Symptom burden and health-related quality of life in moderate to severe chronic rhinosinusitis with nasal polyposis*

Background : Chronic rhinosinusitis with nasal polyposis (CRSwNP) affects up to 4% of individuals. Common symptoms include nasal congestion/obstruction, nasal discharge, facial pain, and reduced sense of smell. This study describes patient-and physician-reported CRSwNP symptom burden and health-related quality of life (HRQOL) in a real-world clinical setting. Methods : This multinational, geographically diverse, point-in-time survey invited physicians to evaluate 5 consecutive adults with confirmed bilateral moderate to severe CRSwNP (consecutive sampling) plus the next 2 patients with recurrent nasal polyps and ≥1 surgery for polyp removal (oversampling). Patients’ and physicians’ surveys were assessed in the entire consecutive sample and by categories of physician-determined CRSwNP severity, and by categories of asthma comorbidity (total sample). Patients’ and physicians’ responses were compared in a matched sample. Results : The total sample of 1,782 patients comprised 1,296 (72.7%) from consecutive sampling and 486 (27.3%) from oversam-pling. Among the consecutive sample (mean age, 46.9 years), 1,122 (86.6%) had moderate and 174 (13.4%) had severe CRSwNP. Of 1,697 patients from total sampling with known asthma status, 708 (41.7%) had asthma and 989 (58.3%) did not. Patients’ self-reported symptom frequency, severity, and burden on HRQOL worsened with increasing CRSwNP severity and comorbid asthma. Physicians underreported prevalence, severity, and impact of symptoms on daily activities compared with patients (matched sample). Conclusion : Patients and physicians from real-world settings both described a considerable burden of CRSwNP, but physicians consistently reported fewer and less severe symptoms than patients. This suggests a more patient-centric view is needed when assessing CRSwNP symptom burden and HRQOL.


Introduction
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory condition estimated to affect up to 4% of the general population in the United States and Europe (1) .It is characterized by various symptoms, including nasal congestion or obstruction, nasal discharge that can be mucopurulent, facial pain, and reduced or loss of sense of smell (1,2) .CRSwNP presents with significant morbidity and is often associated with other respiratory conditions such as asthma (3,4) , which occurs in up to 56% of cases of CRSwNP (3) .CRSwNP with comorbid asthma can be characterized by tissue eosinophilia and high local immunoglobulin E levels (which may make patients candidates for biologic treatments against this type 2 inflammation) (5) and confers a higher symptom burden and worse quality of life than CRSwNP without comorbid asthma (4) .Additionally, the impact of CRSwNP on patients' health-related quality of life (HRQOL) has long been recognized (6)(7)(8) .Patients with CRSwNP of any severity have been found to have significantly lower physical and mental HRQOL than population norms (7) and a higher burden of emotional symptoms (8) .
Despite the prevalence and significant morbidity of CRSwNP, data from patients' perspectives on symptom severity and impact on HRQOL are limited (6) .Moreover, evidence evaluating whether physicians' assessments of symptoms reflect patients' experience is lacking.Real-world assessments of symptoms and HRQOL burden associated with CRSwNP, with and without asthma, are needed from both patients' and physicians' perspectives to provide a holistic view of CRSwNP.We assessed the symptom burden and HRQOL of CRSwNP from the perspectives of physicians and patients with moderate to severe CRSwNP according to disease severity and comorbid asthma status.We further assessed the discordance between physician and patient reports of disease burden and HRQOL.

Study design
This study analysed data collected by the Adelphi CRSwNP Disease Specific Programme (DSP) TM , an independent, multicentre, point-in-time physician and patient survey conducted in Europe (France, Germany, Italy, Spain, and the United Kingdom), the United States, and Japan between 2018 and 2019.The DSP TM provides established methods for acquiring real-world observations of current clinical practice from physicians' and their patients' viewpoints, as published previously (9) .The survey received ethical exemption determination by the Western institutional review board, a centralised international board for the United States (Study Number: #1-1090610-1), Europe, and Japan (Study Number: #1-1162676-1).and presence of mucosal disease at endoscopy for moderate to severe CRSwNP) (2,10) .Physicians were instructed to complete a patient record form for 5 consecutive patients with the presence of bilateral, moderate to severe NPs (consecutive sample), followed by the next 2 patients with bilateral, recurrent NPs who had ≥1 previous surgery for polyp removal (oversample).The consecutive sample and oversample were collected independently and are mutually exclusive.The consecutive sample was representative of patients with CRSwNP seen in routine care practice, and the oversample was necessary to increase the proportion of patients with surgical history.The same patients were invited by their physicians, but not required, to fill out a patient self-completion form independently. Patients with physiciandetermined mild CRSwNP, aged <18 years, or currently participating in a clinical trial were excluded.

Outcome measures
The outcome measures were physician-and patient-reported presence of NP symptoms as well as scores of disease burden, symptom severity, and HRQOL.The patient record forms completed by physicians recorded enrolled patients' demographic and clinical characteristics at survey date, including selected comorbidities (type 2 inflammation), derived Charlson comorbidity index (CCI)-a measure of long-term mortality risk, with a lower score indicating lower risk (11,12) , and current NP score-a physician-reported grade of the extent/severity of NPs, ranging from 0 (no polyps) to 4 (large, obstructive polyps) in each nostril.
Physicians also reported their perceived current level of patients' overall disease severity (by checking either moderate or severe in response to the question "How would you rate the severity of this patient's nasal polyps, currently?");presence of individual NP symptoms (by responding to the question "Thinking about this patient's nasal polyps symptoms in the last 2 weeks, which of the following nasal polyps symptoms are you aware this patient experiences?Select all that apply" and selecting from a list of 22 symptoms included in the patient-reported outcome instrument 22-item Sino-Nasal Outcome Test [SNOT-22] (13) ); and impact level of symptoms (by selecting 1 response [as bad as can be, severe, moderate, mild, very mild, no problem, and not stated/don't know] to the question "How problematic have these symptoms been for the patient in terms of frequency and severity?Select one") on different aspects of daily life (i.e., work/education, leisure/sport, attending social events, being self-conscious in social situations, forming personal relationships, and having intimate relationships).

Analyses
Descriptive analyses were performed on means (SDs) for continuous variables and percentages of patients for categorical variables, without any formal statistical comparisons.Missing data were not imputed or included in calculations of percentages.

Analyses were generated using IBM SPSS Data Collection Survey
Reporter and performed by Adelphi Real World.
Overall assessments and analyses by categories of physiciandetermined CRSwNP severity (moderate, severe) were performed in the consecutive survey sample because it was reflective of the routine care population.Analyses by categories of asthma comorbidity status and asthma severity included all patients with available physician-confirmed data on asthma comorbidity status taken from the total sample population (consecutive sample and oversample) (Figure 1).Physician-and patient-reported data were matched to allow direct comparisons of perspectives from physicians and patients on presence of symptoms and overall disease severity.Matched analyses were performed using physician-reported data limited to patients who had filled out self-completion forms to allow direct descriptive comparisons between the same patient population; they excluded patients who had not completed their self-completion forms.Matched physician/patient analyses were conducted for 6 different subgroups of patients: patients Physicians also reported whether the patient had a confirmed diagnosis of asthma.Patients with asthma were further categorized by asthma severity at survey date using Global Initiative for Asthma (GINA) 2018 treatment step criteria (14) .Asthma was considered severe based on GINA steps 4 or 5 derived from currently prescribed therapy and level of inhaled corticosteroid dose (low, medium, or high).All other patients with asthma and GINA steps 1-3 were qualified as having mild to moderate asthma.
After providing informed consent, patients reported their overall rating of disease severity (mild, moderate, severe) and the symptoms (SNOT-22) they were experiencing (13) in the patient self-completion form.The form also captured the impact of symptoms using multiple questionnaires.The first questionnaire assessed the level of impact of symptoms on the same aspects of daily life as reported by physicians.Second, the work productivity and activity impairment (WPAI) questionnaire assessed the percentages of work time missed (absenteeism), work time impaired (presenteeism), overall work impairment (combination of absenteeism and presenteeism), and total activity impairment (15) .and NP size scoring systems.Abbreviations: CRSwNP, chronic rhinosinusitis with nasal polyposis; NP, nasal polyp.ted with severe asthma and 187 (11.0%) with mild to moderate asthma per GINA treatment step criteria (14) .
In all, 629 of the patients in the consecutive sample had matched patient-and physician-reported data; these patients were examined both as a whole group and in subgroups of CRSwNP severity (moderate vs. severe).Of the total sample, 841 patients had matched patient-and physician-reported data; these patients were examined in subgroups of asthma comorbidity status (without vs. with) and in subgroups of comorbid asthma severity (mild/moderate vs. severe).

Patient demographic and clinical characteristics
The consecutive sample population had a mean age of 46.9 (SD 15.9) years, with the majority being men (59.6%) and non-smokers (54.8%) (Table 1).The most prevalent comorbidities were allergic rhinitis (48.7%) and asthma (39.7%).No major differences were observed between patients with severe and moderate CRSwNP, although those with severe CRSwNP were slightly older (47.8 vs. 46.7 years), had a higher percentage of current smokers (17.2% vs. 13.4%), and had higher NP scores (5.9 vs. 3.1) than with severe CRSwNP, patients with moderate CRSwNP, patients without comorbid asthma, patients with comorbid asthma, patients with comorbid mild/moderate asthma, and patients with comorbid severe asthma.A sensitivity analysis compared the demographic characteristics and CRSwNP severity of patients from the consecutive sample who had agreed to complete their self-completion forms (and were included in the matched physician/patient analyses) with those who had declined to complete a self-completion form (and were not included in the matched analyses).
Among 1,697 patients of the total sample population with available comorbid asthma data, mean age, overall CCI, and NP sco-res were similar among individuals without asthma, those with asthma, and those with severe asthma (Table 1).Patients with asthma were less frequently male (54.7% vs. 63.9%) and had a higher frequency of comorbid allergic rhinitis (64.8% vs. 38.8%)than those without asthma.There were no significant differences in demographics or clinical characteristics noted between patients who completed the self-report forms (included in the matched analyses) and those who did not, with the exception of NP score (mean [SD] of 3.4 [1.9] vs. 3.6 [1.9]; p=0.046), presence of comorbid depression (6.3% vs. 3.5%; p=0.021), and racial/ethnic distribution (p=0.012)(Supplemental Table 1).

Patient-and physician-reported prevalence of symptoms and overall disease severity
Both patients and physicians most frequently identified the same top 3 symptoms as being experienced daily: nasal blockage, need to blow nose, and runny nose (matched analysis; Figure 2).The prevalence of patient-reported decreased sense of smell/taste was also high, and at least 42.5% of patients reported experiencing non-nasal and non-clinical symptoms (e.g., facial symptoms and impact on sleep, mental abilities, and emotional domains).Across all symptoms, the prevalence of patient-and physician-reported symptoms was always greater among those with severe CRSwNP than for those with moderate CRSwNP (Figure 3).Notably, non-nasal and non-clinical symptoms were reported at 10% to 20% higher frequencies by patients with severe versus moderate CRSwNP.Additionally, a greater proportion of patients determined by their physicians to have severe CRSwNP reported their overall disease to be severe compared with those determined to have moderate CRSwNP (72.3% vs. 18.5%; Figure 4).Similar trends were observed among patients who had confirmed asthma status.The prevalence of patient-reported symptoms was greater among those with comorbid asthma compared with those without asthma (Supplemental Figure 1), and among those with severe comorbid asthma compared with those with mild/moderate comorbid asthma (Supplemental Figure 2).For example, nasal blockage, the most frequently reported symptom, was listed by 96.6% of patients with asthma vs. 94.7% of patients without asthma, and by 98.8% of patients with severe asthma vs. 90.1% with mild/moderate asthma.In comparison, symptoms of nasal blockage were identified by physicians in greater percentages of patients with vs. without comorbid asthma (90.2% vs. 87.4%),and in patients with severe vs. mild/moderate comorbid asthma (92.2% vs. 84.0%).In these subgroups of patients with known comorbid asthma status, a greater proportion of those with comorbid asthma reported their overall disease to be severe than those without asthma (35.6% vs. 25.6%; Figure 4).

Impact of symptoms on daily activities and work productivity
The impact level of CRSwNP symptoms on aspects of daily activities was assessed using data from all patient record forms filled out by physicians, resulting in approximately twice as many patients included for physician-reported data than for patientreported data.Both patients and physicians reported a more severe impact of symptoms on daily activities, relationships, and work/education among individuals with severe CRSwNP than among those with moderate CRSwNP (Supplemental Figure 3).
For example, the percentages of patients and physicians who noted the impact of symptoms on work/education to be severe were approximately 6 and 8 times higher among patients with severe CRSwNP than those with moderate CRSwNP (32.1% patients and 33.3% physicians vs. 4.2% patients and 5.4% physicians, respectively).Similarly, the severity of symptom impact on daily activities was greater among those with comorbid asthma than those without asthma (Supplemental Figure 4).This is illustrated by a greater percentage of patients and physicians listing a severe impact on work/education in 11.7% and 13.3% of patients with asthma compared with 7.5% and 9.6% of those without asthma, respectively (approximately 1.5 to 2 times greater percentages).
The patient-reported impact of CRSwNP symptoms on work productivity and activity was greater among patients with severe CRSwNP than among those with moderate disease and was also greater for those with asthma than for those without asthma (Supplemental Figure 5).The mean percentage of impairment while working affected by symptoms was 41.0% for those with severe CRSwNP vs. 27.9% for those with moderate CRSwNP; 35.6% vs. 27.0% in those with and without asthma; and 39.5% vs. 25.2% in those with severe and mild/moderate asthma.

Patient-reported burden of symptoms on HRQOL
Worse HRQOL scores (as observed by higher SNOT-22 total scores and lower EQ-VAS scores) were reported by patients with severe CRSwNP compared with moderate CRSwNP and by patients with comorbid asthma compared with patients without asthma (Figure 5).The mean SNOT-22 total score was approximately 1.5-fold higher, and the mean EQ-VAS score was approximately 1.2-fold lower for patients with severe vs. moderate CRSwNP, indicating a higher burden of CRSwNP symptoms on HRQOL.
Among patients with confirmed asthma status, the mean SNOT-22 total score was greater and the mean EQ-VAS score was lower among those with comorbid asthma vs. those without asthma.
Similar trends were observed when comparing patients with severe vs. mild/moderate asthma.

Discordance of patient-and physician-reported disease burden
In the matched analyses, a clear discordance was observed between reports of symptom prevalence and overall disease severity between physicians and patients across all subpopulations, with patients reporting both higher symptom prevalence and overall disease severity than physicians (Figures 2, 3, and 4; Supplemental Figures 1 and 2).Lower frequencies of symptoms were reported by physicians vs. patients for the most frequent nasal symptoms such as nasal blockage, need to blow nose, and runny nose, as well as across all the symptoms.Although there was an overall agreement between physicians and patients in the ranking of symptoms, the level of discordance appeared to be the greatest with non-nasal symptoms and impact of CRSwNP on HRQOL domains.For example, the difference between physicians and patients in reporting nasal blockage was 1.1-fold lower (87.8% vs. 95.1%)compared with 1.7-fold lower for decreased sense of smell/taste (45.5% vs. 75.8%),2.6fold lower for waking up tired (26.4% vs. 68.2%),4.1-fold lower for reduced productivity (14.6% vs. 59.6%),5-fold lower for dizziness (8.6% vs. 42.9%),and 6-fold lower for feeling embarrassed (7.5% vs. 45.0%)(Figure 2).
The discordance between patients' and physicians' reports persisted in the analysis of the level of impact of CRSwNP symptoms on daily activities (Supplemental Figures 3 and 4).In these analyses, across patient populations and domains of daily activities, physicians consistently reported higher percentages of moderate level of impact than patients did, whereas patients reported higher percentages of severe or as-bad-as-can-be level of impact than physicians did.

Discussion
This patients with CRSwNP brought to light the significant underestimation of the burden of this condition (17) .
Although previous evaluations of CRSwNP symptom burden across disease severity categories are limited, they are consistent with our findings (7,18) .Our findings also confirmed those of previous studies that demonstrated a higher burden of CRSwNP symptoms on HRQOL and daily activities for patients with comorbid asthma (4,7) .Furthermore, in this study, patients with severe asthma per GINA criteria experienced a greater burden of CRSwNP symptoms than patients with asthma that was not severe.Research suggests that this may be due to the overlap in allergic phenotype between CRSwNP and asthma, involving Thelper type 2 lymphocytes and immunoglobulin E-mediated inflammation in both the upper and lower airways (4,19) .This results in more severe symptoms and higher symptomatic burden in patients with CRSwNP and asthma, with a cumulative negative impact on a patient's HRQOL.
Symptom impact on work productivity and activity impairment was highest for patients with severe CRSwNP.This is in line with findings from analyses that reported higher rates of absenteeism and lost productivity for patients with sinusitis and CRSwNP than for those without sinus problems, which also highlights the substantial economic burden of this condition to society (6,17,(20)(21)(22)(23)(24) .
One of this study's limitations was that the sample collected was  (2,10) and NP size scoring systems.
Target specialist physicians (otolaryngologists, pulmonologists, allergists, and internists [Japan only]) from geographically diverse regions (recruitment proportional to population density) were identified from publicly available lists of health care providers.Information about physicians' practice specialty and workload was collected through an online survey to screen candidate participants for pre-established eligibility criteria.Eligible physicians were responsible for treatment decisions and cared for a minimum of 3 patients with moderate to severe CRSwNP per week.Physician participation was voluntary and compensated at a fair market value.Enrolled physicians recruited patients aged ≥18 years with moderate to severe CRSwNP based on a physician-confirmed diag-nosis.Physicians were advised to rely on their clinical expertise to establish a patient diagnosis.They were also provided with guidance for defining disease severity and determining nasal polyp (NP) scores according to the European Position Paper on Rhinosinusitis and Nasal Polyps, such as using visual analogue scale (VAS) symptom scores and endoscopy (with VAS >3-10

Figure 1 .
Figure 1.Flowchart of patient sampling and populations analysed.a Included 1,127 patients from Europe (197 from France, 245 from Germany, 246 from Italy, 245 from Spain, and 194 from the United Kingdom), 351 from the United States, and 304 from Japan, that were recruited by 266 physicians (otolaryngologists, pulmonologists, allergists, and internists [Japan only]) including 165 from Europe (35 from France, 36 from Germany, 36 from Italy, 35 from Spain, and 23 from the United Kingdom), 52 from the United States, and 49 from Japan.b Number of patients with available data (who had both physician and patient forms completed) for matched analyses.c CRSwNP severity determined by physician for each patient based on physician's clinical expertise and provided guidance to follow the European Position Paper on Rhinosinusitis and Nasal Polyps guidelines(2,10) and NP size scoring systems.Abbreviations: CRSwNP, chronic rhinosinusitis with

Figure 3 .
Figure 3. Prevalence of reported CRSwNP symptoms from matched patient/physician perspectives by categories of CRSwNP severity a (consecutive sample).a CRSwNP severity determined by physician for each patient based on physician's clinical expertise and provided guidance to follow the European Position Paper on Rhinosinusitis and Nasal Polyps guidelines(2,10) and NP size scoring systems.Abbreviations: CRSwNP, chronic rhinosinusitis with nasal polyposis; NP, nasal polyp.

Figure 4 .
Figure 4. Overall severity of CRSwNP from matched patient/physician perspectives.a CRSwNP severity determined by physician for each patient based on physician's clinical expertise and provided guidance to follow the European Position Paper on Rhinosinusitis and Nasal Polyps guidelines(2,10) and NP size scoring systems.Abbreviations: CRSwNP, chronic rhinosinusitis with nasal polyposis; NP, nasal polyp.

Figure 5 .
Figure 5. Patient-reported burden of CRSwNP symptoms on overall health-related quality of life.a CRSwNP severity determined by physician for each patient based on physician's clinical expertise and provided guidance to follow the European Position Paper on Rhinosinusitis and Nasal Polyps guidelines (2,10) and NP size scoring systems.Gray line indicates SD.Abbreviations: CRSwNP, chronic rhinosinusitis with nasal polyposis; EQ-VAS, EuroQoL visual analogue scale; NP, nasal polyp; SNOT-22, 22-item Sino-Nasal Outcome Test.

Table 1 .
Patient demographic and clinical characteristics at survey date.
(2,10)NP severity determined by physician for each patient based on physician's clinical expertise and provided guidance to follow the European Position Paper on Rhinosinusitis and Nasal Polyps guidelines(2,10)and NP size scoring systems.bComorbidconditions related to CRSwNP and reported in >5% of patients.cTheCCI is calculated based on the presence of select comorbidities.Abbreviations: BMI, body mass index; CCI, Charlson comorbidity index; COPD, chronic obstructive pulmonary disease; CRSwNP, chronic rhinosinusitis with nasal polyposis; NP, nasal polyp.

Table 1 .
Sensitivity analysis of matched patient/physician reports.