Jin Young Min

A pilot study of symptom profiles from a polyp vs an eosinophilic-based classification of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is likely a biologically heterogeneous disease process. Current guidelines propose subclassification using polyp status while others propose using mucosal eosinophilia. We hypothesized that appropriate CRS subclassification would increase homogeneity of baseline symptoms, and identify characteristic symptoms of each subtype.

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate the expression of eotaxin‐3, an eosinophil chemoattractant, in patients with eosinophilic diseases suggest therapeutic potential for PPIs in those with CRSwNP. Objective: We assessed the effect of type 2 mediators, particularly IL‐13 and eotaxin‐3, on tissue eosinophilia and disease severity in patients with chronic rhinosinusitis (CRS). Further investigation focused on PPI suppression of eotaxin‐3 expression in vivo and in vitro, with exploration of underlying mechanisms. Methods: Type 2 mediator levels in nasal tissues and secretions were measured by using a multiplex immunoassay. Eotaxin‐3 and other chemokines expressed in IL‐13–stimulated human sinonasal epithelial cells (HNECs) and BEAS‐2B cells with or without PPIs were assessed by using ELISA, Western blotting, real‐time PCR, and intracellular pH imaging. Results: Nasal tissues and secretions from patients with CRSwNP had increased IL‐13, eotaxin‐2, and eotaxin‐3 levels, and these were positively correlated with tissue eosinophil cationic protein levels and radiographic scores in patients with CRS (P < .05). IL‐13 stimulation of HNECs and BEAS‐2B cells dominantly induced eotaxin‐3 expression, which was significantly inhibited by PPIs (P < .05). Patients with CRS taking PPIs also showed lower in vivo eotaxin‐3 levels compared with those without PPIs (P < .05). Using intracellular pH imaging and altering extracellular K+, we found that IL‐13 enhanced H+,K+‐exchange, which was blocked by PPIs and the mechanistically unrelated H,K‐ATPase inhibitor, SCH‐28080. Furthermore, knockdown of ATP12A (gene for the nongastric H,K‐ATPase) significantly attenuated IL‐13–induced eotaxin‐3 expression in HNECs. PPIs also had effects on accelerating IL‐13–induced eotaxin‐3 mRNA decay. Conclusion: Our results demonstrated that PPIs reduce IL‐13–induced eotaxin‐3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the nongastric H,K‐ATPase is necessary for IL‐13–mediated epithelial responses, and its inhibitors, including PPIs, might be of therapeutic value in patients with CRSwNP by reducing epithelial production of eotaxin‐3.

Risk Factors For Chronic Rhinosinusitis

Purpose of reviewTo review the recent literature on risk factors for chronic rhinosinusitis (CRS) with an emphasis on genetic, comorbid diseases and environmental factors associated with CRS. Through identifying potential risk factors for CRS, we aim to glean insights into the underlying pathogenic mechanisms essential for developing effective therapeutic strategies. Recent findingsRecent findings demonstrate that genetics and comorbid medical conditions including airway diseases, gastroesophageal reflux disease, inflammatory and autoimmune diseases, and various demographic and environmental factors are associated with having a CRS diagnosis. Limitations of current studies include variable application of disease definitions, lack of prospective longitudinal studies and a disproportionate focus on tertiary care populations. SummaryCRS has a broad spectrum of associations ranging from genetics to comorbid diseases and environmental factors. These predisposing factors may provide valuable information for possible designing of therapeutic and preventive interventions. However, to better understand whether these associations cause CRS, further studies are needed to independently replicate findings, establish temporal relationships between exposure and disease onset, evaluate the influence of exposure dose on disease severity, and to understand the biological effects of these risk factors in the context of CRS.

Superior turbinate eosinophilia correlates with olfactory deficit in chronic rhinosinusitis patients

To evaluate if molecular markers of eosinophilia in olfactory‐enriched mucosa are associated with olfactory dysfunction.

Measurement and comparison of health utility assessments in chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a common condition encountered in primary care medicine and is estimated to affect 12.5% of the United States population. This study aims to compare methods of assessing health utility in CRS.

Antibiotic Prescribing by Physicians Versus Nurse Practitioners for Pediatric Upper Respiratory Infections

Background: This study investigates differences in antibiotic prescribing rates for pediatric upper respiratory infections (URIs) between physicians and nurse practitioners (NPs). Methods: Visits by children <18 years old diagnosed with URI to physicians or NPs between 2001 and 2010 were abstracted from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey. Logistic regression analyses examined variations in antibiotic prescribing rates. Results: Upper respiratory infections accounted for approximately 439 ± 21.5 million visits. Patients seen by NPs were more likely to have Medicaid, live in the lowest median household income quartile zip codes and micropolitan locations, and live in the South compared to patients seen by physicians. Nurse practitioners prescribed antibiotics 66.7% ± 4.2% of the time versus physicians at 52.8% ± 0.8% for URI visits (unadjusted P-value = .002). Adjusted by specialty, URI type, and chronic diseases, NPs had marginally significantly different odds of prescribing antibiotics (OR = 1.6, 95% CI, 1.0-2.6, P-value = .048), but the association with prescribing broad-spectrum antibiotics is not as strong (adjusted P-value = .063). Patient visits to a pediatric (OR = 0.54, 95% CI, 0.43-0.67) or ENT/surgery practice (OR = 0.11, 95% CI, 0.06-0.18) had lower odds of antibiotic prescribing compared to general/family medicine practices. Year (2001-2010) was not significantly associated with antibiotic or broad-spectrum antibiotic prescribing rates for physicians, but rates for NPs fell for otitis media (P-value = .007) from 90.2% ± 8.2% (2001-2002) to 74.8% ± 6.8% (2009-2010) of visits. Conclusions: Nurse practitioners have higher rates of antibiotic prescribing compared to physicians for pediatric patients with URIs; however, this difference is less after adjusting for specialty. Examining comparative antibiotic prescribing is important to promote evidence-based practice and adoption of clinical guidelines.

Evidence for altered levels of IgD in the nasal airway mucosa of patients with chronic rhinosinusitis

Background: IgD is an enigmatic antibody isotype best known when coexpressed with IgM on naive B cells. However, increased soluble IgD (sIgD) levels and increased IgD+IgM− B‐cell populations have been described in the human upper respiratory mucosa. Objective: We assessed whether levels of sIgD and IgD+ B cell counts are altered in nasal tissue from patients with chronic rhinosinusitis (CRS). We further characterized IgD+ B‐cell populations and explored clinical and local inflammatory factors associated with tissue sIgD levels. Methods: sIgD levels were measured by means of ELISA in nasal tissues, nasal lavage fluid, sera, and supernatants of dissociated nasal tissues. IgD+ cells were identified by using immunofluorescence and flow cytometry. Inflammatory mediator levels in tissues were assessed by using real‐time PCR and multiplex immunoassays. Bacterial cultures from the middle meatus were performed. Underlying medical history and medicine use were obtained from medical records. Results: sIgD levels and numbers of IgD+ cells were significantly increased in uncinate tissue (UT) of patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared with that of control subjects (4‐fold, P < .05). IgD+ cells were densely scattered in the periglandular regions of UT from patients with CRSsNP. We also found that IgD+CD19+CD38bright plasmablast numbers were significantly increased in tissues from patients with CRSsNP compared with control tissues (P < .05). Among numerous factors tested, IL‐2 levels were increased in UT from patients with CRSsNP and were positively correlated with tissue IgD levels. Additionally, supernatants of IL‐2–stimulated dissociated tissue from patients with CRSsNP had significantly increased sIgD levels compared with those in IL‐2–stimulated dissociated control tissue ex vivo (P < .05). Tissue from patients with CRS with preoperative antibiotic use or those with pathogenic bacteria showed higher IgD levels compared with tissue from patients without these variables (P < .05). Conclusion: sIgD levels and IgD+CD19+CD38bright plasmablast counts were increased in nasal tissue of patients with CRSsNP. IgD levels were associated with increased IL‐2 levels and the presence of pathogenic bacteria. These findings suggest that IgD might contribute to enhancement mucosal immunity or inflammation or respond to bacterial infections in patients with CRS, especially CRSsNP.

Association of a PAI-1 Gene Polymorphism and Early Life Infections with Asthma Risk, Exacerbations, and Reduced Lung Function

Background Plasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk. Methods We included Latino children, adolescents, and young adults aged 8–21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function. Results RSV infection (OR 9.9, 95%CI 4.9–20.2) and other LRI (OR 9.1, 95%CI 7.2–11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3–50.2) and genotype-LRI (OR 11.7, 95% CI 8.8–16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (β -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted. Conclusions A genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population.

B-Cells and Antibody-Mediated Pathogenesis in Chronic Rhinosinusitis with Nasal Polyps

The sinonasal mucosa forms a dynamic immune barrier where epithelial cells and the immune system interact with the inhaled environment and nasal microbiome. Recent studies suggest that B-cells, plasma cells and antibody production are highly activated locally within the nasal mucosa of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Findings additionally suggest that polyp tissue contains elevated levels of cytokines, chemokines and complement that may drive this profound B-cell response. Currently, the data are conflicting on whether the B-cell response found in the CRSwNP nasal mucosa is antigen-specific, a superantigen response or an expansion of natural antibody responses. Indeed, investigations into the specificity of the mucosal antibody responses find increased production of class-switched antibodies that bind to aeroallergens, staphylococcus aureus as well as autoantigens. A continuation of these studies is needed to elucidate whether extrinsic factors, like the inhaled environment, or intrinsic factors, like the mucosal microbiome and host inflammatory response, are key to the pathogenesis of CRSwNP. This chapter will cover the current evidence regarding local B-cell responses in CRSwNP.

Potential Involvement of the Epidermal Growth Factor Receptor Ligand Epiregulin and Matrix Metalloproteinase-1 in Pathogenesis of Chronic Rhinosinusitis

&NA; Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease of the nose and paranasal sinuses that presents without or with nasal polyps (CRSwNP). Notable features of CRSwNP are the frequent presence of type 2 allergic inflammation and high prevalence of Staphylococcus aureus (SA) colonization. As inflammation persists, sinus tissue undergoes epithelial damage and repair along with polyp growth, despite active medical management. Because one feature of damaged tissue is enhancement of growth factor signaling, we evaluated the presence of epidermal growth factor receptor (EGFR) ligands and matrix metalloproteinases (MMPs) in CRS. The objectives of this study were to analyze the expression of EGFR ligands and MMPs in patients with CRS and to investigate the possible role of SA on epithelial activation. Sinonasal tissues were collected during surgery from control subjects and patients with CRS. Tissues were processed as described previously for analysis of mRNA (RT‐PCR) and proteins (ELISA) for the majority of EGFR ligands within the tissue extracts. CRS tissue was used for evaluation of the distribution of epiregulin (EREG), an EGFR ligand, and MMP‐1 by immunohistochemistry. In parallel studies, expression of these genes and proteins was analyzed in cultured primary airway epithelial cells. Elevated expression of EREG and MMP‐1 mRNA and protein was observed in uncinate and polyp tissue from patients with CRSwNP. Immunohistochemistry study of clinical samples revealed that airway epithelial cells expressed both of these proteins. Cultured primary human airway epithelial cells expressed MMP‐1, and MMP‐1 was further induced by stimulation with EREG or heat‐killed SA (HKSA). The induction of MMP‐1 by HKSA was blocked by an antibody against EREG, suggesting that endogenous EREG induces MMP‐1 after stimulation with HKSA. EREG and MMP‐1 were found to be elevated in nasal polyp and uncinate tissues in patients with CRSwNP. Elevated expression of EREG and MMP‐1 may be related to polyp formation in CRS, and colonization of SA might further enhance this process.