A modest proposal for a new way forward for clinical research: Involve insurance companies.

Is it time for medical insurance companies to organize and fund clinical research that evaluates the role of new treatments (drugs or device-based therapies) in the context of existing clinical paradigms for common diseases?

Immunopathological features of air pollution and its impact on inflammatory airway diseases (IAD).

Air pollution causes significant morbidity and mortality in patients with inflammatory airway diseases (IAD) such as allergic rhinitis (AR), chronic rhinosinusitis (CRS), asthma, and chronic obstructive pulmonary disease (COPD). Oxidative stress in patients with IAD can induce eosinophilic inflammation in the airways, augment atopic allergic sensitization, and increase susceptibility to infection. We reviewed emerging data depicting the involvement of oxidative stress in IAD patients. We evaluated biomarkers, outcome measures and immunopathological alterations across the airway mucosal barrier following exposure, particularly when accentuated by an infectious insult.

Persistence of Sinonasal Disease Despite Mepolizumab.

The treatment paradigm for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP) is currently undergoing a rapid evolution with the development of monoclonal antibody therapies targeted at type 2 inflammatory pathways. The use of these biologic therapies in asthmatic patients, and more recently, patients with CRSwNP has produced promising results, especially for patients with severe disease. Many questions regarding the appropriate timing of these medications, whether or not these new treatment strategies should be used as a monotherapy or in conjunction with traditional therapies such as sinus surgery, the role of appropriate phenotyping, and identification of biomarkers, remain unanswered. We herein present a case of a patient with severe eosinophilic asthma and comorbid CRSwNP who failed to achieve control of his respiratory symptomology and ultimately progressed to sinus surgery despite treatment with an anti-interleukin 5 monoclonal antibody therapy (mepolizumab). Consideration is given to the mechanistic underpinnings of the reported patient's failure. This case highlights the need for further understanding of the optimal usage of these novel therapeutics in the management of CRSwNP and in the need to better understand the pathophysiology of CRSwNP.

Dupilumab improves health-related quality of life in patients with chronic rhinosinusitis with nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) negatively affects health-related quality of life (HRQoL). In a previously reported randomized clinical trial (NCT01920893), addition of dupilumab to mometasone furoate in patients with CRSwNP refractory to intranasal corticosteroids (INCS) significantly improved endoscopic, radiographic, and clinical endpoints and patient-reported outcomes. The objective of this analysis was to examine the impact of dupilumab treatment on HRQoL and productivity using secondary outcome data from this trial. METHODS: Following a 4-week mometasone furoate nasal spray run-in, patients were randomized to commence subcutaneous dupilumab (600 mg loading dose, then 300 mg once weekly for 15 weeks [n = 30], or matched placebo [n = 30]). Outcomes included scores on the CRS disease severity visual analog scale (VAS), 22-item Sino-Nasal Outcome Test (SNOT-22), 5-dimension EuroQoL (EQ-5D) general health status VAS, and 36-item Short-Form Health Survey (SF-36) for HRQoL and nasal polyp-related healthcare resource use questionnaires. RESULTS: Following 16 weeks of treatment, the proportion of patients with moderate-to-severe CRSwNP (VAS > 3-10) decreased from 86.2% to 21.4% with dupilumab and 88.0% to 84.2% with placebo. Dupilumab (vs placebo) resulted in significantly greater improvement in HRQoL, based on SNOT-22, SF-36, and EQ-5D VAS scores. The dupilumab group had a significantly lower adjusted annualized mean number of sick leave days (0.09, vs 4.18 with placebo, P = .015) and significantly greater improvement (vs placebo) in the SNOT-22 item "reduced productivity." CONCLUSIONS: In adults with CRSwNP refractory to treatment with INCS alone, the addition of dupilumab reduced disease severity, significantly improved HRQoL, and improved productivity.

Dupilumab reduces opacification across all sinuses and related symptoms in patients with CRSwNP.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with substantial sinus opacification. In a phase 2a study (NCT01920893), dupilumab, a fully human anti-IL-4Rα monoclonal antibody, improved outcomes in CRSwNP refractory to intranasal corticosteroids. We evaluated dupilumab’s effect on sinus opacification in relation to effects on nasal polyp burden, symptoms, and health-related quality of life (HRQoL) in patients with CRSwNP. METHODOLOGY: 16-week randomized, double-blind, placebo-controlled, parallel-group study in 60 adults with CRSwNP. Patients received weekly subcutaneous dupilumab 300-mg or placebo and daily mometasone furoate nasal spray. Sinus opacification was assessed using standard and Zinreich-modified Lundâ€"Mackay (zLMK) scoring. Correlation was assessed between zLMK score and CRSwNP endpoints, including nasal polyp score (NPS), SNOT-22, daily symptom scores, and UPSIT smell-test score. RESULTS: Baseline characteristics were similar across treatment groups. Mean plus/minus SD baseline LMK scores of 18.7 plus/minus 5.5 (placebo) and 18.6 plus/minus 5.0 (dupilumab) indicated severe disease with extensive opacification involving all sinuses. Baseline LMK and LMK scores correlated with NPS severity and loss of sense of smell (daily symptoms; SNOT-22 smell/taste; loss of sense of smell [UPSIT]). At Week 16, dupilumab-treated patients had significantly improved sinus opacification measured by LMK in all individual sinuses vs placebo. Dupilumab also showed similar efficacy with zLMK, with only small differences from LMK, and correlated with SNOT22 smell/taste. The most common adverse events were nasopharyngitis, injection-site reactions, and headache. CONCLUSIONS: In patients with CRSwNP, baseline LMK showed extensive sinus opacification and correlated with symptoms, HRQoL, and hyposmia. Dupilumab treatment reduces opacification across all sinuses and related symptoms in patients with CRSwNP.

Uncharted Waters: Challenges in the Era of Biologic Therapies for Nasal Polyposis.

Several new, promising, targeted therapies for nasal polyposis are being tested in large-scale clinical trials. These agents target pathways thought to be involved in the disease, including IgE, IL-5, IL-4/IL-13, and others. Designing these trials poses significant challenges: who and when to enroll is not completely clear, optimal dosing is not known, outcome measures are insufficiently robust, there are no validated biomarkers, trial regimens may not comport with how clinicians might use these drugs once approved, and cost-benefit ratios have not been assessed. Thus, there is a need to consider such questions, as trials of these novel treatments continue and these biologics become available. Despite these uncertainties about trial design, there remains a great deal of excitement in the field as we approach the dawn of a new era of therapeutic options for nasal polyposis. In this rostrum, we enumerate these issues and call for a conference that will allow stakeholders in the field to confront them as we enter this new era of opportunity to advance the treatment of nasal polyposis.

Monoclonal Antibodies for the Treatment of Nasal Polyps.

Biologics are novel therapeutic medications developed for the targeted therapy for a variety of inflammatory conditions. The biologics currently investigated for the treatment of chronic rhinosinusitis (CRS) with nasal polyps modulate specific inflammatory pathways involved in the pathogenesis of disease. Investigations have focused on the most severe form of the disease, namely, CRS with nasal polyps. It is hoped that specific targeted therapies using these biologics can significantly modulate the immune system, offering both disease control and symptomatic relief. This review summarizes those therapies that have been used to treat nasal polyps.

Allergy and asthma medication use in home-dwelling U.S. older adults.

BACKGROUND: Little is known about the use of allergy and asthma medications in older adults. This study aimed to assess the prevalence of use of these medications in older adults and evaluate predictors of their use. METHODS: Cross-sectional study using data from the National Social Life, Health, and Aging Project (NSHAP), a nationally representative sample of community-dwelling, U.S. adults 57 to 85 years (n = 2976) collected in 2005-2006. We determined prevalence of medication use and used logistic regression to evaluate sociodemographic and health factors associated with their use. RESULTS: Overall prevalence of allergy medication usage was 8.4% (most commonly antihistamines), and prevalence of asthma medication usage was 8.0% (most commonly bronchodilators). Allergy medication use was significantly associated with history of asthma (odds ratio [OR] 2.37; 95% confidence interval [CI], 1.52 to 3.69), chronic obstructive pulmonary disease (COPD) (OR 2.35; 95% CI, 1.58 to 3.51), or nasal surgery (OR 1.97; 95% CI, 1.00 to 3.86). Older age was associated with decreased allergy medication use (per decade, OR 0.80; 95% CI, 0.66 to 0.98). Although increased education was associated with increased overall allergy medication use, it was associated with decreased use of allergy medications generally contraindicated in the elderly. In contrast, the only significant predictors of asthma medication use were history of asthma (OR 19.66; 95% CI, 3.18 to 121.70) or COPD (OR 4.25; 95% CI, 0.88 to 20.44). CONCLUSION: Allergy and asthma medication use is prevalent among older adults and driven mostly by history of asthma or COPD. Additional sociodemographic factors predict allergy (but not asthma) medication use. Further studies are needed to evaluate efficacy of these drugs in the elderly.

Other Phenotypes and Treatment of Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) is difficult to define, partly because the disease recognized by clinicians is both heterogeneous and the endpoint of different pathophysiologic, genetic, and environmental interactions. For this article, we define CRS as symptoms lasting more than 3 months combined with an imaging study showing inflammation in the sinuses. This article comments on some factors that are believed to influence the expression of CRS. These factors include anatomic abnormalities, immotile cilia, age, allergic sensitization, immune deficiency, dental infections, gastrointestinal reflux, smoking, biofilm, and the microbiome. Other factors are discussed in other sections. The article concludes with an overview of treatment. In brief, nasal steroids and large volume nasal irrigations are the first line of treatment for this inflammatory disease. Antibiotics are used when infections are thought to contribute. Oral steroids are frequently used in severe disease. Endoscopy and sinus computed tomography scans are used when surgery is contemplated.

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.

Diagnostic algorithm for unilateral sinus disease: a 15-year retrospective review.

BACKGROUND: Patients presenting with unilateral sinus symptoms or nasal polyps raise concerns about sinister pathology. Yet despite the relatively common occurrence of this presentation, and its potential severity, an organized diagnostic approach to unilateral sinus disease (USD) has never been defined. The purpose of this work was to propose a diagnostic algorithm for managing patients with USD based on prior experience. METHODS: We performed a retrospective review of the medical records of all patients with USD who underwent surgical intervention and had pathological specimens during a 15-year period at an urban academic center. Nasal endoscopy and computed tomography (CT) scan findings, demographic characteristics, presenting symptoms, medical histories, and previous treatments were analyzed. RESULTS: A total of 191 patients met the inclusion criteria, 153 of whom were initially diagnosed at our center. Among the latter group, 51 (33%) presented with a nasal mass or polyp observed by endoscopy. Inverted papilloma was present in 16% of those cases, and malignant tumors comprised 14%. In contrast, of patients without an obvious nasal polyp (n = 102), 2% had inverted papilloma and 3% had malignancies. Overall, chronic rhinosinusitis was the most common diagnosis both in patients with polyps (67%) and those without nasal polyps (69%). CONCLUSION: Although USD is most likely to represent chronic inflammation, there exists a fair likelihood of finding malignant pathology, particularly in cases where patients have a unilateral polyp. Based on this review, we propose a strategy for the management of new presentations of USD.

Prelaminated fascia lata free flap for large nasal septal defect reconstruction.

Nasal septal defects can be challenging to repair, given their location, size, and the unique, tri-layered structure of the septum, which includes a thin piece of cartilage positioned between mucosal layers. The report herein presents a case of a 47 year-old woman with a large symptomatic nasal septal perforation, despite saline irrigations and ointment. Placement of a septal button or a traditional surgical approach was not considered because of the extremely large nature of the perforation. We describe the use of a tri-layered fascia lata flap prelaminated with buccal mucosa grafts to successfully repair this complicated defect. Subsequent follow-up visits showed complete repair of the defect and patent nasal passages, without the need for any debulking procedures. Based on these results, we conclude that a prelaminated fascia lata flap is a good reconstructive option for large, complex nasal septal defects, bringing thin, healthy mucosalized tissue to the defect and minimizing future surgical procedures.