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2.  Chronic rhinosinusitis, race, and ethnicity 
Background
Little is known regarding the epidemiology of chronic rhinosinusitis (CRS) in racial and ethnic minorities in the United States(US).
Objective
Comprehensively evaluate the current prevalence of chronic rhinosinusitis (CRS) across various treatment settings in order to identify possible disparities in health care access and utilization between racial and ethnic populations.
Methods
The NHIS, NAMCS, and NHAMCS database registries were extracted to identify the national prevalence of CRS in race/ethnic populations and resource utilization in ambulatory care settings. Systematic literature review identified studies reporting treatment outcomes in minority patients electing endoscopic sinus surgery(ESS). Data was supplemented using a multi-institutional cohort of patients undergoing surgical treatment.
Results
National survey data suggests CRS is a significant health condition for all major race/ethnic groups in the US, accounting for a sizable portion of office, emergency, and outpatient visits. Differences in insurance status, work absenteeism, and resource utilization were found between race/ethnic groups. Despite its prevalence, few published studies include information regarding minority patients with CRS. Most(90%) cohort studies did not provide details of race/ethnicity for ESS outcomes. Prospective cohort analysis demonstrated that minority surgical patients accounted for only 18%, as compared to national census estimates(35%).
Conclusions
Chronic rhinosinusitis is an important health condition for all major race/ethnic groups in the US. Significant differences may exist across racial and ethnic categories with regard to CRS health status and healthcare utilization. Given current demographic shifts in the US, specific attention should be given to understanding CRS within the context of racial and ethnic populations.
doi:10.2500/ajra.2012.26.3741
PMCID: PMC3345896  PMID: 22487286
Sinusitis; Continental Population Groups; Ethnology; Quality of Life; Outcomes Research; Registries; Database; Prevalence; Centers for Disease Control and Prevention; United States
3.  Chronic rhinosinusitis, race, and ethnicity 
Background:
Little is known regarding the epidemiology of chronic rhinosinusitis (CRS) in racial and ethnic minorities in the United States. This study was designed to comprehensively evaluate the current prevalence of CRS across various treatment settings to identify possible disparities in health care access and use between racial and ethnic populations.
Methods:
The National Health Interview Survey (NHIS), National Ambulatory Medical Care Survey (NAMCS), and National Hospital Ambulatory Medical Care Survey (NHAMCS) database registries were extracted to identify the national prevalence of CRS in race/ethnic populations and resource use in ambulatory care settings. Systematic literature review identified studies reporting treatment outcomes in minority patients electing endoscopic sinus surgery (ESS). Data were supplemented using a multi-institutional cohort of patients undergoing surgical treatment.
Results:
National survey data suggest CRS is a significant health condition for all major race/ethnic groups in the United States, accounting for a sizable portion of office, emergency, and outpatient visits. Differences in insurance status, work absenteeism, and resource use were found between race/ethnic groups. Despite its prevalence, few published studies include information regarding minority patients with CRS. Most (90%) cohort studies did not provide details of race/ethnicity for ESS outcomes. Prospective cohort analysis indicated that minority surgical patients accounted for only 18%, when compared with national census estimates (35%).
Conclusion:
CRS is an important health condition for all major race/ethnic groups in the United States. Significant differences may exist across racial and ethnic categories with regard to CRS health status and health care use. Given current demographic shifts in the United States, specific attention should be given to understanding CRS within the context of racial and ethnic populations. Public clinical trial registration (www.clinicaltrials.gov) I.D. No. NCT00799097.
doi:10.2500/ajra.2012.26.3741
PMCID: PMC3345896  PMID: 22487286
Centers for Disease Control and Prevention; continental population groups; database; ethnology; outcomes research; prevalence; quality of life; registries; sinusitis; United States
4.  Factors driving the aspirin exacerbated respiratory disease phenotype 
Background:
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.
Methods:
Literature review.
Results:
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.
Conclusion:
This review will examine the evidence supporting this model.
doi:10.2500/ajra.2015.29.4123
PMCID: PMC4288232  PMID: 25590316
Leukotriene; cyclooxygenase; prostaglandin; aspirin-exacerbated respiratory disease
5.  Epidemiological analysis of chronic rhinitis in pediatric patients 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.2500/ajra.2011.25.3640
PMCID: PMC4152912  PMID: 22186247
6.  Differential expression of innate immunity genes in chronic rhinosinusitis 
Background:
Prior research has identified several components of the innate immune system that may play a significant role in chronic rhinosinusitis (CRS), but the role of innate immunity in patients with CRS is poorly understood. The objective of this study was to determine differential expression of innate immunity genes in the mucosa of patients with CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP) when compared with controls.
Methods:
Control patients (n = 9) and patients with CRS (n = 36) who failed medical management were prospectively enrolled. Ethmoid mucosa samples were harvested during surgery and quantitative real-time polymerase chain reaction was used to determine levels of mRNA expression of Toll-like receptor (TLR) 2 and TLR9 and interleukin-22 receptor (IL-22R). The average change in crossover threshold and fold change were calculated and differences between controls, CRSwNP, and CRSsNP were compared. Statistical analysis was performed using the Kruskall–Wallis and adjusted Mann–Whitney U tests.
Results:
Patients with CRSwNP (n = 16) and CRSsNP (n = 20) showed lower mean expression of TLR2 (p < 0.05) compared with controls. Patients with CRSsNP showed significantly higher mean expression of IL-22R (p < 0.05) than controls.
Conclusion:
The sinonasal innate immune system may have a significant role in the development of CRS. We found differential expression of innate immune mediators between patients with and without nasal polyposis. These results provide further evidence of disruption of innate immunity at the mucosal level in CRS and highlight differences between polyp- and non–polyp-forming CRS phenotypes at the molecular level. In addition to our knowledge, this is the first report of altered IL-22R expression in CRSsNP patients. This study was a part of the clinical trial NCT01332136 registered in www.clinicaltrials.gov.
doi:10.2500/ajra.2014.28.4082
PMCID: PMC4151703  PMID: 25198021
Chronic rhinosinusitis; chronic rhinosinusitis with nasal polyposis; IL-22R; innate immunity; TLR2; TLR9; Toll-like receptors
7.  Seasonal allergic rhinitis affects sinonasal microbiota 
Background:
Microbes and allergens can stimulate the nasal mucosa, potentially leading to the development of acute bacterial rhinosinusitis (ABRS). This study was designed to determine if allergen exposure alters the sinonasal microbiome.
Methods:
We performed a parallel observational study of healthy adults with seasonal allergic rhinitis (SAR; grass or tree, n = 20) or nonallergic subjects (n = 19). Microbiota specimens were obtained by endoscopy from the middle meatus and vestibule before and during the relevant season and were analyzed by terminal restriction fragment length polymorphism analysis. Differences in bacterial microbiota were assessed by standard ecological measures of bacterial diversity. Quality of life and symptom scores were recorded, and nasal lavages for eosinophils were performed.
Results:
SAR subjects had increased nasal symptoms in season, impaired disease-specific quality of life, and increased nasal eosinophils, compared with no changes in nonallergic subjects. During the season, SAR subjects had a significantly greater variety of organisms in the middle meatus compared with nonallergic subjects (p < 0.036) and increased bacterial diversity (Shannon index, p < 0.013). We found a significant positive correlation between bacterial diversity in the middle meatus during the season and the nasal lavage eosinophil count of SAR subjects. There were no significant changes in the nasal vestibule (p > 0.05, all comparisons).
Conclusion:
The interaction of allergy and microbiota may affect the sinonasal physiology, with broad implications for several airway diseases. Characterization of the specific organisms involved using next-generation sequencing may clarify the relationship between allergic inflammation and ABRS. This finding may help explain why allergic inflammation predisposes to ABRS.
doi:10.2500/ajra.2014.28.4050
PMCID: PMC4101129  PMID: 25197913
Allergy; bacteria; microbes; microbiome; microbiota; osteomeatal unit; rhinosinusitis; seasonal allergic rhinitis
8.  Passive smoke exposure in chronic rhinosinusitis as assessed by hair nicotine 
Background:
Prevalence of passive smoke exposure is relatively unknown in chronic rhinosinusitis (CRS). Previous studies have attempted to establish this relationship using subjective, questionnaire-based methodologies to assess smoke exposure, thus introducing the potential for error bias. The purpose of this study was to accurately determine the prevalence of passive smoke exposure in CRS and control patients using hair nicotine levels as a quantitative measure of cigarette smoke exposure.
Methods:
Hair samples were obtained at time of surgery from 569 patients: 404 undergoing surgery for CRS and 165 controls undergoing surgery for repair of cerebrospinal fluid leak, removal of pituitary tumors, or adenoidectomy from 2007 to 2013. Patient charts were reviewed for reported smoking status. Hair nicotine was quantified using reversed-phase high-performance liquid chromatography. Nonsmoking patients were classified as passive smoke exposed or smoke naïve according to the hair nicotine results. Statistical analysis was performed to test for differences in demographic information and smoke exposure prevalence between CRS, CRS subtypes, and controls.
Results:
The prevalence of passive smoke exposure in CRS as documented by hair nicotine was lower than previously reported subjective estimates. Passive smoke exposure rates were equivalent between those with CRS versus controls and significantly higher in children. Severity of passive smoke exposure was also equivalent between CRS subsets and controls. Annual passive smoke exposure prevalence did not change over time.
Conclusion:
There is no clear evidence of avoidance of passive smoke exposure in the CRS population compared with controls. Passive smoke exposure also remained stable over time despite recent regional implementation of smoking bans. Given the constancy of exposure, it is critical that the impact of passive smoke on CRS exacerbation, outcomes, and pathophysiology be evaluated in large-scale clinical studies.
doi:10.2500/ajra.2014.28.4058
PMCID: PMC4101130  PMID: 25197916
Chronic rhinosinusitis; hair nicotine; passive smoke; prevalence; quantitative
9.  Decision-making analysis for allergen immunotherapy versus nasal steroids in the treatment of nasal steroid–responsive allergic rhinitis 
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
doi:10.2500/ajra.2014.28.3998
PMCID: PMC3899446  PMID: 24717886
10.  The link between rhinitis and rapid-eye-movement sleep breathing disturbances in children with obstructive sleep apnea 
Background:
Rhinitis and obstructive sleep apnea (OSA) often coexist during childhood. To delineate this clinical association, we examined OSA severity and polysomnogram (PSG) features in children with rhinitis and OSA. Given that rapid-eye-movement (REM) sleep is characterized by nasal congestion, we hypothesized that children with rhinitis have more REM-related breathing abnormalities.
Methods:
We conducted a retrospective cross-sectional analysis of 145 children with PSG-diagnosed OSA. Outcomes included PSG parameters and obstructive apnea–hypopnea index (OAHI) during REM and non-REM. Linear multivariable models examined the joint effect of rhinitis and OSA parameters with control for potential confounders.
Results:
Rhinitis was present in 43% of children with OSA (n = 63) but overall OAHI severity was unaffected by the presence of rhinitis. In contrast, OAHI during REM sleep in children with moderate–severe OSA was significantly increased in subjects with rhinitis and OSA (44.1/hr; SE = 6.4) compared with those with OSA alone (28.2/hr; SE = 3.8).
Conclusion:
Rhinitis is highly prevalent in children with OSA. Although OSA is not more severe in children with rhinitis, they do have a distinct OSA phenotype characterized by more REM-related OSA. Further research is needed to delineate the link between REM-sleep and the physiology of the nose during health and disease.
doi:10.2500/ajra.2014.28.3994
PMCID: PMC3899447  PMID: 24717885
Apnea; OSA; pediatric OSA; REM; REM-related OSA; rhinitis; sleep; sleep breathing
11.  Chronic rhinosinusitis and antibiotics: The good, the bad, and the ugly 
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
doi:10.2500/ajra.2013.27.3960
PMCID: PMC3836217  PMID: 24274221
Antibiotic resistance; aspirin exacerbated respiratory disease; biofilms; chronic hyperplastic eosinophilic sinusitis; inflammatory sinusitis; local antibiotic therapy; planktonic
12.  Epidemiology and differential diagnosis of nasal polyps 
Background:
Chronic rhinosinusitis (CRS) is one of the most common chronic medical conditions, with a significant impact on patient quality of life. CRS is broadly classified into two groups: CRS with nasal polyposis (CRSwNP) and CRS without NP (CRSsNP). Clinically, the major subtypes of CRSwNP may be divided into eosinophilic chronic rhinosinusitis (e.g., allergic fungal rhinosinusitis and aspirin-exacerbated respiratory disease [AERD]) and nasal polyps associated with neutrophilic inflammation (e.g., cystic fibrosis [CF]). CF is characterized by mutation of the gene encoding the CF transmembrane conductance regulator. Functional endoscopic sinus surgery is usually required for most NP patients with increased frequency in patients with AERD. This study provides a review of the epidemiology and major classification of CRSwNP.
Methods:
A review was performed of the literature regarding different subtypes of CRSwNP.
Results:
Many definitions of CRSwNP exist and estimates of prevalence vary.
Conclusion:
CRSwNP is a clinical syndrome with a heterogeneous inflammatory profile. Of the subtypes associated with eosinophilic inflammation, AERD remains the most recalcitrant to medical and surgical therapeutic interventions.
doi:10.2500/ajra.2013.27.3981
PMCID: PMC3899526  PMID: 24274222
Allergic fungal rhinosinusitis; aspirin-exacerbated respiratory disease; CFTR; chronic sinusitis; cystic fibrosis; functional endoscopic sinus surgery; nasal polyps; rhinosinusitis; Samter's triad; sinus surgery
13.  Leukotriene antagonists in nasal polyposis: A meta-analysis and systematic review 
Background:
Leukotriene antagonists (LTAs) provide a potential strategy for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP), which is often refractory to medical and surgical treatment. The purpose of this study is to determine the impact of LTA treatment alone and in conjunction with intranasal corticosteroids (INCSs) on nasal symptoms, objective clinical outcomes, and immune parameters in CRSwNP.
Methods:
A systematic review was performed including studies that assessed the effectiveness of LTAs on clinical outcome measures of CRSwNP. Exclusion criteria were trials assessing LTAs in CRS without nasal polyps or asthma symptoms only. Quantitative analysis was performed using a random effects model.
Results:
Twelve studies fulfilled eligibility: five randomized control trials and seven case series. LTAs showed significant improvements in CRSwNP symptoms over placebo; however, these randomized trials were unable to be combined via meta-analysis. The two studies used in meta-analysis showed a standardized mean difference of pooled overall symptom scores of 0.02 (95% confidence interval, −0.39–0.44) between LTA and INCS study arms, indicating no difference between the treatment modalities. Improvement was described by all studies in symptoms, clinical outcomes, and/or immune parameters after LTA treatment, with greater improvements in a subset of symptoms beyond that observed with INCSs. Concomitant asthma, aspirin-exacerbated respiratory disease, and atopy did not significantly or consistently affect these results.
Conclusion:
LTAs are an effective tool for treating CRSwNP, with limited benefit as an adjunctive therapy. Additional study is required to determine the most beneficial strategy and patient population for their use.
doi:10.2500/ajra.2013.27.3976
PMCID: PMC3899527  PMID: 24274224
Antagonist; chronic; leukotriene; montelukast; polyps; rhinosinusitis; sinusitis; symptoms; zafirlukast; zileuton
14.  Allergic rhinoconjunctivitis in the Australian population: Burden of disease and attitudes to intranasal corticosteroid treatment 
Background:
Allergic rhinoconjunctivitis (AR/C) is a global health problem causing significant morbidity and has a major impact on quality of life (QOL) and health expenditure. Despite the widespread prevalence, the overall health impact of AR/C may be underappreciated. The results of a survey designed to capture the burden of allergic rhinitis within the Asia-Pacific region have been published recently. Of particular note when evaluating treatment in this region was the fact that despite the value of intranasal corticosteroid (INCS) use, only a small percentage of patients used them. Whether this same trend is present within the population of Australian sufferers is unknown. This study examines the burden of AR/C and explores use of, and attitudes, to INCS sprays in the Australian population.
Methods:
Three hundred three completed interviews from adults and children who had physician-diagnosed AR/C and who were symptomatic or had received treatment in the previous 12 months were analyzed for QOL measures and attitudes to INCS use.
Results:
Most patients surveyed had received their diagnosis from a general practitioner (GP), and in most cases, a GP provided the majority of ongoing medical care. Only 8% of respondents had consulted a relevant specialist. Diagnostic tests had not been performed in 55% of respondents. The major symptoms causing most distress were nasal congestion and ocular symptoms. The burden of AR/C was considerable; 42% described significant work or school interference because of symptoms, one-third reporting moderate-to-extreme interference with sleep. Despite the significant impact on QOL reported by this sample, 17% had never used INCS and 27% had not used them in the previous 12 months. Respondents' knowledge about INCSs was poor.
Conclusion:
AR/C is a common disease associated with significant morbidity and impairment of QOL. Improvement in diagnosis, management, and patient education is needed.
doi:10.2500/ajra.2013.27.3965
PMCID: PMC3899528  PMID: 24274227
Allergic rhinoconjunctivitis; Australian data; intranasal corticosteroid use; quality of life; rhinitis
15.  Chronic sinusitis pathophysiology: The role of allergy 
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
doi:10.2500/ajra.2013.27.3906
PMCID: PMC3781389  PMID: 23601202
Allergy; chronic hyperplastic eosinophilic sinusitis; chronic sinusitis; eosinophil; nasal polyposis; omalizumab; Staphylococcus; superantigen; systemic humoral recirculation
16.  Cystic fibrosis chronic rhinosinusitis: A comprehensive review 
Background:
Advances in the care of patients with cystic fibrosis (CF) have improved pulmonary outcomes and survival. In addition, rapid developments regarding the underlying genetic and molecular basis of the disease have led to numerous novel targets for treatment. However, clinical and basic scientific research focusing on therapeutic strategies for CF-associated chronic rhinosinusitis (CRS) lags behind the evidence-based approaches currently used for pulmonary disease.
Methods:
This review evaluates the available literature and provides an update concerning the pathophysiology, current treatment approaches, and future pharmaceutical tactics in the management of CRS in patients with CF.
Results:
Optimal medical and surgical strategies for CF CRS are lacking because of a dearth of well-performed clinical trials. Medical and surgical interventions are supported primarily by level 2 or 3 evidence and are aimed at improving clearance of mucus, infection, and inflammation. A number of novel therapeutics that target the basic defect in the cystic fibrosis transmembrane conductance regulator channel are currently under investigation. Ivacaftor, a corrector of the G551D mutation, was recently approved by the Food and Drug Administration. However, sinonasal outcomes using this and other novel drugs are pending.
Conclusion:
CRS is a lifelong disease in CF patients that can lead to substantial morbidity and decreased quality of life. A multidisciplinary approach will be necessary to develop consistent and evidence-based treatment paradigms.
doi:10.2500/ajra.2013.27.3919
PMCID: PMC3899543  PMID: 24119602
Ataluren; CFTR; chloride secretion; chronic sinusitis; cystic fibrosis; dornase alpha; endoscopic medial maxillectomy; functional endoscopic sinus surgery; ivacaftor; lumacaftor; macrolide; mucociliary clearance; Pseudomonas; PTC124; rhinosinusitis; saline irrigation; sinus surgery; transepithelial ion transport; VX-770; VX-809
17.  The use of postoperative topical corticosteroids in chronic rhinosinusitis with nasal polyps: A systematic review and meta-analysis 
Background:
Topical intranasal corticosteroids (INCSs) are used to control disease symptoms in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). The evidence to recommend INCSs as part of the postoperative care is limited. This study was designed to assess the efficacy of INCSs in the postoperative care of patients undergoing functional endoscopic sinus surgery (FESS) during the 1st year postoperatively.
Methods:
We searched the Cochrane Central Register of Controlled Trials (1995 to May 2012), MEDLINE (January 1948 to May 2012), EMBASE (January 1980 to May 2012), and the reference lists of articles. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Randomized controlled trials (RCT) and cohort studies comparing INCSs with placebo or comparing different types of INCSs were included.
Results:
Eleven studies (n = 945 patients) were RCTs and one prospective cohort study (n = 32 patients). As measured by the standardized mean difference (SMD) INCSs had a beneficial effect on symptom scores (SMD, −1.35; 95% CI, −2.05 to −0.64; p = 0.0002; 3 trials; 137 patients) and polyp score (SMD, 0.53; 95% CI, −0.91 to −0.14; p = 0.007; 5 trials; 223 patients). Compared with placebo, the use of INCSs decreased the odds of polyp recurrence (odds ratio, 0.17; 95% CI, 0.06–0.51; p = 0.002; 2 trials; 74 patients). Two RCTs (n = 105) and one cohort study (n = 32) reported normal adrenocorticotropic hormone levels postintervention.
Conclusion:
INCS use is a safe therapy in postoperative management of CRSwNP patients. INCS showed significant improvement in polyp score, patients' symptoms and significant decrease in polyp recurrence in the first year postoperatively.
doi:10.2500/ajra.2013.27.3950
PMCID: PMC3899544  PMID: 24119596
Endoscopic sinus surgery; intranasal corticosteroid; meta-analysis; nasal polyps; polyp recurrence; postoperative care; rhinosinusitis; symptom score; systematic review
18.  Relationships between severity of chronic rhinosinusitis and nasal polyposis, asthma, and atopy 
Background
The effect of comorbid conditions such as asthma and atopy on the severity of chronic rhinosinusitis (CRS) and the presence of nasal polyps (NPs) remains an area of investigation. We sought to elucidate the relationship among these entities.
Methods
The study population included 106 consecutive patients who were referred to a multidisciplinary, university-based allergy and sinus clinic that underwent computed tomography (CT) scan, skin-prick testing, and had CRS. Data were analyzed to determine Lund-MacKay score (LMS), presence of NPs, asthma status, and sensitivity to seven classes of aeroallergens.
Results
Skin tests were positive in 52 cases and negative in 54 cases. Although, there was no statistical relationship between LMS and atopic status in the entire group, among the asthmatic subgroup, mean LMS was greater in nona topic asthmatic patients than in atopic asthmatic patients. Asthmatic patients had a higher LMS than nonasthmatic patients (p < 0.0001). Asthmatic patients were more likely than nonasthmatic patients to have NPs (57.6% versus 25%; p = 0.0015), regardless of atopic status. Mean LMS was higher in NP patients compared with nonpolyp patients (p < 0.0001), independent of atopic status. Mean LMS was not affected by sensitivity to any particular allergen, with the exception of cockroach-allergic patients who were more likely to have an LMS of >10 (p = 0.0236) and had more severe maxillary sinus involvement (p = 0.0391).
Conclusion
These data indicate a strong relationship between CRS severity, as measured by LMS, and chronic airway inflammatory diseases, asthma, and NPs. The association between LMS and atopic status appears weak. The present study suggests that CRS is an inflammatory disease that occurs independently of systemic IgE-mediated pathways.
doi:10.2500/ajra.2009.23.3284
PMCID: PMC3747516  PMID: 19401038
Allergy; asthma; atopy; chronic rhinosinusitis; computed tomography; eosinophil; epidemiology; Lund-MacKay score; nasal polyposis; staging
19.  Toxin-induced chemosensory dysfunction: A case series and review 
Background
Toxic chemical exposures are estimated to account for 1–5% of all olfactory disorders. Both olfactory neurons and taste buds are in direct contact with environmental agents because of their relatively unprotected anatomic locations, thereby making them susceptible to damage from acute and chronic toxic exposures. The aim of this study was to illustrate different aspects of the diagnostic and therapeutic approach to this disorder using a series of case reports and review of the literature.
Methods
Cases were selected for inclusion based on a retrospective chart review of patients who presented to a university-based nasal dysfunction clinic with toxin-induced olfactory or gustatory dysfunction between January 1985 and December 2008. Workup included complete history, otolaryngologic examination, psychophysical testing, and imaging.
Results
Patient ages ranged from 31 to 67 years (mean, 49.3 years). Etiology of chemosensory impairment included exposure to ammonia, isodecanes, hairdressing chemicals, chemotherapy, gasoline, and intranasal zinc. Five of the seven patients (71%) presented with olfactory dysfunction alone, one patient (14%) presented with dysgeusia alone, and one patient (14%) presented with both smell and taste loss. Only one patient (14%) reported parosmias. Tests of olfaction revealed normosmia in one patient (14%), mild-to-moderate hyposmia in one patient (14%), and severe hyposmia to anosmia in five patients (72%). Both patients who reported taste disorders had hypogeusia on testing.
Conclusion
This case series illustrates the wide spectrum of this disorder and provides a framework for the workup and treatment of these patients.
doi:10.2500/ajra.2009.23.3368
PMCID: PMC3740152  PMID: 19958605
Ammonia; anosmia; dysgeusia; gasoline; hyposmia; olfaction; smell; taste disorders; zinc
20.  Perennial is more effective than preseasonal subcutaneous immunotherapy in the treatment of seasonal allergic rhinoconjunctivitis 
Background:
Two different regimens of subcutaneous immunotherapy (IT), perennial or preseasonal, may be used in the treatment of seasonal allergy. The aim of this study was to compare the efficacy and safety of perennial IT (PIT) and preseasonal IT (PSIT) in patients suffering from seasonal rhinoconjunctivitis.
Methods:
The study was planned as a randomized, double-blind, comparative study on the efficacy and safety of PIT and PSIT. The study group comprised 120 patients allergic to grass and rye pollen. After the observational season they were randomized to receive PIT or PSIT for 3 years. The effect of IT was assessed based on symptom severity and medication use recorded in diaries.
Results:
Ninety-nine patients completed the study. No difference was seen between the groups regarding combined symptom medication score (SMS) in the first season of IT. During the second season, the difference between PIT and PSIT regarding combined SMS was 27.9% (p = 0.063) and reached 42.7% (p = 0.012) in favor of PIT in the third season. Both treatments had a similar safety profile.
Conclusion:
PIT was more effective than PSIT in the treatment of rhinoconjunctivitis in patients allergic to grass and rye pollens.
Clinicaltrials.gov registration number NCT01555736.
doi:10.2500/ajra.2013.27.3935
PMCID: PMC3711679  PMID: 23636036
Comparison; perennial immunotherapy; preseasonal immunotherapy; rhinoconjunctivitis; subcutaneous immunotherapy
21.  Schneiderian papillomas: Comparative review of exophytic, oncocytic, and inverted types 
Background:
Sinonasal papillomas are benign epithelial neoplasms arising from Schneiderian mucosa. The three subtypes, exophytic, oncocytic, and inverted (inverted papilloma [IP]), should be distinguished from one another histopathologically. This study (1) highlights the histopathological and clinical differences between the Schneiderian papilloma subtypes and (2) identifies clinical features that potentially predict papilloma subtypes.
Methods:
A retrospective review was performed of patients with Schneiderian papillomas over an 11-year period.
Results:
Seventy patients with sinonasal papillomas who underwent sinus surgery were identified. There were 50 (71%) male and 20 (29%) female subjects diagnosed at an average age of 53 years (range, 13–80 years). Exophytic (n = 25), oncocytic (n = 9), and IP (n = 37) were identified. IP was associated with transformation into squamous cell carcinoma in three (8%) cases and dysplasia in three (8%) cases. Neither oncocytic nor exophytic subtypes were associated with dysplasia or malignancy. On multivariate analysis of potential predictors of papilloma subtype, history of chronic rhinosinusitis (CRS) and location of papilloma were significantly associated with papilloma subtype. Using classification and regression tree model, papilloma subtypes can be predicted based on presence or absence of CRS and papilloma location with nominal 82.4% accuracy.
Conclusion:
The inverted and exophytic type are the most common sinonasal papillomas, with the inverted type having an 8% rate of malignant transformation in this study. In contrast, the oncocytic type was not associated with dysplasia or malignancy in our series despite reports in the literature indicating malignant potential. History of CRS and papilloma location can provide clues to the histological subtype, which is important for surgical planning and patient counseling.
doi:10.2500/ajra.2013.27.3904
PMCID: PMC3901443  PMID: 23883810
Cylindrical cell; exophytic; inverted; oncocytic; Schneiderian papillomas; sinonasal papillomas
22.  Common variable immunodeficiency 
Common variable immunodeficiency (CVID) is a common primary immunodeficiency characterized by a failure in B-cell differentiation with defective immunoglobulin production. Affected patients are uniquely susceptible to recurrent infection with encapsulated organisms and have an increased propensity for the development of inflammatory and autoimmune manifestations. The diagnosis of CVID is commonly delayed and the underlying cause of the disorder is not understood. Replacement antibody therapy reduces the risk of serious infections. However, optimal treatment regimens for the uncommon manifestations associated with this disease, such as granulomatous lymphocytic interstitial lung disease, require further research.
doi:10.2500/ajra.2013.27.3899
PMCID: PMC3901442  PMID: 23883805
Antibody deficiency; CVID; granulomatous disease; lung disease; primary immune disease; treatment
23.  Incidental sinonasal findings identified during preoperative evaluation for endoscopic transsphenoidal approaches 
Background:
The endoscopic transsphenoidal approach (eTSA) to lesions of the sellar region is typically performed jointly by neurosurgeons and otolaryngologists. Occasionally, the approach is significantly altered by sinonasal disease, anatomic variants, or previous surgery. However, there are no current guidelines that describe which physical or radiological findings should prompt a change in the plan of care. The purpose of this study was to determine the incidence of sinonasal pathology or anatomic variants noted endoscopically or by imaging that altered preoperative or intraoperative management.
Methods:
A retrospective review was performed of 355 consecutive patients who underwent combined neurosurgery–otolaryngology endoscopic sella approach from August 1, 2007 to April 1, 2011. Our practice in these patients involves preoperative otolaryngology clinical evaluation and MRI review. Intraoperative image guidance is not routinely used in uncomplicated eTSA.
Results:
The most common management alteration was the addition of image guidance based on anatomic variants on MRI, which occurred in 81 patients (35.0%). Eight patients (2.9%) were preoperatively treated with antibiotics and surgery was postponed secondary to acute or chronic purulent rhinosinusitis; two (0.7%) required functional endoscopic sinus surgery for medically refractory disease before eTSA. Five patients (1.8%) required anterior septoplasty intraoperatively for severe nasal septal deviation. Two patients (0.7%) had inverted papilloma and one patient had esthesioneuroblastoma identified preoperatively during rigid nasal endoscopy.
Conclusion:
This is one of the larger reviews of patients undergoing eTSA for sellar lesions and the only study that describes how intraoperative management may be altered by preoperative sinonasal evaluation. We found a significant incidence of sinonasal pathology and anatomic variants that altered routine operative planning; therefore, a thorough sinonasal evaluation is warranted in these cases.
doi:10.2500/ajra.2013.27.3871
PMCID: PMC3649855  PMID: 23710956
Endoscopic; image-guided surgery; incidental; preoperative; sella; sinonasal; transsphenoidal
24.  Surfactants in the management of rhinopathologies 
Background:
Surfactants are a class of amphiphilic surface active compounds that show several unique physical properties at liquid–liquid or liquid–solid surface interfaces including the ability to increase the solubility of substances, lower the surface tension of a liquid, and decrease friction between two mediums. Because of these unique physical properties several in vitro, ex vivo, and human trials have examined the role of surfactants as stand-alone or adjunct therapy in recalcitrant chronic rhinosinusitis (CRS).
Methods:
A review of the literature was performed.
Results:
The data from three different surfactants have been examined in this review: citric acid zwitterionic surfactant (CAZS; Medtronic ENT, Jacksonville FL), Johnson's Baby Shampoo (Johnson & Johnson, New Brunswick NJ), and SinuSurf (NeilMed Pharmaceuticals, Santa Rosa, CA). Dilute surfactant therapy shows in vitro antimicrobial effects with modest inhibition of bacterial biofilm formation. In patients with CRS, surfactants may improve symptoms, most likely through its mucolytic effects. In addition, surfactants have several distinct potential benefits including their ability to improve an irrigant's penetration of the nonoperated sinus and their synergistic effects with antibiotics. However, surfactants potential for nasal irritation and possible transient ciliotoxicity may limit their use.
Conclusion:
Recent data suggest a possible therapeutic role of surfactants in treating rhinopathologies associated with mucostasis. Further investigation, including a standardization of surfactant formulations, is warranted to further elucidate the potential benefits and drawbacks of this therapy.
doi:10.2500/ajra.2013.27.3873
PMCID: PMC3901440  PMID: 23710951
Biofilms; cilia; contamination; mucociliary clearance; nasal irrigation; sinusitis; surfactants; surface tension
25.  Sinus surgery and delivery method influence the effectiveness of topical corticosteroids for chronic rhinosinusitis: Systematic review and meta-analysis 
Background:
Published randomized controlled trials (RCTs) on the efficacy of intranasal corticosteroid (INCS) in chronic rhinosinusitis (CRS) use either nasal delivery (nasal drop or nasal spray) or sinus delivery (sinus catheter or sinus irrigation) in patients with or without sinus surgery. This influences topical drug delivery and distribution. The effect of these factors on the published results of RCTs is assessed. This systematic review explores the strength of evidence supporting the influence of sinus surgery and delivery methods on the effectiveness of topical steroids in studies for CRS with meta-analyses.
Methods:
A systematic review was conducted of RCTs comparing INCS with either placebo or no intervention for treating CRS. Data were extracted for meta-analysis and subgroup analyses by sinus surgery status and topical delivery methods.
Results:
Forty-eight studies (3961 patients) met the inclusion criteria. INCS improved overall symptoms (standardized mean difference [SMD], −0.49; p < 0.00001) and the proportion of responders (risk ratio [RR], 0.59; p < 0.00001) compared with placebo. It decreased nasal polyp size with a greater proportion of responders (RR, 0.48; p < 0.00001) and prevented polyp recurrence (RR, 0.59; p = 0.0004) compared with placebo. Reduction of polyp size was greater in patients with sinus surgery (RR, 0.31; 95% confidence interval [CI], 0.20, 0.48) than those without (RR, 0.61; 95% CI, 0.46, 0.81; p = 0.009). Greater symptom improvement occurred when sinus delivery methods (SMD, −1.32; 95% CI, −2.26, −0.38) were compared with nasal delivery methods (SMD, −0.38; 95% CI, −0.55, −0.22; p < 0.00001).
Conclusion:
INCS is effective for CRS. Prior sinus surgery and direct sinus delivery enhance the effectiveness of INCS in CRS.
doi:10.2500/ajra.2013.27.3880
PMCID: PMC3901441  PMID: 23710959
Chronic rhinosinusitis; intranasal corticosteroid; nasal drop; nasal polyps; nasal spray; sinus irrigation; sinusitis; sinus surgery; steroids

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