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 initially received omalizumab continued to improve in NPS, NCS, and SNOT-22 through week 52. However, when omalizumab was discontinued at week 52, there was gradual worsening of the key measurements during the withdrawal period. During the open label study, the CRSwNP subjects who initially received omalizumab continued to improve in NPS, NCS, and SNOT-22 through week 52.16 In the open label study for omalizumab, the initial placebo group experienced rapid and large improvements after administration of omalizumab. However, when omalizumab was discontinued at week 52, there was gradual worsening of the key measurements during the withdrawal period. It is important to understand the time frame in which clinical responses to a given treatment are expected. This knowledge can help identify patients who are not responding to treatment and in turn prevent unnecessary continuation of an ineffective therapy and reduce medical costs. There are several monoclonal antibodies currently being investigated for the treatment of CRSwNP; at present, only dupilumab and omalizumab are currently FDA approved. In the phase III studies of CRSwNP patients, omalizumab significantly reduced polyp size and nasal congestion compared with placebo by 24 weeks.10 However, in another smaller study of CRSwNP patients, omalizumab improved nasal symptoms such as congestion, rhinorrhea, and sense of smell as early as 4 weeks into treatment.17 Similarly, in phase III studies of CRSwNP, dupilumab improved both nasal polyp size and nasal congestion within the first 4 to 8 weeks of treatment. Patients continued to report continued improvements in symptoms throughout the treatment period (24 weeks in the SINUS-24 study and 52 weeks in SINUS-52).9 Sense of smell (as measured by the University of Pennsylvania Smell Identification Test) and more global assessments of patient-reported symptoms (i.e., SNOT-22 and total symptoms scores) started improving 2 to 4 weeks after treatment initiation. All patients in the dupilumab and omalizumab studies were on a background treatment of maintenance topical nasal steroid sprays. A phase III study, SYNAPSE, evaluating the efficacy of mepolizumab, which targets IL-5, was recently published.18 In SYNAPSE, a randomized double-blind placebo-controlled trial was performed in patients with recurrent and refractory nasal polyposis after sinus surgery. Patients treated with mepolizumab had significantly improved nasal obstruction and reduced NPS by week 52 when compared with placebo. The mepolizumab group had reduced risk of nasal surgery and need for systemic corticosteroids during the 52-week period. Despite the known variability among the different biologics, patients on average have reported improvements in nasal symptoms as early as 4 to 9 weeks. However, the critical clinical studies for the two currently FDA-approved biologics for CRSwNP measured primary endpoints at 6 months. This suggests that patients should continue treatment with a biologic for 6 months before clinical improvement is assessed. After this point, if no benefit is reported, the treating physician should consider stopping the therapy and using an alternative approach. New biologics for type 2 inflammation offer the promise of targeting key cytokines involved in immune dysregulation and overexpression in CRSwNP patients. Incorporating biologic therapy before or after surgery has not been formally studied and therefore there is no evidence to answer this question definitively. Factors that can help answer this question for a particular individual include: the level of severity of CRSwNP, the frequency of recurrence of nasal polyps or ESS, the specific endotype for CRSwNP (e.g., AERD), the degree of completeness of prior ESS, the presence of comorbidities (especially moderate to severe asthma), patient preferences and finally, the cost/benefit of these interventions. Take the case of the mild CRSwNP patient with small nasal polyps and limited sinus inflammation, and a possible comorbidity of allergic rhinitis but without any significant asthma. This patient has low SNOT-22 and Lund-Mackay CT scores. Most specialists would agree that after initial evaluation there would be treatment with an oral corticosteroid burst followed by long-term topical INCSs. With the advent of a newly approved enhanced topical delivery system (EDS-FLU) for nasal polyps, many of these cases will improve.19 If there is co-morbid allergic rhinitis, treatment with environmental avoidance, additional agents like intranasal antihistamines and consideration for immunotherapy should be helpful adjuncts. Surgery is rarely needed in these cases nor is a T2 biological therapy. On the other extreme is the severe, refractory CRSwNP patient. This is someone who has multisinus diffuse inflammation, presence of remodeling, osteitis and/or inspissated secretions, anosmia, moderate to large sized polyps, high SNOT-22 and Lund-MacKay scores, and likely moderate to severe asthma. Most otolaryngologists and allergists would agree that this patient would require a host of interventions including a complete ESS, oral and topical corticosteroids, endotype-specific therapies such as type 2 targeting biologics and consideration for aspirin desensitization in aspirin triad (also known as AERD) patients. Controversy in the treatment options most frequently occurs in CRSwNP with “moderate” severity. Much of the disagreement between otolaryngologists and allergists lies with this group of patients; among them exists the most room for consideration of patient-specific factors and shared decision making between the patient and the treating physician. Although shared decision making is necessary for all patient encounters, it is especially required when there can be more than one way to achieve the desired end results. Also, it is especially in this moderate category where a cost/benefit analysis should be considered. Such an analysis would encompass not only the cost to the patient, but also the cost to the healthcare system. There are not enough studies comparing the different approaches but these are surely needed. The value of healthcare is based on obtaining the best results at the best possible cost. Clearly, T2 biologics have prices high enough to merit thorough analysis of their real need and to assess if these treatments maybe prescribed for the long term. The value of these therapies compared with those of time tested and better studied therapies such as ESS and aspirin desensitization certainly need to be considered on an individual basis. Therefore, the answer to the question “Should biologics be used before or after sinus surgery for the management of nasal polyps?” is “It depends.” Many factors, including severity of disease, comorbid conditions, cost, and value, as well as patient preference should all be part of the decision-making process. Fortunately for all of us treating these challenging patients, more excellent treatment options are beginning to become available for use. Corticosteroids act to induce anti-inflammatory gene transcription while repressing pro-inflammatory gene transcription, leading to reduction in tissue inflammatory cell infiltration and cytokine production. Due to short-term and long-term side effects of systemic corticosteroids, topical intranasal corticosteroids have assumed an important role in maintenance therapy for CRSwNP. The currently available FDA-approved modalities vary from anterograde spray to exhalation delivery to coated stents and implants. Off-label delivery of corticosteroids in nasal saline irrigations, atomizers, or gels is also utilized in clinical practice. In a double-blinded placebo-controlled trial, off-label corticosteroid irrigations were shown to have superior clinical outcomes compared with a standard nasal corticosteroid spray when used in CRSwNP patients following ESS. In this study, 44 patients who underwent ESS received either 2 mg of mometasone daily via nasal spray or 240 ml irrigation for 12 months. Each patient was given both a nasal irrigation bottle and spray device, but were blinded as to which contained the steroid. After 12 months of follow-up, the steroid irrigation group was found to have significantly greater improvement in Lund-MacKay scores, nasal blockage, and modified Lund-Kennedy scores compared with the spray group.20 Based on the evidence in the literature, corticosteroid irrigations have been strongly recommended in the treatment of CRSwNP by the International Consensus Statement on Rhinosinusitis.2 Although this current multidisciplinary algorithm specifically focuses on FDA-approved treatments for CRSwNP, off-label steroid irrigations were included given the high level of evidence for this non–FDA-approved therapy. Limitations of topical corticosteroids include adequate and effective delivery into the paranasal sinuses. Penetration of the nasal cavity and middle meatus is poor with anterograde pump sprays, which largely deposit in the nasal valve region and inferior turbinate.20 The EDS improves deposition in the posterior nasal cavity, middle meatus, and superior meatus but with either approach, the three-dimensional anatomy of the sinuses can limit access, which can be further compounded by the presence of polyps. Surgical removal of polyps and opening of the sinuses seeks to increase access for topical application, particularly using a high-volume, low-pressure delivery system.21 However, once polyps recur, even after complete sinus surgery, it becomes difficult to deliver steroids beyond the polyp mucosal surface. Eosinophilic mucin can also impair topical drug delivery into the paranasal sinus mucosa. Nonadherence with topical nasal steroid dosing and administration techniques may further reduce effectiveness of these treatments. Sinus surgery allows for placement of corticosteroid-eluting sinus implants, which avoid issues of adherence by remaining in place for months. The major limitation of such implanted elution devices is that the effect is confined to mucosa directly in contact with the implant, so the majority of the total sinus mucosal surface area remains untreated. Also, because the drug is reduced from the implant over time, effectiveness decreases temporally and there is a need for multiple procedures to remove and replace implants to maintain control over persistent inflammation.22 The latest addition to the medical armamentarium for nasal polyps is the option for biologic therapy. Early efficacy results are promising for these agents, particularly anti-IL-4Rα (dupilumab) and anti-IgE (omalizumab). The relative inexperience with these agents presents some degree of limitation to their use at this time, but further awareness and education regarding the role of type 2 inflammation in CRSwNP and associated comorbid conditions is changing the landscape for multi-disciplinary treatment by otolaryngologists, allergist/immunologists, and pulmonologists. Practical limitations include the high cost of biologics relative to other therapies, as well as obtaining insurance authorization in many cases. Adherence and comfort-level with self-injection may be a limitation for many patients. Side effects in general appear to be acceptable and are therefore not limiting. Similar to other medical therapies, the benefit of treatment is transient unless the medication is continued. This raises potential long-term concerns regarding cumulative cost and possible yet-unknown health sequelae that could limit use of biologics as a primary single-agent therapeutic modality for CRSwNP treatment. Patients with CRSwNP represent a significant direct cost burden to the healthcare system. A large insurance database study estimated an annual incremental cost of $11,507 compared with controls without CRS.23 The highest cost is seen in those undergoing ESS, with overall costs of $26,724 in the year of surgery. These direct costs do not account for indirect costs from lost productivity, estimated at $7182/year, and do not include the substantial yearly cost of biologics.24 Considering these figures, increased attention has been given to understanding the economic implications of various treatment strategies, including surgical and medical options. When comparing possible treatments, it is important to consider perspective, as specific costs to patients, hospital systems, insurance providers, governments, and society may be quite different. Evaluating the timeframe of treatment is also an important consideration, as ESS has high up-front costs but benefits may be sustained. Biologics, in contrast, may have lower initial costs but require ongoing, long-term treatment. There have been a number of cost utility analyses for CRS comparing ESS to ongoing medical therapy. One study suggested with 74% certainty that ESS was the most cost-effective strategy for any willingness to pay (WTP) threshold >$25,000 and time horizon greater than 3 years.25 A similar study in a separate cohort estimated with 95% certainty that ESS was the more cost-effective strategy for CRSwNP at an WTP >$20,000.26 It is important to point out that these studies assumed a 5-year revision surgery rate of roughly 20% and were done before the availability of newer treatments such as biologics. A more recent cost utility analysis comparing ESS to dupilumab over a 36-year time horizon showed that ESS was the more upfront cost-effective strategy at any frequency of revision surgery and at any yearly cost of dupilumab >$855.27 Although these analyses are instructive, they represent models and are not always easy to extrapolate to the individual patient. Regardless, these data informed the recommendation to consider ESS before biologics in most cases. In November 2018 and January 2020, the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized two multidisciplinary expert board meetings comprised of rhinologists, pulmonologists, and allergists from Europe and the United States.28, 29 The purpose of the summit was to assess the available evidence and develop proposals for the role of biologics in CRSwNP patients with or without asthma as well as better define CRS control and disease severity. The EUFOREA expert team initially established five criteria that were considered essential in the decision-making process for administration of biologics in CRSwNP patients: (1) evidence of type 2 inflammation (i.e., biological biomarker), (2) need for systemic corticosteroids in the past 2 years, (3) significant impairment of quality-of-life, (4) significant loss of smell, and (5) diagnosis of comorbid asthma. Consensus was reached that biologics were indicated in patients with bilateral nasal polyposis and a history of prior surgery if three of the five criteria were met. However, in patients with bilateral nasal polyposis without a history of prior surgery, four of the five criteria would need to be met for biologics to be prescribed. The EUFOREA update in 2020 further highlighted the definition of “uncontrolled CRS” as persistent or recurring inflammation despite INCS, having received at least one course of systemic corticosteroids in the preceding 2 years and/or prior ESS. Disease severity was further defined by EUFOREA as patients with a NPS of ≥5 and with persistent symptoms despite INCS. Persistent symptoms were also defined by several parameters including a loss of smell score ≥2 points, NCS ≥2 points, SNOT-22 score of ≥35 points and total symptom VAS ≥5 out of 10 cm. Contraindications to initiation of biologic treatment were also delineated and were as follows: (1) CRSsNP and lack of signs of type 2 inflammation, (2) cystic fibrosis, (3) unilateral nasal polyps, (4) mucoceles, (5) contraindications such as immunodeficiencies, and (6) patient-related factors such as nonadherence. The 2019 EUFOREA expert team aimed to define response to biologic therapy. The following five criteria were identified: (1) reduced nasal polyp size, (2) reduced need for systemic corticosteroids, (3) improved quality of life, (4) improved sense of smell, and (5) reduced impact of comorbidities. A response was categorized as being “poor” if one to two criteria were met, “good” if three to four criteria were met, and “excellent” if all five criteria were met. Consensus was reached that treatment response should be evaluated after 16 weeks of biologic therapy, and discontinued if no response in any of the five criteria were observed. Several modifications were made in the 2020 update to better define treatment response and criteria for continuation of biologic therapy. Evaluation after 6 and 12 months of biologic treatment was proposed with use of patient-reported outcome measures including SNOT-22, VAS, NCS, sense of smell score, as well as NPS score. If any one of the outcome measures improved (SNOT-22 reduction by ≥8.9, VAS reduction of ≥2 cm, NCS decrease by ≥0.5, sense of smell from anosmia to hyposmia/normosmia or smell score increase by ≥0.5, and NPS decrease by ≥1), the committee agreed that continuation of a biologic would be indicated. After 12 months of treatment, adequate response to a biologic was also defined by demonstrated continuing improvements in subjective and objective outcomes. Shared decision making was advised with recognition that biomarkers are currently still not available to determine if a patient will respond to treatment. Multidisciplinary collaboration to help select a biologic treatment and continue to manage patients was also highlighted as an important consideration. It should be noted that the initial EUFOREA consensus document was developed based on the current available evidence at the time, prior to any biologic being FDA-approved for CRSwNP and publication of any phase III data. In addition, the role of steroid-releasing implants and EDS-FLU were not considered when this consensus document was created. Finally, the EUFOREA expert team also recognized that there were multiple unmet needs that still required future research. These areas included (1) evaluation of biologic treatment in CRSsNP with signs of type 2 inflammation, (2) biomarker research to identify responders to biologic treatment, (3) evaluation of disease-modifying effects of biologics, (4) evaluation of required duration of treatment and discontinuation criteria, (5) protocols of long-term treatment, (6) interplay between biologics and sinus surgery, and (7) health-economics research. After appropriate diagnosis of CRSwNP including assessment of symptoms, evaluation of objective findings, and comorbidities, INSs are considered first-line therapy for CRSwNP (Figure 1A). In addition to INS, a short burst of systemic corticosteroids could be recommended if not contraindicated. Symptom response should be evaluated after treatment with 1 month of INS coupled with assessment of objective evidence of persistent inflammation and associated comorbidities. If there is subjective and objective evidence of ongoing inflammation, an oral steroid can be considered or EDS-FLU. EDS-FLU may not be beneficial if there is complete nasal blockage. If sinonasal mucosa inflammation remains after the initial treatment, evaluation of contributing comorbidities should be considered when appropriate. The initial evaluation could consist of allergy testing, aspirin challenge, and possibly blood work to evaluate for type 2 biomarkers such as peripheral eosinophils and total IgE. If a patient with CRSwNP fails to improve after INS, systemic steroids, or EDS-FLU, then ESS may be considered (Figure 1B). For patients with moderate to severe asthma or corticosteroid dependent asthma, who have either a contraindication to ESS or decline surgery, a biologic may be an option at this point. However, the clinician should keep in mind that ESS may also improve asthma. Postoperative medical management for CRSwNP should include the use of topical corticosteroids such as an INS, steroid irrigations, EDS-FLU, or steroid sinus implant.30, 31 Aspirin desensitization can be an option for patients with AERD and should be timed appropriately with surgical intervention. Even though steroid irrigations and aspirin desensitization are not FDA-approved treatments for nasal polyps, these treatments have shown to be efficacious in symptom and inflammation control. If the patient continues to have persistent sinonasal inflammation despite complete ESS and adherence to postoperative medical management, there are other options available (Figure 1B) that include the use of the steroid eluting sinus implants in patients who have had prior sinus surgery, biologic therapy, aspirin desensitization for AERD patients, and oral corticosteroids. Shared decision making throughout this process is advocated in order to determine patient preferences and availability as well as cost of therapeutic options. A thoughtful discussion including risks and benefits of each option is important in order to achieve the best outcome for the patient. Joseph K. Han: consultant to Sanofi Genzyme, Regeneron, Astra Zeneca, Medtronic, Optinose, Genentech, Novartis, GlaxoSmithKline. John V. Bosso: Advisory Boards/Consultant: Sanofi-Genzyme, AstraZeneca, Novartis, GSK, Regeneron. Zachary M. Soler: Consultant to Novartis, Olympus, Lyra, Optinose. Medical Board Sinusonic. Stella E. Lee: Advisory board: Sanofi Genzyme, Regeneron, Astra Zeneca, Genentech, Novartis, GlaxoSmithKline. Jivianne T. Lee: Consultant: Sanofi-Genzyme, Stryker ENT.