Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size.

OBJECTIVE: Chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilia is a disease of the upper respiratory tract for which few therapies are available. Because the oral investigational drug dexpramipexole serendipitously decreased blood eosinophils in amyotrophic lateral sclerosis studies, we assessed its safety, eosinophil-lowering activity, and preliminary clinical efficacy in patients with CRSwNP and eosinophilia. METHODS: Sixteen subjects with CRSwNP, absolute eosinophil count (AEC) ≥ 0.300 × 109 /L, and polyp tissue eosinophils were evaluable for efficacy in a 6-month open-label, multi-center study of dexpramipexole 150 mg twice daily. The coprimary endpoints were change in AEC and change in total polyp score (TPS) from baseline to month 6, with additional clinical and histologic endpoints assessed. RESULTS: Thirteen of 16 subjects completed 6 months of dexpramipexole treatment. Geometric mean baseline AEC was 0.525 ± 0.465 eosinophils × 109 /L and decreased to 0.031 ± 0.019 after 6 months of dexpramipexole treatment, a 94% reduction (P < 0.001). Ten of 16 subjects had eosinophil counts reduced to ≤ 0.020 × 109 /L at month 6. In 12 subjects with nasal polyp biopsies at baseline and month 6, tissue eosinophils were reduced from a mean of 168 ± 134 to 5 ± 2 per high-power field (HPF) (P = 0.001), a 97% reduction from baseline. There was no significant reduction in TPS or improvement in other clinical endpoints. Dexpramipexole was well tolerated, with no drug-related serious adverse events. CONCLUSION: Dexpramipexole treatment produced profound eosinophil-lowering in peripheral blood and nasal polyp tissue. Despite the near-elimination of polyp eosinophils, decreased TPS and nasal symptom improvement were not observed. LEVEL OF EVIDENCE: 2 Laryngoscope, 129:E61-E66, 2019.

The Relationship of Paranasal Sinus Opacification to Hospital-Acquired Pneumonia in the Neurologic Intensive Care Unit Patient.

BACKGROUND: The association between intensive care unit (ICU) sinusitis and the development of lower airway infections remains unclear. The objective of this study was to determine the correlation between the development of radiographic sinus opacification and pneumonia in the neurologic ICU setting. METHODS: A retrospective review of head computed tomography or magnetic resonance imaging of 612 patients admitted to the neurocritical care unit at a tertiary care center from April 2013 through April 2014 was performed. Paranasal sinus opacification was measured using Lund-Mackay scores (LMS). A diagnosis of pneumonia was determined by the ICU team from radiographic, laboratory, and pulmonary data. Exclusion criteria included a history of endonasal surgery, sinonasal malignancy, facial fractures, ICU admission less than 3 days, or inadequate imaging. RESULTS: Worsening sinus opacification occurred in 42.6% of patients and pneumonia in 18.5% of patients during ICU admission. Of the patients who developed pneumonia, 71.7% also developed worsening sinus opacification (P < .001). In 80.2% of cases, the sinus opacification developed prior to the diagnosis of pneumonia. The mean highest LMS for patients who developed pneumonia was 4.24 compared to 1.99 in patients who did not develop pneumonia (P < .001). Sinus air-fluid levels or complete sinus opacification occurred in a larger proportion of patients who developed pneumonia (46.9% vs 19.4%, P < .001). Mortality rates for patients with no pneumonia or sinusitis, pneumonia only, sinusitis only, and sinusitis with pneumonia were 7.6%, 15.6%, 18.3%, and 25.9%, respectively (P < .001). CONCLUSIONS: This study finds a strong relationship between worsening sinus opacification in the neurologic ICU patient to the development of hospital-acquired pneumonia and increased mortality.

Sinus opacification in the intensive care unit patient.

OBJECTIVES/HYPOTHESIS: The significance of sinus opacification in intensive care unit (ICU) patients remains uncertain. Our objectives were to determine the baseline incidence and risk factors associated with the development of radiographic sinus abnormalities in the ICU population. METHODS: A retrospective study of head computed tomography scan or magnetic resonance imaging from April 2013 through April 2014 of 612 neurologic ICU patients at the University of Pittsburgh Medical Center Presbyterian Hospital, Pittsburgh, Pennsylvania, was performed. Images were scored by the Lund-Mackay system (LMS). Exclusion criteria included prior sinus or skull base surgery, history of sinonasal malignancy, facial fractures, ICU admission less than 3 days, or inadequate imaging. RESULTS: At the time of admission, 40.7% of patients had a LMS greater than zero (mean 2.2). Worsening sinus opacification occurred in 42.6% of patients (mean highest LMS 4.6) during ICU admission. There was a peak between days 8 and 10, during which 65% of scans exhibited worsening opacification compared to baseline. On multivariate analysis, risk factors associated with increased sinus opacification (higher LMS) included the presence of an endotracheal tube (odds ration [OR] 3.28, P < .001) or nasogastric tube (OR 3.34, P < .001) and increased length of stay (OR 2.50, P < .001). Age greater than 60 was found to be protective for the development of worsening sinus opacification (OR 0.57, P = .007). CONCLUSION: Using serial imaging and comparison control groups, this study finds that there is a high baseline incidence of sinus opacification in the ICU population. Prolonged length of stay, younger age, and presence of nasogastric or endotracheal tubes all corresponded to worsening LMS. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2433-2438, 2016.

Predictive factors in patients undergoing endoscopic sinus surgery for odontogenic sinusitis.

BACKGROUND: Odontogenic sinusitis (OS) presents a therapeutic dilemma. Evidence is lacking whether dental treatment alone is sufficient or whether patients will eventually require endoscopic sinus surgery (ESS). Our aim was to identify predictors of OS patients undergoing ESS. METHODS: Retrospective review performed of OS patients (n = 43) analyzing multiple factors including age, sex, symptoms, prior dental procedures, treatment, diabetes, immunosuppression, smoking history, retained dental hardware, oral-antral fistula (OAF), and Lund-Mackay scores (LMSs). Descriptive statistics, Wilcoxon rank sum, and logistic regression analyses were performed. RESULTS: Common presenting symptoms included facial pressure, discolored nasal drainage, and foul smell/taste. Half of patients presented either after a recent dental procedure or with dental complaints. Forty-eight percent required ESS after failing medical and dental therapy alone. Total LMS was significantly higher in the group undergoing ESS (8.3 vs 3.7; p = 0.0003). Multivariate analysis showed 2 significant predictors of undergoing ESS: (1) OMC involvement (OR 37.3, p = 0.003) and prior dental procedure (OR 7.4, p = 0.03). All patients with OAF or retained dental hardware required ESS. CONCLUSION: Forty-eight percent of patients who presented with OS underwent ESS for symptom control and prevention of complications. Patients who underwent ESS had significantly higher total LMS than those who did not. In multivariate analysis, prior dental procedures and OMC involvement significantly increased the likelihood of requiring ESS.

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial.

IMPORTANCE: Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases. OBJECTIVE: To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up. INTERVENTIONS: Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. MAIN OUTCOMES AND MEASURES: Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety. RESULTS: Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%). CONCLUSIONS AND RELEVANCE: Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01920893.

Clear anterior rhinorrhea in the population.

BACKGROUND: Clear anterior rhinorrhea is commonly observed in older adults and is widely known as "senile rhinorrhea." Although appreciated in the literature, no studies support that clear rhinorrhea increases with age. Our goal was to determine the prevalence of clear rhinorrhea in adults and the variation between young and old. Additionally, we sought to determine if clear rhinorrhea was bothersome enough for patients to seek treatment. METHODS: A questionnaire was randomly distributed to 158 adults, 76 young adults on the University of Pittsburgh Undergraduate campus, and 82 older adults at Longwood Retirement Community in 2011. RESULTS: Older subjects reported more drip and an increase in rhinorrhea over time regardless of gender (p < 0.05). Participants wanting to seek treatment reported drip occurred more often, that they used more tissues, and were more bothered by drip compared to those not wanting treatment (p < 0.05). CONCLUSION: Clear, anterior rhinorrhea affects older adults regardless of gender significantly more often and more severely than young adults (p < 0.05). The more frequent and bothersome the nasal drip, the more likely individuals would elect treatment.

Impact of quality improvement measures on the delivery of allergy immunotherapy: a 2-year follow-up.

BACKGROUND: Anaphylaxis is the most serious potential complication from allergy treatment with subcutaneous immunotherapy (SCIT). Quality measures were developed with the goal to decrease the incidence of complications resulting from SCIT and improve the safety of care provided. METHODS: The incidence and characteristics of anaphylaxis episodes resulting from SCIT was measured between 2008 and 2012 prior to implementation of quality measures including vial verification, vial testing, and standardized training across 6 allergy delivery sites. Errors and anaphylaxis rates were then tracked prospectively over a 2-year period after implementation of these process measures. RESULTS: From 2008 to 2012 there were 9 episodes of anaphylaxis or 0.02% of injections/year. Eight patients had sufficient information from which to derive meaningful data. Patient identification error led to anaphylaxis in 2 patients, dosing error in 2, and compounding error in 1 patient. In 2 patients, anaphylaxis occurred with advancement during pollen season, and in 1 patient no clear reason could be identified although she had asthma as a risk factor. After implementation of quality improvement measures the anaphylaxis rate fell to 0 of 8948 injections for years 2013 and 2014. CONCLUSION: Errors in the mixing and administration of allergy serum comprised the majority of identifiable factors that led to anaphylaxis. Implementation of quality measures, including vial verification and vial testing, can improve safety and decrease anaphylaxis rates in the delivery of allergy immunotherapy.

Clinical and pathologic characteristics of intranasal abuse of combined opioid-acetaminophen medications.

BACKGROUND: The nonmedical abuse of prescription opioids via intranasal administration is a growing problem. The objective of this study is to investigate of the typical presentation of intranasal opioid-acetaminophen abuse and outline optimal therapy. METHODS: This study was a retrospective chart review. Patients with intranasal pathology from inhalation of combined opioid-acetaminophen medications (COAMs) from 3 academic otolaryngology practices in western Pennsylvania from January 2012 to October 2012 were included in the review. RESULTS: Seven adults ranging in age from 23 to 46 years were identified with nasal complaints from the intranasal inhalation of COAMs. All patients presented with nasal pain and were found to have fibrinous necrotic nasal mucosa involving the posterior nasal cavity and nasopharynx. Of the 7 patients, 6 (85.7%) presented with a septal perforation. Pathology and culture revealed fungus in 85.7% of the patients; however, no invasive fungal disease was noted in any of the specimens. Patients did not improve with either systemic or topical antifungal therapy. Polarizable material characteristic of talc used as a tablet binder was present in the histopathology of 4 of 7 (57.1%) patients. Patients who abstained from intranasal drug use along with serial debridement demonstrated the greatest improvement. CONCLUSION: Intranasal COAM abuse causes nasal pain, tissue necrosis with potential septal and palatal perforation, and noninvasive fungal colonization. Antifungal therapy was of no benefit in the current series of patients. Current therapy should focus on recognition of the etiology of patients' pathology and encourage abstinence from intranasal use of these drugs along with serial debridements.

Medical management of allergic fungal rhinosinusitis following endoscopic sinus surgery: an evidence-based review and recommendations.

BACKGROUND: Allergic fungal rhinosinusitis (AFRS) is a subset of polypoid chronic rhinosinusitis that is characterized by the presence of eosinophilic mucin with fungal hyphae within the sinuses and a Type I hypersensitivity to fungi. The treatment of AFRS usually involves surgery in combination with medical therapies to keep the disease in a dormant state. However, what constitutes an optimal medical regimen is still controversial. Hence, the purpose of this article is to provide an evidence-based approach for the medical management of AFRS. METHODS: A systemic review of the literature on the medical management of AFRS was performed using Medline, EMBASE, and Cochrane Review Databases up to March 15, 2013. The inclusion criteria were as follows: patients >18 years old; AFRS as defined by Bent and Kuhn; post-sinus surgery; studies with a clearly defined end point to evaluate the effectiveness of medical therapy in postoperative AFRS patients. RESULTS: This review identified and assessed 6 medical modalities for AFRS in the literature: oral steroids; topical steroids; oral antifungals; topical antifungals; immunotherapy; and leukotriene modulators. CONCLUSION: Based on available evidence in the literature, postoperative systemic and standard topical nasal steroids are recommended in the medical management of AFRS. Nonstandard topical nasal steroids, oral antifungals, and immunotherapy are options in cases of refractory AFRS. No recommendations can be provided for topical antifungals and leukotriene modulators due to insufficient clinical research reported in the literature.

Defining quality metrics and improving safety and outcome in allergy care.

BACKGROUND: The delivery of allergy immunotherapy in the otolaryngology office is variable and lacks standardization. Quality metrics encompasses the measurement of factors associated with good patient-centered care. These factors have yet to be defined in the delivery of allergy immunotherapy. We developed and applied quality metrics to 6 allergy practices affiliated with an academic otolaryngic allergy center. METHODS: This work was conducted at a tertiary academic center providing care to over 1500 patients. We evaluated methods and variability between 6 sites. Tracking of errors and anaphylaxis was initiated across all sites. A nationwide survey of academic and private allergists was used to collect data on current practice and use of quality metrics. RESULTS: The most common types of errors recorded were patient identification errors (n = 4), followed by vial mixing errors (n = 3), and dosing errors (n = 2). There were 7 episodes of anaphylaxis of which 2 were secondary to dosing errors for a rate of 0.01% or 1 in every 10,000 injection visits/year. Site visits showed that 86% of key safety measures were followed. Analysis of nationwide survey responses revealed that quality metrics are still not well defined by either medical or otolaryngic allergy practices. Academic practices were statistically more likely to use quality metrics (p = 0.021) and perform systems reviews and audits in comparison to private practices (p = 0.005). CONCLUSION: Quality metrics in allergy delivery can help improve safety and quality care. These metrics need to be further defined by otolaryngic allergists in the changing health care environment.

Identifying asthma triggers.

Asthma has many triggers including rhinosinusitis; allergy; irritants; medications (aspirin in aspirin-exacerbated respiratory disease); and obesity. Paradoxic vocal fold dysfunction mimics asthma and may be present along with asthma. This article reviews each of these triggers, outlining methods of recognizing the trigger and then its management. In many patients more than one trigger may be present. Full appreciation of the complexity of these relationships and targeted therapy to the trigger is needed to best care for the patient with asthma.

Subcutaneous immunotherapy for allergic rhinitis: an evidence based review of the recent literature with recommendations.

BACKGROUND: Allergic rhinitis is a common allergic disease with increasing prevalence in Western Societies. Medical therapy is first line treatment, and is aimed at reducing symptoms of immunoglobulin E (IgE)-mediated inflammation of the nasal passages. In patients with disease refractory to medical therapy, subcutaneous immunotherapy is an option. The aim of this study is to update a recent Cochrane review with available level 1 evidence for seasonal and perennial allergic rhinitis. METHODS: A systematic review of the literature was performed from 2006 to 2011 and compared with data from a 2007 Cochrane review on immunotherapy for seasonal allergic rhinitis. We included all studies of level 1 evidence. All forms of single extract immunotherapy were considered. Studies with primary asthma related end-points were excluded. Primary end-points were instruments of clinical efficacy (ie, symptom-medication scores) and adverse events. RESULTS: We retrieved 12 level 1 studies for review. In total, 1512 patients were randomized into treatment groups, alternative study groups (alternative duration of therapy or sublingual immunotherapy [SLIT]), or placebo. Efficacy was evaluated based on reported symptom and/or medication score, validated quality of life instruments, immunological assays, challenge testing, and adverse events. CONCLUSION: Subcutaneous immunotherapy improves symptom and/or medication scores and validated quality of life measures. In addition, associated changes in surrogate markers of immunologic protection are observed. Subcutaneous immunotherapy is safe when administered to carefully selected patients and in settings capable of responding to systemic reactions. Subcutaneous immunotherapy is recommended for patients with seasonal or perennial allergic rhinitis not responsive to conservative medical therapy, and whose symptoms significantly affect quality of life.

Evidence for primary laryngeal inhalant allergy: a randomized, double-blinded crossover study.

BACKGROUND: Despite anecdotal reports, no controlled studies to date link allergen exposure with a change in vocal function or dysphonia. The aim of this study was to determine whether allergen exposure in susceptible individuals impairs vocal function. METHODS: The study was a prospective, double-blind, placebo-controlled study in which subjects serve as their own controls. The participants were 5 inhalant allergic adults with suspected dysphonia from allergies, without evidence of reactive lower airways based on methacholine challenge. All subjects were exposed to 2 experimental conditions in which they were challenged with (1) orally inhaled diluent placebo on 1 day, and (2) orally inhaled allergen on another day. Conditions were randomly ordered across subjects and separated by at least 48 hours. Phonatory threshold pressure (PTP) at the 80th percentile pitch was measured prior to diluent and allergen challenge, and 15 and 60 minutes postchallenge to assess potential change in vocal function after challenge testing. RESULTS: A repeated measures ANOVA revealed a significant main effect for treatment (allergen vs placebo, p = 0.013) with greater PTP required post-allergen challenge compared to placebo and an effect size of 0.821. CONCLUSION: A primary causal relationship between allergen exposure and impaired vocal function, as assessed by PTP, was observed in adults with documented allergy independent of asthma or nasal exposure. The current design establishes a safe model for laryngeal inhalant allergen challenge.

Use of nasopharyngeal culture to determine appropriateness of antibiotic therapy in acute bacterial rhinosinusitis.

BACKGROUND: Rhinosinusitis is one of the top 5 diagnoses for which an antibiotic is prescribed, often without a clear bacterial etiology. This study evaluated whether nasopharyngeal culture and gram stain could serve as a surrogate for endoscopically obtained middle meatal cultures in directing appropriate therapy for acute bacterial rhinosinusitis (ABRS). This study also investigated the utility of a rapid sinus test screen in differentiating bacterial from nonbacterial rhinosinusitis. METHODS: Thirty-one adult patients met inclusion criteria for ABRS. Samples were obtained from both the middle meatus and nasopharynx for Gram stain and culture. Nasal mucous samples were tested with a rapid sinus test strip measuring pH, levels of protein, nitrites, and leukocyte esterase. RESULTS: Sixty-one percent (61%) of nasopharyngeal and 48% of middle meatal samples grew pathogenic bacteria. The concordance rate was 84% between the 2 sites (p = 0.0006). The following pathogenic organisms were detected: Moraxella catarrhalis, Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus. For nasopharyngeal samples, reliance on Gram stain alone exhibited a sensitivity of 31% and specificity of 100% and, similarly, for middle meatus samples, 47% and 93%, respectively. The rapid sinus test revealed a sensitivity of 83% and specificity of 7%. CONCLUSION: Nasopharyngeal and middle meatal cultures exhibited high concordance for pathogenic bacteria. Gram stain exhibited moderate sensitivity and excellent specificity. Nasopharyngeal cultures could provide a viable method, especially in a primary care setting, for determining the appropriateness of antibiotic therapy. The rapid sinus test's lack of specificity precluded its utility in the differentiation between bacterial and nonbacterial rhinosinusitis.

Bilateral sinonasal polyposis in a patient with unilateral choanal atresia.

Sinonasal polyposis is a disorder of hyperplastic mucosal inflammation that subsequently leads to the development of smooth, pale, non-neoplastic masses. The theories on its pathogenesis are diverse and remain debated within the medical community. A distinct, widely accepted, and unifying theory is absent, and probably unrealistic given the varying possible causes. The case reported here, which demonstrates nasal polyp formation within an atretic nasal cavity, suggests that nasal airflow or aerodynamics may have little to no effect on its etiology. It also seems to provide evidence that at least in some individuals nasal polyps appear to be due to an inflammatory disorder independent of inhalant allergen challenge.

Chronic rhinosinusitis: observation or treatment.

PURPOSE OF REVIEW: Several treatment options have been proposed for chronic rhinosinusitis (CRS). Our purpose is to present a protocol/tool to treat patient symptoms, which is initially independent of assessment for presence of CRS. RECENT FINDINGS: This protocol is called the Rational Patient Experiment (RPE), and its concept is largely based on the fact that CRS is overrepresented in incidence based on surveys, because symptoms of CRS are nonspecific and overlap multiple other disorders. Patients whose symptoms persist, despite the RPE, require further objective assessment of CRS with endoscopy and computed tomography. SUMMARY: This review outlines the RPE and the evidence base for observation versus treatment with saline washes, steroids, or antibiotics.

Clinical consensus statement: appropriate use of computed tomography for paranasal sinus disease.

OBJECTIVE: To develop a consensus statement on the appropriate use of computed tomography (CT) for paranasal sinus disease. SUBJECTS AND METHODS: A modified Delphi method was used to refine expert opinion and reach consensus by the panel. RESULTS: After 3 full Delphi rounds, 33 items reached consensus and 16 statements were dropped because of not reaching consensus or redundancy. The statements that reached consensus were grouped into 4 categories: pediatric sinusitis, medical management, surgical planning, and complication of sinusitis or sinonasal tumor. The panel unanimously agreed with 13 of the 33 statements. In addition, at least 75% of the panel strongly agreed with 14 of 33 statements across all of the categories. CONCLUSIONS: For children, careful consideration should be taken when performing CT imaging but is needed in the setting of treatment failures and complications, either of the pathological process itself or as a result of iatrogenic (surgical) complications. For adults, imaging is necessary in surgical planning, for treatment of medical and surgical complications, and in all aspects of the complete management of patients with sinonasal and skull base pathology.