A Decade of Clinical Advances in Chronic Rhinosinusitis: 2012-2022.

The field of chronic rhinosinusitis (CRS) is constantly evolving. In the past 10 years, key advancements in basic and translational research as well as clinical studies have improved our understanding and management of CRS. Notably, treatment options have expanded to include novel therapeutic drugs, devices, and surgical techniques. Assessments of patient symptoms and their impact on quality of life have become more standardized. Progress has also been made in both determining the true prevalence of CRS and recognizing comorbidities that can impact CRS severity. Practice guidelines have also shifted from expert opinion to more data-driven analyses. This review highlights major clinical advancements made in the field of CRS over the past 10 years as well as identifies current gaps in knowledge that can form the basis for new areas of study over the next decade.

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?

Efficacy and safety of treatment with biologicals for severe chronic rhinosinusitis with nasal polyps: A systematic review for the EAACI guidelines.

This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared with the standard of care. PubMed, Embase, and Cochrane Library were searched for RCTs. Critical and important CRSwNP-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab-2, omalizumab-4, mepolizumab-2, and reslizumab-1) included 1236 adults, with follow-up of 20-64 weeks. Dupilumab reduces the need for surgery (NFS) or oral corticosteroid (OCS) use (RR 0.28; 95% CI 0.20-0.39, moderate certainty) and improves with high certainty smell evaluated with UPSIT score (mean difference (MD) +10.54; 95% CI +9.24 to +11.84) and quality of life (QoL) evaluated with SNOT-22 (MD -19.14; 95% CI -22.80 to -15.47), with fewer treatment-related adverse events (TAEs) (RR 0.95; 95% CI 0.89-1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95% CI 0.78-0.92, high certainty), decreases OCS use (RR 0.38; 95% CI 0.10-1.38, moderate certainty), and improves high certainty smell (MD +3.84; 95% CI +3.64 to +4.04) and QoL (MD -15.65; 95% CI -16.16 to -15.13), with increased TAE (RR 1.73; 95% CI 0.60-5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95% CI 0.64-0.94) and improving QoL (MD -13.3; 95% CI -23.93 to -2.67) and smell (MD +0.7; 95% CI -0.48 to +1.88), with increased TAEs (RR 1.64; 95% CI 0.41-6.50). The evidence for reslizumab is very uncertain.

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.

International expert consensus on the management of allergic rhinitis (AR) aggravated by air pollutants: Impact of air pollution on patients with AR: Current knowledge and future strategies.

Allergic rhinitis affects the quality of life of millions of people worldwide. Air pollution not only causes morbidity, but nearly 3 million people per year die from unhealthy indoor air exposure. Furthermore, allergic rhinitis and air pollution interact. This report summarizes the discussion of an International Expert Consensus on the management of allergic rhinitis aggravated by air pollution. The report begins with a review of indoor and outdoor air pollutants followed by epidemiologic evidence showing the impact of air pollution and climate change on the upper airway and allergic rhinitis. Mechanisms, particularly oxidative stress, potentially explaining the interactions between air pollution and allergic rhinitis are discussed. Treatment for the management of allergic rhinitis aggravated by air pollution primarily involves treating allergic rhinitis by guidelines and reducing exposure to pollutants. Fexofenadine a non-sedating oral antihistamine improves AR symptoms aggravated by air pollution. However, more efficacy studies on other pharmacological therapy of coexisting AR and air pollution are currently lacking.

Therapeutic Potential of Dupilumab in the Treatment of Chronic Rhinosinusitis with Nasal Polyps: Evidence to Date.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is one of the most severe forms of chronic rhinosinusitis. CRSwNP is characterized by nasal and facial congestion, loss of sense of smell, rhinorrhea, and post-nasal drip. Treatments have been ineffective at controlling disease recurrence, despite multiple courses of medical and surgical therapies. Oral glucocorticoid therapy is often used to control exacerbations leaving the patient exposed to steroid-induced adverse effects. Thus, there is a clear unmet need for new treatments to achieve better control of the disease. Advances in understanding Type 2 inflammatory processes that occur in about 80% of the Western world patients with CRSwNP have resulted in new avenues for disease control. Biologics in the form of monoclonal antibodies, which target Type 2 inflammation, have helped control the severest forms of atopic dermatitis and asthma. Treatment regimes for CRSwNP now include biologics. In July 2019, dupilumab was the first monoclonal antibody to gain FDA approval for the treatment of CRSwNP. In this review, we summarize the proof of concept clinical trials and Phase 3 trials leading to approval of dupilumab, an anti-IL4 alpha receptor antagonist that blocks the actions of both IL4 and IL13. These studies show that dupilumab is a proven treatment option to control disease. Collective studies demonstrate a high safety profile. Questions arise as to the best use of dupilumab in the context of current treatment paradigms, and for which sub-population of the varied heterogeneous endotypes of CRSwNP patients. Recognizing the high cost of biologics forces the need for cost-effectiveness analysis.

Clinical Research Needs for the Management of Chronic Rhinosinusitis with Nasal Polyps in the New Era of Biologics: A National Institute of Allergy and Infectious Diseases Workshop.

The development of biologics targeting various aspects of type 2 inflammation for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) will provide clinicians with powerful tools to help treat these patients. However, other therapies are also available, and positioning of biologics in a management algorithm will require comparative trials. In November 2019, the National Institute of Allergy and Infectious Diseases convened a workshop to consider potential future trial designs. Workshop participants represented a wide spectrum of clinical specialties, including otolaryngology, allergy, and pulmonary medicine, as well as expertise in CRSwNP pathophysiology and in trial methodology and statistics. The workshop discussed the current state of knowledge in CRSwNP and considered the advantages and disadvantages of various clinical trial or observational study designs and various clinical outcomes. The output from this workshop, which is presented in this report, will hopefully provide investigators with adequate information and ideas to design future studies and answer critical clinical questions. It will also help clinicians understand the current state of the management of CRSwNP and its gaps and be more able to interpret the new information to come.

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 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.

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.

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.