection.

Clin Exp Allergy 2019 06 25;49(6):847-852. Epub 2019 Mar 25.

Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.

Background: Rhinovirus (RV) infections exacerbate asthma in part by enhancing an allergic state, and these exacerbations can be mitigated via administration of anti-IgE.

Objective: We investigated the presence of local IgE production in the nose of allergic and non-allergic subjects and assessed whether this was enhanced by RV.

Methods: Local production of specific IgE was determined by comparing ratios of specific to total IgE concentrations between nasal and serum samples. Our initial studies were performed in subjects presenting to the emergency department for allergic and non-allergic respiratory complaints. Subsequently, we investigated influences of experimental RV infection on nasal sIgE production in an allergic cohort.

Results: We found evidence of local sIgE production to Dermatophagoides pteronyssinus in 30.3% and to Blomia tropicalis in 14.6% of allergic subjects. None of the non-allergic subjects demonstrated local IgE. Subjects with active RV infection were more than twice as likely to have local sIgE (45% vs 14%), and subjects with local sIgE being produced were ~3 times more likely to be having an asthma exacerbation. Experimental RV infection was able to induce local sIgE production.

Conclusion: These studies confirm local IgE production in a large subset of allergic subjects and demonstrate that allergic asthmatics with local IgE are more likely to develop an asthma exacerbation when infected with RV. Our RV challenge studies demonstrate that at least some allergic asthmatics can be induced to secrete locally generated IgE in their nasal airway after RV infection.
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http://dx.doi.org/10.1111/cea.13372DOI Listing
June 2019

Lung Lavage Granulocyte Patterns and Clinical Phenotypes in Children with Severe, Therapy-Resistant Asthma.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):1803-1812.e10. Epub 2019 Jan 14.

Division of Allergy, Asthma, and Immunology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Va; Beirne Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, Va; Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Va.

Background: Children with severe asthma have frequent exacerbations despite guidelines-based treatment with high-dose corticosteroids. The importance of refractory lung inflammation and infectious species as factors contributing to poorly controlled asthma in children is poorly understood.

Objective: To identify prevalent granulocyte patterns and potential pathogens as targets for revised treatment, 126 children with severe asthma underwent clinically indicated bronchoscopy.

Methods: Diagnostic tests included bronchoalveolar lavage (BAL) for cell count and differential, bacterial and viral studies, spirometry, and measurements of blood eosinophils, total IgE, and allergen-specific IgE. Outcomes were compared among 4 BAL granulocyte patterns.

Results: Pauci-granulocytic BAL was the most prevalent granulocyte category (52%), and children with pauci-granulocytic BAL had less postbronchodilator airflow limitation, less blood eosinophilia, and less detection of BAL enterovirus compared with children with mixed granulocytic BAL. Children with isolated neutrophilia BAL were differentiated by less blood eosinophilia than those with mixed granulocytic BAL, but greater prevalence of potential bacterial pathogens compared with those with pauci-granulocytic BAL. Children with isolated eosinophilia BAL had features similar to those with mixed granulocytic BAL. Children with mixed granulocytic BAL took more maintenance prednisone, and had greater blood eosinophilia and allergen sensitization compared with those with pauci-granulocytic BAL.

Conclusions: In children with severe, therapy-resistant asthma, BAL granulocyte patterns and infectious species are associated with novel phenotypic features that can inform pathway-specific revisions in treatment. In 32% of children evaluated, BAL revealed corticosteroid-refractory eosinophilic infiltration amenable to anti-T2 biological therapies, and in 12%, a treatable bacterial pathogen.
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http://dx.doi.org/10.1016/j.jaip.2018.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612461PMC
September 2020

Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma.

Am J Respir Cell Mol Biol 2019 04;60(4):413-419

3 Division of Asthma Allergy and Immunology, and.

Asthma is associated with the overproduction of leukotrienes (LTs), including LTB4. Patients with severe asthma can be highly responsive to 5-lipoxygenase (5-LO) inhibition, which blocks production of both the cysteinyl LTs and LTB4. Production of LTB4 has traditionally been ascribed to neutrophils, mononuclear phagocytes, and epithelial cells, and acts as a chemoattractant for inflammatory cells associated with asthma. The source of LTB4 is unclear, especially in eosinophilic asthma. We speculated that the benefit of 5-LO inhibition could be mediated in part by inhibition of eosinophil-derived LTB4. LTB4 concentrations were assayed in BAL fluid from patients with severe asthma characterized by isolated neutrophilic, eosinophilic, and paucigranulocytic inflammation. Expression of LTA4 hydrolase (LTA4H) by airway eosinophils was determined by immunohistochemistry (IHC). Subsequently, peripheral blood eosinophils were activated and secreted LTB4 was quantified by enzyme immunoassay. Blood eosinophil LTA4H expression was determined by flow cytometry, qPCR, and IHC. LTB4 concentrations were elevated in BAL fluid from patients with severe asthma, including those with isolated eosinophilic inflammation, and these eosinophils displayed LTA4H via IHC. LTA4H expression by blood eosinophils was confirmed by flow cytometry, IHC, and qPCR. Robust LTB4 production by blood eosinophils was observed in response to some, but not all, stimuli. We demonstrated that eosinophils express LTA4H transcripts and protein, and can be stimulated to secrete LTB4. We speculate that in many patients with asthma, eosinophil-derived LTB4 is increased, and this may contribute to the efficacy of 5-LO inhibition.
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http://dx.doi.org/10.1165/rcmb.2018-0175OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444630PMC
April 2019

Asthma Yardstick Update: Practical recommendations for a sustained step-up in asthma therapy for poorly controlled asthma.

Ann Allergy Asthma Immunol 2018 12 30;121(6):660-661. Epub 2018 Aug 30.

Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, Virginia.

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http://dx.doi.org/10.1016/j.anai.2018.08.018DOI Listing
December 2018

Low Serum IgE Is a Sensitive and Specific Marker for Common Variable Immunodeficiency (CVID).

J Clin Immunol 2018 04 17;38(3):225-233. Epub 2018 Feb 17.

Department of Medicine, University of Virginia, Box 801355, Charlottesville, VA, 22908, USA.

Although small prior studies have suggested that IgE can be low in common variable immunodeficiency (CVID), the workup for patients with recurrent infections and suspected hypogammaglobulinemia does not include the routine measurement of serum IgE. We sought to test the hypothesis that low/undetectable serum IgE is characteristic of CVID by comparing the frequency of low/undetectable serum IgE in healthy controls and patients with CVID. We measured total serum IgE in a large multi-center cohort of patients with CVID (n = 354) and compared this to large population-based cohorts of children and adults. We further compared IgE levels in patients with CVID to those with other forms of humoral immunodeficiency, and in a subset, measured levels of allergen-specific serum IgE and IgG subclasses. Lastly, we evaluated for the presence of IgE in commercially available immunoglobulin replacement therapy (IgRT) products. An undetectable serum IgE (< 2 IU/ml) occurs in only 3.3% (95% CI, 1.9-5.7%) of the general population. In contrast, an undetectable IgE occurs in 75.6% (95% CI, 65.6-85.7%) of patients with CVID. Conversely, a high IgE (> 180 IU/ml) is very uncommon in CVID (0.3% of patients). IgE is > 2 IU/ml in 91.2% of patients with secondary hypogammaglobulinemia, and thus, an IgE < LLOD is suggestive of a primary humoral immunodeficiency. Allergen-specific IgE is not detectable in 96.5% of patients with CVID. Sufficient quantities of IgE to change the total serum IgE are not contained in IgRT. The IgG1/IgG4 ratio is increased in subjects with low IgE, regardless of whether they are controls or have CVID. These findings support the routine measurement of serum IgE in the workup of patients with hypogammaglobulinemia.
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http://dx.doi.org/10.1007/s10875-018-0476-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934300PMC
April 2018

Cytokine-targeting biologics for allergic diseases.

Ann Allergy Asthma Immunol 2018 04 2;120(4):376-381. Epub 2018 Feb 2.

Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, Virginia; Carter Center for Immunology Research, Charlottesville, Virginia. Electronic address:

Objective: Asthma and allergic diseases continue to increase in prevalence, creating a financial burden on the health care system and affecting the quality of life for those who have these diseases. Many intrinsic and extrinsic factors are involved in the initiation and maintenance of the allergic response. Cytokines are proteins with growth, differentiation, and activation functions that regulate and direct the nature of immune responses.

Data Sources: clinicaltrials.gov and PubMed.

Study Selections: Relevant clinical trials and recent basic science studies were chosen for discussion.

Results: Many cytokines have been implicated in the development and perpetuation of the allergic response. Biologics have been and are continuing to be developed that target these molecules for use in patients with asthma and atopic dermatitis where standard treatment options fail. The current state of cytokine-targeting therapies is discussed.

Conclusion: This review focused on cytokines involved in the allergic response with an emphasis on those for which therapies are being or have been developed.
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http://dx.doi.org/10.1016/j.anai.2018.01.009DOI Listing
April 2018

Serum IgE as an immunological marker to predict response to omalizumab treatment in symptomatic chronic urticaria.

J Allergy Clin Immunol Pract 2018 Jul - Aug;6(4):1386-1388.e1. Epub 2017 Nov 23.

Division of Allergy and Clinical Immunology, University of Virginia Health System, Charlottesville, Va. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2017.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966318PMC
November 2019

Chronic rhinosinusitis: Endotypes, biomarkers, and treatment response.

J Allergy Clin Immunol 2017 Dec 26;140(6):1499-1508. Epub 2017 Oct 26.

Departments of Medicine and Microbiology, University of Virginia Health Systems, Charlottesville, Va.

It is increasingly recognized that chronic rhinosinusitis (CRS) comprises a spectrum of different diseases with distinct clinical presentations and pathogenic mechanisms. Defining the distinct phenotypes and endotypes of CRS affects prognosis and, most importantly, is necessary as the basis for making therapeutic decisions. The need for individualized definitions of pathogenic mechanisms before initiating therapy extends to virtually all therapeutic considerations. This is clearly crucial with antibiotics, where, barring an influence from their off-target anti-inflammatory pharmacologic effects, an understanding of the role of the individual biome predicts likelihood of therapeutic benefit. However, this need for identifying individual phenotypes and endotypes also extends to the agent that is currently considered the mainstay of treatment of CRS, specifically glucocorticoids. As with asthma, it is recognized that a large minority of patients with CRS have a steroid-resistant phenotype, identification of which will preclude use of these agents with their potential side effects. Identification of endotypes is also becoming increasingly imperative because targeted biotherapeutic agents, such as anti-IgE and anti-cytokine antibodies, are becoming available. These agents are likely to benefit patients in whom the targeted mediator is not only expressed but demonstrably driving a central mechanism in that patient. In summary, the treatment of CRS is at an exciting crossroad. On the positive side, numerous therapeutics are in development that seem likely to have a positive effect in our patients with this condition. The challenge is that these therapies will require targeted individualized treatments based on identifying subjects with the relevant endotype.
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http://dx.doi.org/10.1016/j.jaci.2017.10.006DOI Listing
December 2017