Multidisciplinary consensus on a stepwise treatment algorithm for management of chronic rhinosinusitis with nasal polyps

Abstract

Chronic rhinosinusitis (CRS) represents a significant health care problem in the United States and CRS patients have a significant decreased quality of life. CRS is typically divided into two phenotypes based on the presence or absence of nasal polyps which are commonly associated with CRS: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). The prevalence of CRS in the United States is estimated to range from 2.1% to 13.8% and specifically, the prevalence of CRSwNP ranges from 1.7% to 2.7% of the US population.1 The initial recommended medical therapy for CRSwNP includes saline irrigations, topical intranasal corticosteroids (INCSs) via several methods including sprays, irrigation, atomization, and short courses of systemic corticosteroids.2 An intranasal mometasone nasal spray became the first US Food and Drug Administration (FDA) approved treatment for CRSwNP in 2004. Other medical treatment options have since been developed over the past several years to address uncontrolled inflammation and persistent symptoms of CRSwNP. Recently, new therapeutic options have been approved by the FDA for the treatment of CRSwNP, including a topical intranasal fluticasone delivered via an exhalation delivery system (EDS-FLU), a mometasone eluting sinus implant, and monoclonal antibody treatments. Endoscopic sinus surgery (ESS) is also an option for patients who do not adequately respond to appropriate medical therapy. Aspirin desensitization may be used post-ESS as a preventive measure in the aspirin-exacerbated respiratory disease (AERD) endotype of CRSwNP. There are an estimated 600,000 ESSs performed annually in the US with a reported surgical recurrence rate of 16.2% within 90 months among patients with CRSwNP.3 The availability of new treatments and the presence of multiple therapeutic options including several medical and procedural interventions for a specific disease can cause confusion among providers regarding the optimal sequence to use those treatment modalities. This has resulted in the development of stepwise treatment paradigms based on evidence and expert opinion which can serve as a basis for reducing unwanted variation and improve quality of care.4, 5 Such living documents are regularly updated with the continual advent of new therapeutic modalities for patients and their providers. With the proliferation of new FDA-approved treatments for CRSwNP available to clinicians for CRSwNP patients, experts with diverse backgrounds and members of national societies vested in the advancement of the care of patients with CRSwNP (ARS, AAAAI, AAOHNS, ACAAI, AAOA) proposed a stepwise treatment paradigm that incorporates both medical and surgical strategies, based on the currently available scientific evidence for FDA-approved treatments for CRSwNP. It should be noted, however, that the views and opinions of the authors in the development of this algorithm are those of the authors alone and are not necessarily held by the organizations of which the authors are members. Treatment decisions ideally should also incorporate the use of a shared-decision making approach with CRSwNP patients.6 The scientific committee of 11 experts including both otolaryngologists and allergists was established to review published research on the management of CRSwNP and develop a stepwise treatment paradigm of FDA-approved treatment options. The committee members are recognized experts in research and clinical practice who contributed in a voluntary capacity. The panel of experts have been active participants in national societies dedicated to the advancement of the care of patients with CRSwNP, including the American Rhinologic Society (ARS), American Academy of Allergy Asthma and Immunology (AAAAI), American Academy of Otolaryngology & Head and Neck Surgery (AAOHNS), American College of Allergy Asthma and Immunology (ACAAI), and American Academy of Otolaryngic Allergy (AAOA). As stated, the views and opinions of the authors in the development of this algorithm are those of the authors alone and are not necessarily held by the organizations of which the authors are members. An English language literature search was performed between January 2000 and December 2020 for FDA-approved treatment options for CRSwNP in multiple databases including PubMed, Medline, clinicaltrials.gov, and Cochrane Library. Only FDA-approved treatment options were considered in this stepwise approach for CRSwNP because these therapies had undergone rigorous safety and efficacy evaluation. To consider all the potential non–FDA-approved treatments for CRSwNP and to incorporate them into a treatment algorithm would be a difficult and complex task. After the review of the literature for FDA-approved treatments for CRSwNP, an organized discussion occurred during which the efficacy, safety, and limitations of each treatment option were considered. After deliberation over all treatment option, the committee developed a clinical care pathway for the treatment of CRSwNP. Each step in the algorithm had to reach consensus by the committee before the next step was considered. If consensus was not achieved, further deliberation and discussion followed until a revised consensus by the committee was reached. Steps in the algorithm were considered to have achieved consensus when agreement was reached and the committee did not have any further points to discuss. Numerous studies of INCSs in CRSwNP, including meta-analyses have shown significant symptom improvement, polyp size reduction, and increased nasal airflow compared with placebo.2, 7 No serious side effects were reported in these studies. In a multinational, randomized, double-blind, placebo-controlled study a total of 354 patients with bilateral nasal polyps received either mometasone furoate nasal spray (MFNS) 200 μg once or twice daily or placebo for 4 months.8 Co-primary endpoints were (1) change in bilateral nasal polyp score (NPS) with a range of 0 to 6, and (2) change from baseline average in nasal congestion score (NCS) ranging from 0 to 3. Compared with placebo, MFNS 200 μg administered once or twice daily resulted in significantly greater reductions in bilateral NPS and NCS, as well as improvement in loss of smell, anterior rhinorrhea, and postnasal drip. MFNS 200 μg twice daily was superior to MFNS 200 μg once daily in reducing the congestion score, although there was no significant difference in NPS between these two treatment groups. MFNS was well tolerated in both groups without any significant adverse effects. The current MFNS dosage for NP is 200 μg twice daily, which was the dosage used in the dupilumab and omalizumab phase III clinical trials as standard baseline treatment.9, 10 The exhalation delivery system (EDS) with fluticasone propionate (FLU) has served as an additional method for topical corticosteroid therapy in CRSwNP management. The EDS-FLU system uniquely employs both a sealing nosepiece and a flexible mouthpiece to administer intranasal corticosteroids with simultaneous exhalation. Exhalation through the EDS effectively increases pressure in the sinonasal compartments, which are separated from the oropharynx when exhalation occurs. Compared with standard intranasal corticosteroid sprays (INSs), the EDS-FLU has demonstrated enhanced deposition of topical fluticasone to the superior and posterior regions of the sinonasal cavities.11 In two separate phase III clinical trials, NAVIGATE I and II, consisting of 646 adult subjects with bilateral nasal polyposis, EDS-FLU at both 186 μg twice per day (BID) and 372 μg BID dosages showed significantly greater reductions in two prespecified primary endpoints compared with placebo: (1) change from baseline average in NCS (0–3), and (2) change in bilateral NPS (0–6).12, 13 Over a 16-week period, subjects receiving EDS-FLU additionally demonstrated similarly superior improvements in other secondary endpoints, including the 22-item Sino-Nasal Outcome Test (SNOT-22) score and patient-reported changes in sense of smell, rhinorrhea, and facial pain/pressure. EDS-FLU was generally well tolerated by subjects, with the incidence of adverse events at rates like those for intranasal steroids, including epistaxis and nasopharyngitis. Given the favorable phase III results, EDU-FLU received approval from the FDA in the United States on September 2017 for use in adults 18 years or older with nasal polyposis. The recommended dosage is one spray (93 μg of FLU per spray) in each nostril twice daily. A dose of two sprays in each nostril twice daily was approved for use for nasal polyps, which serves as the maximum daily dosage for these patients. A corticosteroid-eluting sinus implant containing 1350 μg of mometasone furoate received FDA approval for the treatment of nasal polyps in December 2017. It is currently indicated for the treatment of CRSwNP in patients 18 years of age or older who have had prior ethmoid sinus surgery. The implant is loaded into a delivery system and placed in the ethmoid sinus cavity under endoscopic guidance. The implant may remain in the sinus cavity up to 90 days or can be removed prior to that time period if appropriate. Pivotal trials for the FDA approval of the steroid sinus implant are the RESOLVE I and II studies, which are two prospective, randomized, controlled, parallel-group, blinded clinical trials of approximately 400 patients.14, 15 For each study, patients were considered candidates if they had undergone at least one prior ESS involving the ethmoid sinus cavity for medically refractory CRSwNP, were currently considered to be candidates for revision ESS having had at least one course of oral corticosteroids in the preceding 6 months, were currently using INSs or irrigations, and with bilateral polyposis with a minimum NPS of two on at least one side. The RESOLVE I trial followed 100 enrolled patients in either the treatment group, which received the active implant, or in the control group, which underwent a sham procedure. Both groups were followed with serial nasal endoscopies for 6 months, with the treatment group achieving significant reduction in bilateral polyp grade (−0.71 ± 1.53 vs. 0.02 ± 1.16; p = 0.018) and ethmoid obstruction on a 100-mm visual analog scale (VAS) (−16.5 ± 27.80 vs. 4.96 ± 21.96; p < 0.001) compared to controls. The RESOLVE II trial studied 300 enrolled patients randomized in a 2:1 fashion into treatment and control groups over a similar time period, similar to RESOLVE I, followed by serial endoscopies graded by a centralized independent reviewers. Compared with the control group, the treatment group achieved significant reductions in both NCS (−0.80 ± 0.73 vs. −0.56 ± 0.62; p = 0.0074) and bilateral NPS (−0.56 ± 1.06 vs. −0.15 ± 0.91; p = 0.0073). At day 90, implants were also associated with significant reductions in four of five secondary endpoints compared with controls. In both studies, the overall incidence of adverse events was similar between treatment and control groups. Dupilumab is an immunoglobulin G4 (IgG4) antibody that binds to the interleukin 4 (IL-4) receptor α (IL-4Rα), a shared subunit important in both IL-4 and IL-13 signaling. Binding of dupilumab to this receptor blocks circulating IL-4 and IL-13 from binding to IL-4Rα, thereby inhibiting one of the key pathways in the type 2 inflammatory cascade. Two phase III randomized double-blind, placebo-controlled studies, SINUS-24 (n = 276) and SINUS-52 (n = 448) evaluated the efficacy and safety of dupilumab as an add-on therapy in adult patients with persistent CRSwNP.9 By week 24, dupilumab statistically improved both co-primary endpoints of NPS (−2.06, p < 0.0001) and NCS (−0.89, p < 0.0001). These pivotal studies demonstrated that dupilumab was effective in reducing nasal polyp size, decreasing sinus opacification on computed tomography (CT) scans, and reducing key CRS symptoms such as nasal congestion and anosmia compared with placebo. The most common adverse effects were nasopharyngitis, worsening asthma, headache, epistaxis, and injection-site erythema. Omalizumab is an IgG1 monoclonal antibody that binds to the Fc region of circulating IgE antibody. It prevents IgE from binding to the FcεR1, thereby suppressing one of the pathways of the type 2 cascade. There were two phase III studies (POLYP 1 and POLYP 2) that evaluated omalizumab for CRSwNP, followed by an open label study.10 In these pivotal randomized, double-blind, placebo-controlled studies, patients were either treated with omalizumab or placebo with background intranasal mometasone spray for 24 weeks. A total of 265 CRSwNP patients were enrolled. Significant change in NPS was observed between treatment and placebo groups for POLYP 1 (−1.08 vs. 0.06, p < 0.0001) and POLYP2 (−0.90 vs. −0.31, p = .0140). The change in NCS was −0.89 versus 0.35 (p = 0.0004) in POLYP 1 and −0.70 versus −0.20 (p = .0017) in POLYP 2. The SNOT-22 score also improved −24.7 versus −8.6 (p < .0001) in POLYP 1 and −21.6 versus −6.6 (p < .0001) in POLYP 2. During the open label study, the CRSwNP subjects who received omalizumab to improve in NCS, and SNOT-22 through week when omalizumab was at week there was worsening of the key during the During the open label study, the CRSwNP subjects who received omalizumab to improve in NCS, and SNOT-22 through week In the open label study for the initial placebo group and improvements of when omalizumab was at week there was worsening of the key during the It is important to the time in which clinical to a treatment are This can patients who are not to treatment and in of an therapy and medical There are several monoclonal currently for the treatment of at dupilumab and omalizumab are currently FDA In the phase III studies of CRSwNP patients, omalizumab significantly polyp size and nasal congestion compared with placebo by 24 in study of CRSwNP patients, omalizumab improved nasal symptoms such as rhinorrhea, and sense of as as 4 into in phase III studies of CRSwNP, dupilumab improved both nasal polyp size and nasal congestion within the first 4 to of to improvements in symptoms the treatment period in the SINUS-24 study and in of by the of and of patient-reported symptoms SNOT-22 and total symptoms 2 to 4 treatment patients in the dupilumab and omalizumab studies were on a background treatment of topical nasal steroid A phase III study, the efficacy of which was In a randomized placebo-controlled trial was performed in patients with and refractory nasal polyposis sinus surgery. treated with had significantly improved nasal obstruction and NPS by week when compared with placebo. The group had of nasal surgery and for systemic corticosteroids during the the among the patients on average have reported improvements in nasal symptoms as as 4 to weeks. the clinical studies for the two currently FDA-approved for CRSwNP primary endpoints at 6 This that patients should treatment with a for 6 months before clinical improvement is After this if no is the should consider the therapy and using an for type 2 inflammation the of key in and in CRSwNP patients. therapy before or surgery has not been studied and there is no evidence to this that can this for a the of of CRSwNP, the of recurrence of nasal polyps or the specific endotype for CRSwNP the of of prior the presence of to and the of these the of the CRSwNP with nasal polyps and sinus and a of without any significant This has SNOT-22 and would that initial there would be treatment with an oral corticosteroid followed by topical With the advent of a approved enhanced topical delivery system for nasal polyps, of these If there is treatment with additional like intranasal and for should be Surgery is in these is a therapy. the other is the refractory CRSwNP This is who has presence of to polyps, SNOT-22 and and to otolaryngologists and allergists would that this would a of interventions including a oral and topical therapies such as type 2 and for desensitization in as patients. in the treatment options most in CRSwNP with of the between otolaryngologists and allergists with this group of among them the most for of and shared making between the and the shared making is for all is when there can be one to the is in this a should be considered. Such an would not the to the also the to the There are not studies the these are The of is based on the at the have to of their and to if these treatments for the The of these therapies compared with those of time and studied therapies such as ESS and desensitization to be considered on an the to the be used before or sinus surgery for the management of nasal is including of and as well as should all be of the for all of these patients, treatment options are to available for to to reduction in inflammatory and to and side effects of systemic topical intranasal corticosteroids have an important in therapy for CRSwNP. 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The five were (1) nasal polyp size, (2) for systemic improved quality of improved sense of smell, and of A was as if one to two were if to four were and if all five were was reached that treatment should be evaluated of and if no in any of the five were were in the 2020 to treatment and for of therapy. 6 and months of treatment was proposed with use of patient-reported including NCS, sense of score, as well as NPS If any one of the improved reduction by reduction of NCS by sense of from anosmia to or score by and NPS by the committee that of a would be After months of to a was also by demonstrated improvements in and making was with that are currently not available to if a respond to to a treatment and to patients was also as an important It should be that the initial consensus was developed based on the current available evidence at the prior to any FDA-approved for CRSwNP and of any phase III In the of implants and EDS-FLU were not considered when this consensus was the expert also recognized that there were multiple that These (1) of treatment in with of type 2 (2) research to to of effects of of of treatment and of between and sinus and After appropriate of CRSwNP including of of and INSs are considered therapy for CRSwNP In to a short of systemic corticosteroids be recommended if not should be evaluated treatment with 1 of with of evidence of persistent inflammation and associated If there is and evidence of an oral steroid can be considered or EDS-FLU may not be if there is nasal If sinonasal inflammation the initial of should be considered when appropriate. The initial of and to for type 2 such as and total If a with CRSwNP to improve systemic steroids, or ESS may be considered For patients with to or corticosteroid asthma, who have either a to ESS or a may be an option at this the should in that ESS may also improve medical management for CRSwNP should the use of topical corticosteroids such as an steroid irrigations, or steroid sinus Aspirin desensitization can be an option for patients with and should be with surgical steroid and desensitization are not FDA-approved treatments for nasal polyps, these treatments have shown to be in symptom and inflammation If the to have persistent sinonasal inflammation ESS and to medical there are other options available that the use of the steroid eluting sinus implants in patients who have had prior sinus desensitization for patients, and oral making this is in to and availability as well as of therapeutic options. A discussion including and of each option is important in to the for the to to