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1.  The past, present, and future of monoclonal antibodies to IL-5 and eosinophilic asthma: a review 
Asthma is a heterogeneous syndrome that might be better described as a constellation of phenotypes or endotypes, each with distinct cellular and molecular mechanisms, rather than as a singular disease. One of these phenotypes is eosinophilic asthma. As the development of eosinophilic inflammation is categorically dependent on the biological activity of Interleukin (IL)-5, IL-5 antagonism became an obvious target for therapy in this phenotype. Early trials of monoclonal antibodies targeting the biological activity of IL-5, including reslizumab, mepolizumab, and benralizumab, were performed on asthmatics with no concern for evidence of eosinophilia. These trials were largely unsuccessful. However, during these trials, researchers recognized the need to quantify eosinophilia in asthma subjects in order to identify those asthmatics in whom these medications would be more likely to improve symptoms and lung function. Using biomarkers, such as sputum and blood eosinophilia, recent studies of these medications have shown improvements in blood and sputum eosinophilia, forced expiratory volume in 1 second, and quality of life assessments as well as reducing occurrences of exacerbations. Moving forward, better and less invasive biomarkers of eosinophilia are necessary to ensure that the correct patients are chosen to receive these medications to receive maximal benefit.
PMCID: PMC4639549  PMID: 26604804
eosinophilic asthma; reslizumab; mepolizumab; benralizumab; IL-5; eosinophils
3.  Biological Effects of Leukotriene E4 on Eosinophils 
Studies demonstrate the existence of novel receptors for cysteinyl leukotrienes (CysLTs) that are responsive to leukotriene (LT) E4 and might be pathogenic in aspirin-exacerbated respiratory disease (AERD) asthma. Given the eosinophilic infiltration in this disorder, we investigated eosinophil expression of P2Y12 and gpr99 and their capacity to respond to LTE4. Receptor transcript expression was investigated via quantitative PCR and surface protein expression via flow cytometry. We investigated LTE4 influences on eosinophils including Ca+2 flux, cAMP induction, modulation of adhesion molecule expression, apoptosis and degranulation. Eosinophils displayed both transcript and surface protein expression of P2Y12 and gpr99. We could not find evidence of LTE4 activation of eosinophils, however, LTE4 induced cAMP expression, and preincubation of eosinophils with LTE4 inhibited degranulation. Even though eosinophils are an important source of CysLTs in AERD, eosinophils are not themselves the pro-inflammatory biological target and, in contrast, LTE4 via cAMP primarily elicits anti-inflammatory responses.
PMCID: PMC4127125  PMID: 24768603
aspirin-exacerbated respiratory disease; cysteinyl leukotrienes; eosinophils; calcium; cAMP
4.  Aspirin Activation of Eosinophils and Mast Cells: Implications in the Pathogenesis of Aspirin-Exacerbated Respiratory Disease 
Reactions to aspirin and non-steroidal anti-inflammatory drugs in patients with aspirin-exacerbated respiratory disease (AERD) are triggered when constraints upon activated eosinophils, normally supplied by PGE2, are removed secondary to cyclooxygenase-1 inhibition. However, the mechanism driving the concomitant cellular activation is unknown. We investigated the capacity of aspirin itself to provide this activation signal. Eosinophils were enriched from peripheral blood samples and activated with lysine ASA (LysASA). Parallel samples were stimulated with related non-steroidal anti-inflammatory drugs. Activation was evaluated as Ca+2 flux, secretion of cysteinyl leukotrienes (CysLT), and eosinophil derived neurotoxin (EDN) release. CD34+ progenitor-derived mast cells were also used to test the influence of aspirin on human mast cells with measurements of Ca+2 flux and PGD2 release. LysASA induced Ca+2 fluxes and EDN release, but not CysLT secretion from circulating eosinophils. There was no difference in the sensitivity or extent of activation between AERD and control subjects and sodium salicylate was without effect. Like eosinophils, aspirin was able to activate human mast cells directly through Ca+2 flux and PGD2 release. AERD is associated with eosinophils maturing locally in a high interferon (IFN)-γ milieu. As such, in additional studies, eosinophil progenitors were differentiated in the presence of IFN-γ prior to activation with aspirin. Eosinophils matured in the presence of IFN-γ displayed robust secretion of both EDN and CysLTs. These studies identify aspirin as the trigger of eosinophil and mast cell activation in AERD, acting in synergy with its ability to release cells from the anti-inflammatory constraints of PGE2.
PMCID: PMC4065844  PMID: 24890720
eosinophil; aspirin exacerbated respiratory disease; leukotriene; cyclooxygenase; mast cell
5.  Case Fatality and Population Mortality Associated with Anaphylaxis in the United States 
Anaphylaxis is a serious allergic reaction that may cause death; however, the actual risk of death is unclear.
To estimate the case fatality rate (CFR) among hospitalizations or emergency department (ED) presentations for anaphylaxis and the mortality rate associated with anaphylaxis for the general population.
This was a population-based epidemiologic study using 3 national databases: Nationwide Inpatient Sample (NIS, 1999-2009), Nationwide Emergency Department Sample (NEDS, 2006-2009), and Multiple Cause of Death Data (MCDD, 1999-2009). Sources for these databases are hospital, ED discharge records and death certificates, respectively.
CFRs were between 0.25% and 0.33% among hospitalizations or ED presentations with anaphylaxis as the principal diagnosis (NIS+NEDS, 2006-2009). These rates represent 63 to 99 deaths per year in the United States, approximately 77% of which occurred in hospitalized patients. Rate of anaphylaxis hospitalizations rose from 21.0 to 25.1 per million population between 1999 and 2009 (annual percent change 2.23%; 95% CI: 1.52%–2.94%), contrasting with a declining CFR among hospitalizations (annual percent change –2.35%; 95% CI: –4.98% to 0.34%). Overall mortality rates ranged from 0.63 to 0.76 per million population (186 to 225 deaths per year, MCDD), and appeared stable in the last decade (annual percent change: –0.31%; 95% CI, –1.54% to 0.93%).
From 2006 to 2009, the overwhelming majority of hospitalizations or ED presentations for anaphylaxis did not result in death, with an average CFR of 0.3%. Anaphylaxis-related hospitalizations rose steadily in the last decade (1999-2009), but this increase was offset by the declining CFR among those hospitalized; both inpatient and overall mortality rates associated with anaphylaxis appeared stable and were well under 1 per million population. Although anaphylactic reactions are potentially life threatening, the probability of dying is actually very low. With the prevalence of anaphylaxis on the rise, practitioners need to stay vigilant and follow the treatment guidelines to further reduce anaphylaxis-related deaths.
PMCID: PMC3972293  PMID: 24332862
anaphylaxis; mortality; case fatality; epidemiology; hospitalization; emergency department presentation; death certificate
6.  Comparison of Viral Load in Individuals with and without Asthma during Infections with Rhinovirus 
Rationale: Most virus-induced attacks of asthma are caused by rhinoviruses (RVs).
Objectives: To determine whether people with asthma are susceptible to an increased viral load during RV infection.
Methods: Seventy-four children (4–18 yr old) were enrolled; 28 with wheezing, 32 with acute rhinitis, and 14 without respiratory tract symptoms. Nasal washes were evaluated using quantitative polymerase chain reaction for RV to judge viral load along with gene sequencing to identify strains of RV. Soluble intercellular adhesion molecule-1, IFN-λ1, and eosinophil cationic protein in nasal washes, along with blood eosinophil counts and total and allergen-specific IgE in sera, were also evaluated. Similar assessments were done in 24 young adults (16 with asthma, 8 without) who participated in an experimental challenge with RV (serotype 16).
Measurements and Main Results: Fifty-seven percent of wheezing children and 56% with acute rhinitis had nasal washes testing positive for RV. The geometric mean of viral loads by quantitative polymerase chain reaction in washes from wheezing children was 2.8-fold lower, but did not differ significantly from children with rhinitis (7,718 and 21,612 copies of viral RNA per microliter nasal wash, respectively; P = 0.48). The odds for wheezing were increased if children who tested positive for RV were sensitized to one or more allergens (odds ratio, 3.9; P = 0.02). Similarly, neither peak nor cumulative viral loads differed significantly in washes from adults with asthma compared with those without asthma during the experimental RV challenge.
Conclusions: During acute symptoms, children infected with RV enrolled for wheezing or acute rhinitis had similar viral loads in their nasal washes, as did adults with and without asthma infected with RV-16 experimentally.
PMCID: PMC3977713  PMID: 24471509
asthma; intercellular adhesion molecule-1; quantitative polymerase chain reaction; rhinitis; rhinovirus
7.  Immune Surveillance by Rhinovirus-Specific Circulating CD4+ and CD8+ T Lymphocytes 
PLoS ONE  2015;10(1):e0115271.
It is difficult to experimentally infect volunteers with RV strains to which the subject demonstrates serological immunity. However, in RV challenges, viral clearance begins before de novo adaptive immune responses would develop. We speculated that adaptive immunity to RV reflects heterologous immunity by effector memory cells.
DCs were generated from monocytes using GM-CSF and IL-4 and RV39 loading accomplished with a dose of ∼350 TCID50/105 cells. RV-induced maturation was established as modulation of MHC class II, CD80, CD83, and CD86. Circulating RV targeting CD4 and CD8 T cells were investigated as induction of RV-specific proliferation (CFSE-dilution).
Maturation of DC by RV was confirmed as upregulation of MHC Class II (83.3±5.0% to 87.8±4.1%), CD80 (39.4±7.2% to 47.6±7.7%) and CD86 (78.4±4.7% to 84.1±3.4%). Both CD4 and CD8 memory T cells were recognized in the circulation of healthy subjects.
RV drives DC maturation and results in their ability to present RV antigens to both T helper and cytotoxic lymphocytes. Both CD4 and CD8 cells capable of recognizing RV-associated antigens are present in the circulation of healthy subjects where they are presumably involved in immune surveillance and explain the rapid recruitment of an adaptive immune response during RV infection.
PMCID: PMC4293146  PMID: 25584821
8.  Factors driving the aspirin exacerbated respiratory disease phenotype 
Aspirin-exacerbated respiratory disease (AERD) is explained in part by overexpression of 5-lipoxygenase and leukotriene C4 synthase (LTC4S), resulting in constitutive overproduction of cysteinyl leukotrienes (CysLTs) and driving the surge in CysLT production that occurs with aspirin ingestion. Similarly, AERD is characterized by the overexpression of CysLT receptors. Increased levels of both interleukin (IL)-4 and interferon (IFN)-γ are present in the tissue of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the up-regulation of LTC4S by mast cells.
Literature review.
Our previous studies demonstrated that IFN-γ, but not IL-4, drives this process in eosinophils. These published studies also extend to both IL-4 and IFN-γ the ability to up-regulate CysLT receptors. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD, and our published studies confirm that this reflects diminished expression of cyclooxygenase (COX)-2. A process again that is driven by IL-4. Thus, IL-4 and IFN-γ together play an important pathogenic role in generating the phenotype of AERD. Finally, induction of LTC4S and CysLT1 receptors by IL-4 reflects in part the IL-4-mediated activation of signal transducer and activator of transcription 6 (STAT6). Our previous studies demonstrated that aspirin blocks trafficking of STAT6 into the nucleus and thereby prevents IL-4-mediated induction of these transcripts, thereby suggesting a modality by which aspirin desensitization could provide therapeutic benefit for AERD patients.
This review will examine the evidence supporting this model.
PMCID: PMC4288232  PMID: 25590316
Leukotriene; cyclooxygenase; prostaglandin; aspirin-exacerbated respiratory disease
9.  Sino-nasal Outcome Test (SNOT-22): A predictor of post-surgical improvement in patients with chronic sinusitis 
PMCID: PMC3977600  PMID: 24054358
Chronic Rhinosinusitis; Sino-nasal Outcome Test-22; Functional Endoscopic Sinus Surgery; Predictive factors; Asthma; Allergy; Smoking; Depression
10.  Prominent Role of Interferon-γ in Aspirin-Exacerbated Respiratory Disease 
Aspirin-exacerbated respiratory disease (AERD) is distinguished from aspirin tolerant asthma/chronic sinusitis in large part by an exuberant infiltration of eosinophils that are characterized by their over-expression of metabolic pathways that drive the constitutive and aspirin-induced secretion of cysteinyl leukotrienes (CysLTs).
We defined the inflammatory milieu that in part drives CysLT overproduction and, in particular, the role of interferon (IFN)-γ in the differentiation of eosinophils.
qPCR was performed for Th1 and Th2 signature cytokines on control, chronic hyperplastic eosinophilic sinusitis (CHES), and AERD tissue and their cellular source was determined. The influence of interferon (IFN)-γ on maturation, differentiation, and functionality of eosinophils derived from hematopoietic stem cells was determined.
Gene expression analysis revealed that both aspirin tolerant and AERD tissue display a Th2 cytokine signature, however AERD was distinguished from CHES by the prominent expression of IFN-γ. Intracellular and immunohistochemical cytokine staining revealed that the major source of these cytokines were the eosinophils themselves. IFN-γ promoted the maturation of eosinophil progenitors as measured by increased mRNA and surface expression of CCR3 and Siglec-8. Additionally, IFN-γ increased expression of genes involved in leukotriene synthesis that led to increased secretion of cysteinyl leukotrienes. IFN-γ-matured eosinophil progenitors were also primed as demonstrated by their enhanced degranulation.
High IFN-γ levels distinguish AERD from aspirin tolerant asthma and underlie the robust constitutive and aspirin-induced secretion of CysLTs that characterize this disorder.
PMCID: PMC3788084  PMID: 23806637
aspirin exacerbated respiratory disease; aspirin tolerant asthma; chronic sinusitis; cytokines; eosinophils; interferon-γ; nasal polyps
11.  Epidemiological analysis of chronic rhinitis in pediatric patients 
Nonallergic rhinitis is a poorly understood entity, especially among pediatric patients. Objective: This study identifies clinical features that may distinguish phenotypes of allergic and nonallergic patients and to evaluate the usefulness of current diagnostic modalities.
We reviewed medical records for 151 pediatric patients with perennial rhinitis, evaluated in a multidisciplinary allergy and otolaryngology clinic. Results obtained by standard history, validated questionnaire (SN-5), epicutaneous allergy testing, acoustic rhinometry, and sinus CT were compared.
Nasal congestion was the most frequent primary presenting complaint (62%). Among subjects having a positive allergy test, associated eye symptoms were more frequent (p = 0.01) and responses to the SN-5 allergic domain were higher (p = 0.02). Sinus CT scores were similar among allergic and nonallergic subjects (median 7 and 8, respectively) and did not correlate with symptom scores (p = 0.6). Among nonallergic subjects, quality of life ratings weakly correlated with sinus CT scores (r = 0.4; p = 0.05). By rhinometry, absolute mean cross-sectional area was similar among allergic (0.32 cm2) and nonallergic (0.36 cm2) subjects and did not correlate with symptom scores (p = 0.8 for allergic and p = 0.6 for nonallergic subjects). Distinct groups of nonallergic patients including those with prominent conjunctival pruritus (n = 24), frequent cold symptoms (n = 3), and chronic sinus disease (n = 2) were observed.
It is difficult to distinguish allergic and nonallergic rhinitis in patients with perennial disease, but associated eye symptoms and questionnaire responses are predictive of allergy. Acoustic rhinometry and sinus CT suggest that physical obstruction and sinus disease are not related to nasal symptoms including, surprisingly, the sensation of congestion.
PMCID: PMC4152912  PMID: 22186247
12.  Fifty-five-year-old man with chronic yeast infections 
Allergy and Asthma Proceedings  2014;35(5):415-422.
As immunologists, we are frequently asked to evaluate patients with recurrent infections. These infections can provide us with clues regarding what pathways might be aberrant in a given patient, e.g., specific pyogenic bacteria with Toll-like receptor problems, atypical mycobacteria with interferon gamma receptor autoantibodies, and Candida/staphylococcal infections with cellular immune abnormalities. We present a 55-year-old man who presented to our immunology clinic with onychodystrophy of the toenails and fingernails and recurrent oral–esophageal candidiasis. The differential diagnosis for recurrent yeast infections is complex and includes usual suspects as well as some that are not as straightforward.
PMCID: PMC4147028  PMID: 25295810
Antibody deficiency; autoantibodies; chronic mucocutaneous candidiasis; Good's syndrome; IL-12; interferon alpha; thymoma
14.  Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation 
Nature  2012;493(7433):547-551.
Lung epithelial cells can influence immune responses to airway allergens1,2. Airway epithelial cells also undergo apoptosis after encountering environmental allergens3; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells1,4,5. Administration of exogenous IL-10 ‘rescued’ the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens.
PMCID: PMC3662023  PMID: 23235830
15.  A 71-year-old man with anaphylaxis after eating grits 
The allergist is frequently called on to evaluate patients after episodes of anaphylaxis to determine the cause and implement preventive measures that will reduce the patient’s risk from future episodes. The etiology of anaphylaxis can be the result of numerous causes that may go undiagnosed if a thorough evaluation is not performed. We present a 71-year-old man with no history of food allergy or atopy who presented to the emergency room and then our allergy clinic for evaluation after suffering anaphylaxis after a meal of grits and shrimp. The underlying diagnosis, which was subsequently determined, requires a high index of suspicion and should be included in the differential diagnosis of any patient presenting with unexplained anaphylaxis.
PMCID: PMC3894600  PMID: 22370536
16.  Decision-making analysis for allergen immunotherapy versus nasal steroids in the treatment of nasal steroid–responsive allergic rhinitis 
The purpose of the study was to determine the age at which initiation of specific subcutaneous immunotherapy (SCIT) becomes more cost-effective than continued lifetime intranasal steroid (NS) therapy in the treatment of allergic rhinitis, with the use of a decision analysis model.
A Markov decision analysis model was created for this study. Economic analyses were performed to identify “break-even” points in the treatment of allergic rhinitis with the use of SCIT and NS. Efficacy rates for therapy and cost data were collected from the published literature. Models in which there was only incomplete improvement while receiving SCIT were also evaluated for economic break-even points. The primary perspective of the study was societal.
Multiple break-even point curves were obtained corresponding to various clinical scenarios. For patients with seasonal allergic rhinitis requiring NS (i.e., fluticasone) 6 months per year, the age at which initiation of SCIT provides long-term direct cost advantage is less than 41 years. For patients with perennial rhinitis symptoms requiring year-round NS, the cut-off age for SCIT cost-effectiveness increases to 60 years. Hypothetical subjects who require continued NS treatment (50% reduction of previous dosage) while receiving SCIT also display break-even points, whereby it is economically advantageous to consider allergy referral and SCIT, dependent on the cost of the NS prescribed.
The age at which SCIT provides economic advantages over NS in the treatment of allergic rhinitis depends on multiple clinical factors. Decision analysis models can assist the physician in accounting for these factors and customize patient counseling with regard to treatment options.
PMCID: PMC3899446  PMID: 24717886
17.  Chronic rhinosinusitis and antibiotics: The good, the bad, and the ugly 
Despite the recognition that bacteria are universally present in the sinuses of patients with chronic rhinosinusitis (CRS) no compelling role for a primary infectious etiology of CRS has been elucidated. CRS is a constellation of inflammatory diseases that typically involve either noneosinophilic or eosinophilic processes, distinct conditions that must be treated individually.
The bacteria that are present in the sinuses may be innocuous bystanders but alternatively may contribute to the presence and severity of the disease through their ability to influence immune responses, function as immune adjuvants, provide antigens or superantigens that contribute to adaptive immune activation, or in forming the basis for the frequent acute superinfections. However, those bacteria that do contribute to the persistence and severity of CRS primarily reside in biofilms, and, as such, are not capable of being eradicated with antibiotics at the doses at which they can be used, even when local irrigation is considered.
Biofilms create an inhospitable environment for antibiotic potency by down-regulating the metabolic activity of their “core” bacteria, decreasing the oxygen concentration, and altering the pH at the core of the biofilm.
Ultimately, if topical antibiotics are considered, they should be primarily focused on treating acute exacerbations and choices of antibiotics should optimally be based on endoscopic culture. This should be done with the recognition that while under certain circumstances antibiotics can ameliorate the severity of CRS, even if bacterial eradication were possible, this would not eliminate the underlying primary pathogenic mechanism or the natural history of these conditions.
PMCID: PMC3836217  PMID: 24274221
Antibiotic resistance; aspirin exacerbated respiratory disease; biofilms; chronic hyperplastic eosinophilic sinusitis; inflammatory sinusitis; local antibiotic therapy; planktonic
18.  Autoimmune Mechanisms in Chronic Idiopathic Urticaria 
PMCID: PMC3432140  PMID: 22694931
Chronic idiopathic urticaria; anti-FcεRIα antibodies; mast cells; prostaglandin D2, calcium flux
19.  Etiology of Nasal Polyps in Cystic Fibrosis: Not a Unimodal Disease 
The objective was to determine whether the polyp subtypes observed in cystic fibrosis (CF)–related sinusitis were similar to those observed in non–CF-related sinusitis.
Polyp and mucus samples were collected from CF patients who presented for sinus surgery. The polyps underwent histologic and cytochemical evaluation for the presence of lymphocyte cell populations and their respective cytokine markers. The mucus samples were evaluated for DNA content.
Of the polyps, 42% had an eosinophilic infiltrate, of which 80% had an additional mixed neutrophilic infiltrate. Of the remaining polyp samples, 42% did not have a granulocytic infiltrate, consistent with non-eosinophilic polyps. All samples had CD138-positive plasma cells. The mucus samples from the patients with CF showed higher extracellular DNA concentrations than did the mucus samples from patients with non-CF sinus disease.
Cystic fibrosis–related polyps demonstrated an eosinophil-based dichotomy similar to that of idiopathic non–CF-related polyps. Many also demonstrated neutrophilic infiltrate, indicating that chronic mucus stasis and infection complicate the disease. Agents capable of reducing extracellular DNA may help manage sinusitis in CF patients.
PMCID: PMC3616340  PMID: 23012896
cystic fibrosis; DNA; eosinophil; histology; mucolytic; nasal polyp; neutrophil
20.  Chronic sinusitis pathophysiology: The role of allergy 
Chronic hyperplastic eosinophilic sinusitis (CHES) is an inflammatory disease characterized by eosinophil infiltration of sinus tissue that can present with and without nasal polyps (NPs). Aeroallergen sensitization in CHES occurs regularly, but the causality between allergen sensitivity, exposure, and disease is unclear.
Allergen is unlikely to directly enter healthy sinuses either by diffusion or ciliary flow, and, even this is more problematic given the loss of patency of the ostia of diseased sinuses. Inflammation and tissue eosinophilia can develop secondary to allergen exposure in the nares, with systemic humoral recirculation of allergic cells including eosinophils, Th2 lymphocytes, and eosinophil precursors that are nonspecifically recruited back to the diseased sinuses.
The possibility of an allergic reaction to peptides derived from bacteria (i.e., Staphylococcus or superantigens) or fungi that colonize the diseased sinus also provides a plausible allergic mechanism.
Treatments of this disease include agents directed at allergic mediators such as leukotriene modifiers and corticosteroids, although this does not necessarily signify that an IgE-dependent mechanism can be ascribed. However, more recently, omalizumab has shown promise, including in patients without obvious aeroallergen sensitization. Although many aspects of the role of allergy in CHES remain a mystery, the mechanisms that are being elucidated allow for improved understanding of this disease, which ultimately will lead to better treatments for our patients who live daily with this disease.
PMCID: PMC3781389  PMID: 23601202
Allergy; chronic hyperplastic eosinophilic sinusitis; chronic sinusitis; eosinophil; nasal polyposis; omalizumab; Staphylococcus; superantigen; systemic humoral recirculation
21.  Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study 
Patients with severe or difficult-to-treat asthma are an understudied population but account for considerable asthma morbidity, mortality, and costs. The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study was a large, 3-year, multicenter, observational cohort study of 4756 patients (n = 3489 adults ≥18 years of age, n = 497 adolescents 13-17 years of age, and n = 770 children 6-12 years of age) with severe or difficult-to-treat asthma. TENOR's primary objective was to characterize the natural history of disease in this cohort. Data assessed semiannually and annually included demographics, medical history, comorbidities, asthma control, asthma-related health care use, medication use, lung function, IgE levels, self-reported asthma triggers, and asthma-related quality of life. We highlight the key findings and clinical implications from more than 25 peer-reviewed TENOR publications. Regardless of age, patients with severe or difficult-to-treat asthma demonstrated high rates of health care use and substantial asthma burden despite receiving multiple long-term controller medications. Recent exacerbation history was the strongest predictor of future asthma exacerbations. Uncontrolled asthma, as defined by the 2007 National Heart, Lung, and Blood Institute guidelines’ impairment domain, was highly prevalent and predictive of future asthma exacerbations; this assessment can be used to identify high-risk patients. IgE and allergen sensitization played a role in the majority of severe or difficult-to-treat asthmatic patients.
PMCID: PMC3622643  PMID: 22694932
TENOR; severe or difficult-to-treat asthma; asthma control; asthma exacerbations; burden; medication; quality of life; allergy; IgE
22.  Pathogenesis of Rhinovirus Infection 
Current Opinion in Virology  2012;2(3):287-293.
Since its discovery in 1956, rhinovirus (RV) has been recognized as the most important virus producing the common cold syndrome. Despite its ubiquity, little is known concerning the pathogenesis of RV infections, and some of the research in this area has led to contradictions regarding the molecular and cellular mechanisms of RV-induced illness. In this article, we discuss the pathogenesis of this virus as it relates to RV-induced illness in the upper and lower airway, an issue of considerable interest in view of the minimal cytopathology associated with RV infection. We endeavor to explain why many infected individuals exhibit minimal symptoms or remain asymptomatic, while others, especially those with asthma, may have severe, even life-threatening, complications (sequelae). Finally, we discuss the immune responses to RV in the normal and asthmatic host focusing on RV infection and epithelial barrier integrity and maintenance as well as the impact of the innate and adaptive immune responses to RV on epithelial function.
PMCID: PMC3378761  PMID: 22542099
Rhinovirus; asthma; pathogenesis; viral-induced asthma exacerbations
24.  Evidence for distinct histological profile of nasal polyps: with and without eosinophilia 
The Laryngoscope  2011;121(10):2262-2267.
To evaluate the histology, RNA and protein signatures of nasal polyps in order to demonstrate specific subtypes of disease and differentiate “idiopathic” NPs based on tissue eosinophilia.
Study Design
Prospective laboratory based study
NP tissue was obtained from patients referred to the University of Virginia Health System for sinus surgery. Histology analyses included hematoxylin-eosin, Gomori's trichrome, toluidine blue, and chloroacetate staining. RNA and protein were extracted from tissue and cytokine transcript or protein concentrations determined.
Idiopathic NPs can be divided into distinct subsets characterized by absence (NE) and presence (E) of prominent eosinophilia. The validity of this distinction is supported by the demonstration that NE polyps are further distinguished by glandular hypertrophy, dense collagen deposition, and mononuclear cellular infiltrate. In contrast, E-NP display edema, rare glandularity, and minimal collagen deposition except within the basement membrane. Total mast cell numbers were reduced in E-NP, whereas connective tissue mast cells were increased in NE-NP. Consistent with the distinctive pattern of increased fibrosis, NE-NP displayed increased transforming growth factor (TGF)-ß and vascular endothelial growth factor transcripts. Similarly, NE-NPs had higher concentrations of TGF-ß, fibroblast growth factor-ß, and platelet-derived growth factor protein.
Idiopathic NPs can be distinguished by their presence or absence of eosinophilia and is supported by the observations that these display distinct histological, gene and protein expression patterns. The findings suggest that as unique diseases, idiopathic NPs will require distinct therapeutic interventions.
PMCID: PMC3183261  PMID: 21898422
fibrosis; chronic sinusitis; mast cells; growth factors; nasal polyps
25.  Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort 
Current Respiratory Care Reports  2012;1(4):259-269.
Patients with severe or difficult-to-treat asthma account for substantial asthma morbidity, mortality, and healthcare burden despite comprising only a small proportion of the total asthma population. TENOR, a multicenter, observational, prospective cohort study was initiated in 2001. It enrolled 4,756 adults, adolescents and children with severe or difficult-to-treat asthma who were followed semi-annually and annually for three years, enabling insight to be gained into this understudied population. A broad range of demographic, clinical, and patient self-reported assessments were completed during the follow-up period. Here, we present key findings from the TENOR registry in relation to asthma control and exacerbations, including the identification of specific subgroups found to be at particularly high-risk. Identification of the factors and subgroups associated with poor asthma control and increased risk of exacerbations can help physicians design individual asthma management, and improve asthma-related health outcomes for these patients.
PMCID: PMC3485530  PMID: 23136642
Severe asthma; Difficult-to-treat asthma; Asthma control; Exacerbation

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