The new england journal of

Clinical Practice

Caren G. Solomon, M.D., M.P.H., Editor Chronic Rhinosinusitis with Nasal Polyps

Claire Hopkins, B.M., B.Ch., D.M.​​

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence sup- porting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.

A 50-year-old man presents with a 5-year history of progressive nasal obstruction From Guy’s and St. Thomas’ Hospitals, and reduction in his sense of smell. Symptoms were initially intermittent but have London. Address reprint requests to Dr. Hopkins at the Ear, , and Throat become persistent and very bothersome, with the patient rating them as severe. He Department, Guy’s Hospital, Great Maze reports sleep disturbance and postnasal drip and recently received a diagnosis of Pond, London SE1 9RT, United Kingdom, . Alcohol consumption exacerbates his . Anterior rhinoscopy or at ­claire​.­hopkins@​­gstt​.­nhs​.­uk. reveals pale, fleshy polyps filling both sides of the . How would you fur- N Engl J Med 2019;381:55-63. ther evaluate and manage this case? DOI: 10.1056/NEJMcp1800215 Copyright © 2019 Massachusetts Medical Society.

The Clinical Problem asal polyps are benign inflammatory masses, arising from the mucosa of the nose and . They are considered to be a An audio version subgroup of chronic rhinosinusitis, and clinical diagnosis is made on the of this article N is available at basis of the presence of sinonasal symptoms (Table 1) for more than 3 months and the visualization of polyps in the nasal cavity (Fig. 1).1 NEJM.org Symptoms substantially affect patients’ quality of life.2 Nasal obstruction and reduction in the sense of smell are the most frequent symptoms (present in 97% and 90%, respectively, of patients with polyps who present for surgical treatment3); sleep disturbance and nasal discharge are also common. The size of the nasal polyps correlates well with subjective nasal obstruction but does not predict the severity of other symptoms.4 The incidence of nasal polyps increases with age to a peak in the sixth decade.5 The prevalence, on the basis of endoscopic examination in a Swedish population, is estimated at 2.7% of adults and is twice as high among men as among women.6 Nasal polyps are very uncommon before the third decade of life7; a diagnosis of polyps in childhood should prompt investigation for . Lower rates of for polyps have been reported in black and Hispanic populations than in white populations,8 but this finding may reflect differing access to care or behav- ioral differences rather than lower prevalence. Chronic rhinosinusitis includes a heterogeneous group of conditions with differ- ing pathophysiologies. Two main subgroups are described: with and without nasal polyps. Chronic rhinosinusitis without nasal polyps may be idiopathic or odon- togenic or may be caused by immunodeficiency, vasculitis, or other autoimmune conditions. The majority of cases of chronic rhinosinusitis with nasal polyps are idiopathic but may also occur as part of genetic, metabolic, or immunologic diseases (Table 2). The majority of white patients with chronic rhinosinusitis with nasal polyps

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Key Clinical Points Chronic Rhinosinusitis with Nasal Polyps • Chronic rhinosinusitis with nasal polyps typically manifests as nasal obstruction, reduction in sense of smell, nasal discharge, and sleep disturbance, with adverse effects on quality of life. • In patients with mild symptoms, intranasal glucocorticoids and saline irrigation should be prescribed, and patients should be educated regarding the need for long-term adherence to . • In patients with more severe symptoms, judicious short-term use of systemic glucocorticoids can ameliorate symptoms. • Surgery to remove polyps warrants consideration in patients whose symptoms are not controlled with glucocorticoids, but rates of relapse and repeated intervention are high; intranasal glucocorticoids are continued after surgery. • Biologic agents targeted at the inflammatory cytokines that have been shown to be involved in pathophysiology are currently under study.

have a type 2 pattern of ,12,13 char- workers who have been exposed to occupational acterized by eosinophilia and elevated levels of dust, particularly among those with longer-dura- interleukin-4, interleukin-5, and interleukin-13 tion exposure.19 A survey of persons with and those cytokines. This finding may not apply to other without chronic airway disease indicated that al- racial groups, but further study is required. most one third of patients with chronic rhinosi- Up to 60% of patients with polyps have lower nusitis with polyps, and up to 83% of those with airway disease, including coexisting asthma,14,15 -exacerbated , reported typically with onset in adulthood. With the excep- that alcohol consumption exacerbated their symp- tion of central compartment atopic disease, which toms, such that many abstained from drinking is an IgE-mediated allergic disease triggered by alcohol.20 inhalant allergens, the association between nasal polyps and allergic remains unclear; nasal Strategies and Evidence polyps are reported to be less common in persons with allergic rhinitis7 and childhood-onset allergic Diagnosis and Evaluation asthma16 than in the general population. Smoking The differential diagnosis includes chronic rhino- does not seem to be a strong risk factor for chron- without polyps, rhinitis, structural abnor- ic rhinosinusitis with nasal polyps.17 Genetic fac- malities of the nose, and neurologic causes of hy- tors are likely to play a role in the pathogenesis, posmia. Rhinitis is highly prevalent, affecting up and patients with this condition are more likely to 30% of adults.21 The resulting pale, edematous than controls to report having a first-degree rela- turbinates may be misdiagnosed as nasal polyps tive with nasal polyps.18 An increased prevalence (Fig. 2). In patients with rhinitis, nasal congestion of nasal polyps has been described among textile may fluctuate in severity and alternate from side to side with exaggeration of the nasal cycle (a phys­ Table 1. Diagnostic Criteria for Chronic Rhinosinusitis iologic cycle of congestion and decongestion in with Nasal Polyps. each nasal passage, causing alternating nasal re- sistance).22 The presence of hyposmia suggests Inflammation of the nose and paranasal sinuses that chronic rhinosinusitis with or without polyps is characterized by two or more symptoms, 23 at least one of which should be either nasal rather than rhinitis. blockage (congestion) or nasal discharge: Nasal polyps usually occur in both nasal pas- Nasal obstruction and congestion or nasal dis- sages, although they may be asymmetric in size; charge (anterior or posterior) polyps that occur in only one nasal passage should With or without facial pain or pressure arouse suspicion for benign or malignant tumors, With or without reduction or loss of smell particularly in the presence of bloodstained nasal 24 Endoscopic signs of nasal polyps or evidence of discharge. A meningocele, either congenital or nasal polyps on computed tomography acquired after trauma, may also be mistaken for a nasal polyp.

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Investigations able in primary care for the evaluation of overall is usually necessary to confirm the symptom severity (with scores from 0 to 3 indi- diagnosis of nasal polyps, although anterior rhi- cating a mild condition, >3 to 7 a moderate con- noscopy may allow large polyps to be visualized. dition, and >7 a severe condition)29 but captures Computed tomographic (CT) scans are usually less clinical information. performed as part of surgical planning in cases Patients should also be asked about lower re- that are recalcitrant to medical therapy or before spiratory symptoms and whether nasal or respira- biopsy. Biopsy is rarely required for diagnostic tory symptoms are exacerbated by intake of salicy- purposes unless the polyps are observed on only lates (in nonsteroidal agents and dietary sources one side. However, histopathological examina- such as fresh berries and nuts). Measurement of tion may provide useful prognostic information; peak expiratory flow should be considered. Fur- tissue eosinophilia (>10 cells per high-power field) ther investigations are often not required unless has been associated with higher rates of recur- the polyps are thought to be part of a broader rence.25 condition, although a full blood count (to evalu- Symptom severity should be assessed routinely ate eosinophilia) and total IgE levels may be use- (Fig. 3). A systematic review27 and a core outcome ful in guiding treatment and predicting progno- set for chronic rhinosinusitis28 recommend the use sis. Skin-prick testing is indicated, particularly in of the 22-item Sinonasal Outcome Test (SNOT-22) younger patients in whom central compartment in secondary care to rate the severity of symptoms. atopic disease is suspected. This questionnaire assesses 22 symptoms or social and emotional consequences of the condition, each Topical Therapy on a scale from 0 to 5, with higher numbers In patients with mild symptoms, appropriate treat- indicating worse consequences. A simple 10-cm ment includes intranasal glucocorticoids and sa- visual-analogue scale is also useful and reason- line irrigation.1,26 Saline irrigation is recommend-

Rhinoscopic view Left Sagittal View Coronal Section

Septum Superior turbinate

Left lateral Polyps under wall middle Polyp Middle turbinate Septum Superior turbinate turbinate

MAXILLARY Turbinate SINUS

Polyps Inferior turbinate Inferior turbinate

Figure 1. Nasal Polyps Seen in Left Nasal Cavity on Anterior Rhinoscopy. Polyps can be seen in the nasal cavity, filling the space between the and the middle and inferior turbinates on the lateral wall. Polyps may differ in color. They are often yellow, as shown, but may also appear as white or pink grapelike masses in the nose.

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Table 2. Diseases Associated with Nasal Polyps.

Disease Comments Idiopathic nasal polyps Men are more commonly affected than women; peak incidence occurs in sixth decade of life Aspirin-exacerbated respiratory disease9 Women are more commonly affected than men; associated with onset at younger age and with more severe disease and higher rates of re- currence after surgery than idiopathic nasal polyps; asthma may be difficult to control; involves sensitivity to salicylates, in both nonste- roidal agents and dietary sources (e.g., fresh berries and nuts); 10% of patients also have reaction to acetaminophen Allergic fungal rhinosinusitis10 IgE-mediated response to fungal allergens causing intense eosinophilic inflammation associated with accumulation of eosin-rich mucin; may lead to sinus expansion with proptosis and visual disturbance; wide geographic variation in prevalence, with highest reported rates in the southwestern United States Vasculitis (e.g., eosinophilic granulomatosis Prodromal stage of polyps and asthma that is difficult to differentiate with polyangiitis) from conditions above; high index of suspicion is needed; patients often feel systemically ill and fatigued; patients have elevated eosin- ophil levels (>10% of white-cell count) Cystic fibrosis Consider if onset of nasal polyps is before 16 yr of age; nasal polyps de- velop in 20% patients with cystic fibrosis; disease is characterized by neutrophilic inflammation Central compartment atopic disease11 IgE-mediated allergic disease triggered by inhalant allergens (e.g., house dust mite, molds, or pollens); typically occurs in slightly younger pa- tients than do idiopathic polyps, with often commenc- ing in childhood; polyps arise from middle turbinates with centrally sited sinus disease; treatment focuses on management of

ed by most guidelines. Although evidence from For moderately or severely symptomatic nasal randomized trials is limited and of low quality,30 polyps, clinical experience suggests that intrana- clinical experience supports improved symptom sal delivery of glucocorticoids may be improved by control with nasal saline. Adverse effects are un- the use of topical drops1 or, in patients who have common and usually mild (nasal irritation and had previous sinus surgery with open cavities, by epistaxis). high-volume irrigations. The effectiveness of top- There is a large body of evidence supporting ical glucocorticoids is believed to be enhanced af- the effectiveness of intranasal glucocorticoids over ter surgery, probably owing to improved access.33 placebo in terms of abatement of symptoms (na- A systematic review showed a greater reduction sal obstruction, , and loss of sense of in the polyp score with topical glucocorticoids in smell) and reduction in polyp size.1,30 There is a patients who had undergone sinus surgery than low incidence of adverse events, with nasal irrita- in patients who had never had sinus surgery. tion and epistaxis being the most common. Al- Furthermore, the delivery of glucocorticoids by though formulations do not appear to differ in means of high-volume (240 ml) nasal irrigation effectiveness,30 their absorption is varied. The sys- has been shown to be more effective in reducing temic bioavailability of second-generation com- endoscopic evidence of recurrence than delivery pounds ( and fluticasone) is less than of an equivalent dose by means of in 1%,31 and they are safe for long-term use, without patients after sinus surgery.34 Mometasone was treatment breaks. They are probably underused, used in this trial, but and flutica- presumably owing to both underprescribing and sone are commercially available in liquid formu- poor adherence. A study involving data from an lations. Patients should be educated regarding administrative database showed that only 20% appropriate delivery techniques (Table S1 in the of patients with chronic rhinosinusitis used topi- Supplementary Appendix, available with the full cal glucocorticoids, and most at an inappropriately text of this article at NEJM.org) and the need for low dosage.32 long-term adherence to therapy.

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Rhinoscopic view Right Sagittal View Coronal Section

Superior turbinate Septum Right lateral wall Middle turbinate Inferior Middle turbinate turbinate Septum Superior turbinate

Hypertrophic inferior turbinate

Hypertrophic inferior turbinate

Figure 2. Image from Anterior Rhinoscopy of Right Nasal Cavity in a Patient with Allergic Rhinitis. The mucosa of the inferior turbinate is pale and cobblestoned, with strands of mucus seen between the turbinate and septum. The hypertrophied turbinate can be seen arising from the lateral wall and can be mistakenly diagnosed as a nasal polyp.

Systemic Therapy Agents Glucocorticoids Staphylococcus aureus may be isolated in up to 50% In patients with severe symptoms or in whom ini- of patients with chronic rhinosinusitis with nasal tial treatment has failed to achieve adequate con- polyps, with higher rates of positive cultures and trol, a short course of oral glucocorticoids may be a higher incidence of detection of S. aureus supe- considered. A Cochrane review of eight random- rantigens (which result in excessive immune ac- ized trials35 showed a short-term benefit of a short tivation) among patients than among controls.36 course (2 to 3 weeks) of oral glucocorticoids of Treatment that is aimed at reducing microbial load varying doses (generally averaging 0.5 mg per kilo- or eradicating pathogens from the sinuses involves gram of body weight daily, with a maximum daily an assumption that these play a role in causing dose of 60 mg), as compared with placebo or no or propagating chronic rhinosinusitis. However, treatment. Significant improvements were noted whether sinus microbiota actually cause exacer- in polyp size, nasal symptoms, or quality of life, bations or whether the changes seen are related but the data were considered to be of low quality. to the inflammatory process remains unclear. Gastrointestinal adverse effects and insomnia In a trial in which patients with chronic rhino- were more common with active treatment than sinusitis with nasal polyps were randomly assigned with control. By follow-up at 3 to 6 months, there to receive doxycycline (3-week course), methyl- was little or no difference in symptoms between prednisolone, or placebo, doxycycline and meth- patients who were treated with oral glucocorti- ylprednisolone each significantly reduced polyp coids and those who were not, but all the patients size relative to placebo.37 Methylprednisolone ap- were treated subsequently with maintenance na- peared to have a greater benefit and faster onset sal glucocorticoids. The potential long-term harms of action, whereas doxycycline appeared to have of repeated short courses of systemic glucocorti- a more sustained effect.37 Another randomized coids (including bone loss) must be weighed care- trial involving patients who had undergone sur- fully against potential benefits. gery for nasal polyps showed a lower incidence

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Patients with nasal polyps

Polyps in one nasal passage, Polyps in both nasal passages a visual change, or bloodstained and mild symptoms (VAS score <4) discharge

Administer intranasal glucocorticoid spray and saline Provide an urgent referral irrigation; encourage adherence to therapy

Polyps in both nasal passages and moderate-to-severe symptoms (VAS score ≥4)

Administer intranasal glucocorticoid drops and saline irrigation; consider oral glucocorticoids and doxycycline

Ongoing symptoms or Good response short-lived response

Intranasal glucocorticoid spray and Endoscopic sinus surgery saline irrigation maintenance; after CT evaluation encourage adherence to therapy

Early recurrence

Consider mode of glucocorticoid delivery (delivery devices, irrigations, stents) and long-term use of antibiotic or biologic agents (these treatments are areas of uncertainty, so strong recommendations cannot be made)

Figure 3. Algorithm for Treatment of Adults with Chronic Rhinosinusitis and Nasal Polyps. The treatment algorithm is based on current guidelines and best available evidence.1,26 A 10-cm visual-analogue scale (VAS) is useful and reasonable in primary care for the evaluation of overall symptom severity (with scores from 0 to 3 indicating a mild condition, >3 to 7 a moderate condition, and >7 a severe condition).

of early polyp recurrence, as assessed by endos- trials have shown no benefit of antifungal therapy, copy and CT, among patients given macrolides either orally or topically, in patients with chron- than among controls.38 Available data suggest that ic rhinosinusitis with nasal polyps.39 long-term use of antibiotic agents may be consid- ered as an adjunct to treatment in patients with Surgery chronic rhinosinusitis with nasal polyps, but fur- Endoscopic sinus surgery is usually reserved for ther evaluation is needed, including evaluation of patients who have not had a benefit from medical the effect on antibiotic resistance. Randomized therapy with regard to symptoms, patients who

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have contraindications to or adverse effects from have withdrawn from trials). Using a lower main- such therapy, or rarely, patients who have actual tenance dose may improve adherence; current or impending complications, such as loss of vi- regimens vary between 100 mg and 650 mg of as- sion. Surgery aims to remove polyps as well as to pirin daily, and trials comparing relative effective- improve access to ongoing topical therapy; as ness have been limited. discussed above, the effectiveness of intranasal glucocorticoids is enhanced after sinus surgery. Areas of Uncertainty A recent consensus to define indications for sinus surgery40 recommended that adult patients with A new exhalation delivery device, in which nasal uncomplicated chronic rhinosinusitis with nasal delivery is driven by the patient’s exhaled breath, polyps could be appropriately offered surgery when has been shown to improve symptom control there was objective evidence of chronic rhinosi- significantly, with complete polyp elimination in nusitis on CT imaging, there was a minimum trial 25% of patients in a placebo-controlled trial, but of 8 weeks of treatment with a topical intranasal the treatment has not undergone direct compari- glucocorticoid plus 1 to 3 weeks of systemic glu- son with standard delivery systems.47 Glucocorti- cocorticoids (provided that there were no contra- coid-eluting stents are also being developed for indications), and there was a post-treatment total use before and after sinus surgery, with the aim SNOT-22 score of 20 or more, which is consistent of higher local concentrations leading to greater with at least moderate severity. control of inflammation and overcoming adher- Surgery is conventionally performed while the ence issues. A randomized trial showed signifi- patient is under general anesthesia, although of- cant reductions in the incidence of surgery, in fice-based procedures performed while the patient symptom scores, and in obstruc- is awake are becoming more widespread.41 Sur- tion with a bioabsorbable, glucocorticoid-eluting gery usually involves both the removal of polyps stent, as compared with a sham procedure48; more obstructing the nasal cavity and procedures to data are needed to inform the cost-effectiveness open and extirpate polyps from the paranasal and role of such stents in practice. Data are in- sinuses. consistent regarding a possible benefit of the use In a large binational cohort study, persons who of leukotriene inhibitors as an adjunct to gluco- underwent surgery had long-term, large improve- corticoid therapy. ments in health-related quality of life that were Monoclonal antibodies that directly target the maintained over a period of 5 years.42 However, inflammatory pathway have been suggested as polyp recurrence is common. Recurrent polyps another therapy for chronic rhinosinusitis with have been reported on endoscopy in 40% of pa- polyps. In small, short-term, randomized trials, tients 18 months after surgery,43 and in the large biologic agents that are approved for the treatment cohort study, 20% of patients underwent a revi- of refractory allergic asthma, including omali- sion sinus procedure within 5 years.42 Data from zumab49 (anti-IgE), mepolizumab50 (anti–interleu- randomized trials indicate that postoperative use kin-5), and dupilumab51 (anti–interleukin-4 and of intranasal glucocorticoids improves symptom anti–interleukin-13) significantly reduced both control and endoscopic scores and reduces the symptom scores and polyp size. Clinically sig- need for rescue therapy with prednisolone.44 On- nificant reductions52 in mean polyp scores were going medical therapy is therefore considered to observed in 60% and 70% of participants in the be an essential part of surgical management, and and trials, respectively, patients must be counseled appropriately before with a medium effect size in terms of reduction and after surgery. in the SNOT-22 score. Several ongoing phase 3 In patients with aspirin-exacerbated respirato- trials are further evaluating these agents in pa- ry disease, postoperative aspirin desensitization tients with nasal polyps (including mepolizumab (in which escalating doses are given under close [ClinicalTrials.gov number, NCT03085797] and medical supervision to induce tolerance) may re- dupilumab [NCT02912468]). High costs, the risk duce the risk of polyp recurrence.45,46 However, of anaphylaxis, and the use of subcutaneous in- gastrointestinal side effects and other adverse jection are limiting factors in widespread appli- events contribute to low rates of continued ad- cation of such treatments at present. It is possible herence to therapy (as many as 50% of patients that downstream inhibition of individual cytokines

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may be ineffective, given the redundancy of in- polyps visible on rhinoscopy in both nasal pas- flammatory pathways. sages — findings that are consistent with a diag- Classification of chronic rhinosinusitis into nosis of chronic rhinosinusitis with polyps. He different endotypes on the basis of the inflam- presents with severe symptoms, and therefore I matory profile (e.g., on the basis of the expression would recommend a trial of oral glucocorticoids of different type 2 inflammatory cytokines) has for 14 days, oral doxycycline at a dose of 100 mg been proposed to better predict disease course daily for 3 weeks (although data are limited with and effective .53 Further work is needed regard to showing that the combination of doxy- to identify clinically relevant biomarkers and to cycline and oral glucocorticoids results in better determine whether treatment pathways that are outcomes than either alone), and topical gluco- based on individual endotypes are more effective corticoid drops, applied in a head-down position than current strategies. for 4 weeks. If the patient had a good response, I would Guidelines recommend that he use an intranasal glucocor- ticoid spray daily to maintain benefit, as well as Guidelines endorsed by the European Rhinologic saline irrigation for symptomatic relief. This regi- Society1 as well as those endorsed by the Ameri- men would also be suitable as first-line treatment can Rhinologic Society and American Academy of in patients with mild symptoms. If the patient Otolaryngic Allergy26 address the diagnosis and continued to have moderate-to-severe symptoms management of nasal polyps. The recommenda- at the 4-week follow-up, he should be referred to tions in this review are consistent with these an otorhinolaryngologist for consideration of si- guidelines. nus surgery.

Conclusions and Dr. Hopkins reports receiving lecture fees from Medtronic Recommendations and fees for serving on an advisory board from Sanofi, Glaxo­ SmithKline, Smith and Nephew, and Optinose. No other poten- tial conflict of interest relevant to this article was reported. The patient described in the vignette has pro- Disclosure forms provided by the author are available with the gressive nasal obstruction and hyposmia and has full text of this article at NEJM.org.

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