Clinical Commentary Review Chronic Rhinosinusitis With Nasal Polyps: Quality of Life in the Biologics Era Joaquim Mullol, MD, PhD a , Antoine Azar, MD b , Kathleen M. Buchheit, MD c , Claire Hopkins, DM d , and Jonathan A. Bernstein, MD e Barcelona, Spain; London, United Kingdom; Baltimore, Md; Boston, Mass; and Cincinnati, Ohio Chronic rhinosinusitis (CRS) affects up to 12% of the general population and is traditionally divided into two main phenotypic subsets, based on the presence of nasal polyps (CRSwNP) or their absence. It is well-established that many patients with CRSwNP report poor quality of life (QoL), which is further compromised by comorbidities (eg, asthma, bronchiectasis, aspirin-exacerbated respiratory disease). Chronic rhinosinusitis CRS with nasal polyps is managed with a combination of medical therapy and surgical interventions, and biologics are emerging as a promising new treatment option for patients with inadequate response to the standard of care. A range of patient-reported outcome measures have been used to assess QoL for patients with CRSwNP in clinical trials, including disease-specific questionnaires (eg, Sino-Nasal Outcome Test-22) and generic ones (eg, Short Form-36). Significantly impaired QoL has been identified as a criterion for the indication to use biologics in patients with CRSwNP. This review summarizes clinical evidence (2010-2021) on QoL outcomes with currently available treatments for CRSwNP and assesses the improvement in QoL after biologic treatments, especially for patients with comorbidities reported in interventional studies (randomized controlled trials and real-world experience). Ó 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). (J Allergy Clin Immunol Pract 2022;10:1434-53) Key words: Nasal polyposis; Patient-reported outcomes; Loss of smell; Asthma; Nonsteroidal anti-inflammatory drugeexacerbated respiratory disease; Aspirin-exacerbated respiratory disease INTRODUCTION Chronic rhinosinusitis (CRS) is a highly prevalent inflam- matory condition of the paranasal sinuses and nasal cavities, 1-3 which affects 5% to 12% of the general population and can have a profound impact on quality of life (QoL). 2,3 Chronic rhinosinusitis can be divided into two major phenotypes based on nasal polyps (NPs), which are inflammatory swellings of the nasal sinus mucosa or cavity: their presence (CRSwNP) or absence (CRSsNP). 1 Approximately 20% of patients with CRS have CRSwNP. 4 Whereas CRSwNP more commonly affects men, women often experience more severe inflammation and are more likely to have comorbidities. 5 The pathogenesis of CRSwNP is not fully understood, but it results in chronic inflammation involving eosinophil infiltration, local IgE forma- tion, and cytokine production. 1 Chronic rhinosinusitis with NPs has traditionally been associated with type 2 inflammation; however, this inflammatory pattern is not unique to CRSwNP. Recently, there has been increased focus has on disease charac- terization based on pathophysiologic endotypes rather than clinical phenotypes. This had laid the groundwork for individ- ualized treatment strategies as new options targeting specific immunologic processes have become available. 6 Chronic rhinosinusitis with NPs is diagnosed through nasal endoscopy, computed tomography scans, and the Lund-Mackay score, whereas QoL is assessed through patient-reported outcome measures (PROMs). 2,3,7,8 Validated PROMs serve a vital role in assessing patient-perceived health, QoL, and functional status linked to treatment. 8 a Clinical and Experimental Respiratory Immunoallergy, Hospital Clinic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Centro Investigación Biomédica En Red Enfermedades Respiratorias, Barcelona, Spain b Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Md c AERD Center, Allergy and Immunology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass d Guy’s and St Thomas NHS Foundation Trust, London, United Kingdom e Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio Editorial support (in the form of writing assistance, including development of the initial draft based on author direction, assembling tables and figures, collating authors’ comments, grammatical editing, and referencing) was provided by Ewa Kilinska, MSc, of Fishawack Communications Limited, part of Fishawack Health, UK, and was funded by Novartis Pharmaceuticals Corp. J. Mullol has participated in advisory boards for, has received research grants from, or participated in speakers’ bureaus for AstraZeneca, Genentech, GlaxoSmithK- line, Glenmark, Menarini, Mitsubishi Tanabe Pharma, MSD, Mylan-Meda Phar- maceuticals (Viatris), Novartis, Procter & Gamble, Regeneron Pharmaceuticals, Inc, Sanofi-Genzyme, UCB Pharma, and Uriach Group. A. Azar has served as principal investigator for X4 and AstraZeneca, principal investigator and consultant for Grifols, Sanofi, and Regeneron Pharmaceuticals, and consultant for Optinose, Horizon, and CSL. K.M. Buchheit has served on advisory boards for AstraZeneca, Regeneron Pharmaceuticals, Sanofi, and GlaxoSmithKline and has served as a speaker for GlaxoSmithKline. C. Hopkins has served on advisory boards for AstraZeneca, Sanofi-Regeneron, and GlaxoSmithKline. J.A. Bernstein has served as a principal investigator, consultant, and speaker for Sanofi-Regen- eron, Novartis, Genentech, and Astra Zeneca; consultant and speaker for Opti- nose; and member of JTF Guideline and CRS work group. Received for publication August 6, 2021; revised March 4, 2022; accepted for publication March 8, 2022. Available online March 16, 2022. Corresponding author: Joaquim Mullol, Hospital Clinic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Centro Investigación Biomédica En Red Enfermedades Respiratorias, Barcelona 08036, Catalonia, Spain. E-mail: [email protected]. 2213-2198 Ó 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.jaip.2022.03.002 1434
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Chronic Rhinosinusitis With Nasal Polyps: Quality of Life in the Biologics EraClinical Commentary Review
Chronic Rhinosinusitis With Nasal Polyps: Quality of Life in the Biologics Era
Joaquim Mullol, MD, PhD a , Antoine Azar, MD
b , Kathleen M. Buchheit, MD
c , Claire Hopkins, DM
d , and
Jonathan A. Bernstein, MD e Barcelona, Spain; London, United Kingdom; Baltimore, Md; Boston, Mass; and Cincinnati, Ohio
Chronic rhinosinusitis (CRS) affects up to 12% of the general population and is traditionally divided into two main phenotypic subsets, based on the presence of nasal polyps (CRSwNP) or their absence. It is well-established that many patients with CRSwNP report poor quality of life (QoL), which is further compromised by comorbidities (eg, asthma, bronchiectasis, aspirin-exacerbated respiratory disease). Chronic rhinosinusitis CRS with nasal polyps is managed with a combination of medical therapy and surgical interventions, and biologics are emerging as a promising new treatment option for patients with inadequate response to the standard of care. A range of patient-reported outcome measures have been used to assess QoL for patients with CRSwNP in clinical trials, including
aClinical and Experimental Respiratory Immunoallergy, Hospital Clinic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Centro Investigación Biomédica En Red Enfermedades Respiratorias, Barcelona, Spain
bDivision of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Md
cAERD Center, Allergy and Immunology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass
dGuy’s and St Thomas NHS Foundation Trust, London, United Kingdom eDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
Editorial support (in the form of writing assistance, including development of the initial draft based on author direction, assembling tables and figures, collating authors’ comments, grammatical editing, and referencing) was provided by Ewa Kilinska, MSc, of Fishawack Communications Limited, part of Fishawack Health, UK, and was funded by Novartis Pharmaceuticals Corp.
J. Mullol has participated in advisory boards for, has received research grants from, or participated in speakers’ bureaus for AstraZeneca, Genentech, GlaxoSmithK- line, Glenmark, Menarini, Mitsubishi Tanabe Pharma, MSD, Mylan-Meda Phar- maceuticals (Viatris), Novartis, Procter & Gamble, Regeneron Pharmaceuticals, Inc, Sanofi-Genzyme, UCB Pharma, and Uriach Group. A. Azar has served as principal investigator for X4 and AstraZeneca, principal investigator and consultant for Grifols, Sanofi, and Regeneron Pharmaceuticals, and consultant for Optinose, Horizon, and CSL. K.M. Buchheit has served on advisory boards for AstraZeneca, Regeneron Pharmaceuticals, Sanofi, and GlaxoSmithKline and has served as a speaker for GlaxoSmithKline. C. Hopkins has served on advisory boards for AstraZeneca, Sanofi-Regeneron, and GlaxoSmithKline. J.A. Bernstein has served as a principal investigator, consultant, and speaker for Sanofi-Regen- eron, Novartis, Genentech, and Astra Zeneca; consultant and speaker for Opti- nose; and member of JTF Guideline and CRS work group.
Received for publication August 6, 2021; revised March 4, 2022; accepted for publication March 8, 2022.
Available online March 16, 2022. Corresponding author: Joaquim Mullol, Hospital Clinic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Centro Investigación Biomédica En Red Enfermedades Respiratorias, Barcelona 08036, Catalonia, Spain. E-mail: [email protected].
2213-2198 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.jaip.2022.03.002
1434
disease-specific questionnaires (eg, Sino-Nasal Outcome Test-22) and generic ones (eg, Short Form-36). Significantly impaired QoL has been identified as a criterion for the indication to use biologics in patients with CRSwNP. This review summarizes clinical evidence (2010-2021) on QoL outcomes with currently available treatments for CRSwNP and assesses the improvement in QoL after biologic treatments, especially for patients with comorbidities reported in interventional studies (randomized controlled trials and real-world experience). 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). (J Allergy Clin Immunol Pract 2022;10:1434-53)
Key words: Nasal polyposis; Patient-reported outcomes; Loss of smell; Asthma; Nonsteroidal anti-inflammatory drugeexacerbated respiratory disease; Aspirin-exacerbated respiratory disease
INTRODUCTION Chronic rhinosinusitis (CRS) is a highly prevalent inflam-
matory condition of the paranasal sinuses and nasal cavities,1-3
which affects 5% to 12% of the general population and can have a profound impact on quality of life (QoL).2,3 Chronic rhinosinusitis can be divided into two major phenotypes based on nasal polyps (NPs), which are inflammatory swellings of the nasal sinus mucosa or cavity: their presence (CRSwNP) or absence (CRSsNP).1 Approximately 20% of patients with CRS have CRSwNP.4 Whereas CRSwNP more commonly affects men, women often experience more severe inflammation and are more likely to have comorbidities.5 The pathogenesis of CRSwNP is not fully understood, but it results in chronic inflammation involving eosinophil infiltration, local IgE forma- tion, and cytokine production.1 Chronic rhinosinusitis with NPs has traditionally been associated with type 2 inflammation; however, this inflammatory pattern is not unique to CRSwNP. Recently, there has been increased focus has on disease charac- terization based on pathophysiologic endotypes rather than clinical phenotypes. This had laid the groundwork for individ- ualized treatment strategies as new options targeting specific immunologic processes have become available.6
Chronic rhinosinusitis with NPs is diagnosed through nasal endoscopy, computed tomography scans, and the Lund-Mackay score, whereas QoL is assessed through patient-reported outcome measures (PROMs).2,3,7,8 Validated PROMs serve a vital role in assessing patient-perceived health, QoL, and functional status linked to treatment.8
MULLOL ETAL 1435
CRS- C
hronic rhinosinusitis
CRSsNP- C
CRSwNP- C
ESS- E
Health-related QoL (HR-QoL) is a multidimensional concept and includes physical, psychological, and social domains. Physical symptoms of CRSwNP include nasal congestion, rhinorrhea or postnasal drainage, facial pressure or pain, and anosmia.9,10 Sec- ondary consequences include sleep impairment, anxiety, and depression.11-13 The largest QoL impairments are often experi- enced by patients with comorbidities including asthma, nonste- roidal anti-inflammatory druge or aspirin-exacerbated respiratory disease (N-ERD/AERD), chronic obstructive pulmonary disease, bronchiectasis, and obstructive sleep apnea, or those with rare CRS subtypes such as allergic fungal rhinitis.2,3,14-19 Both symptoms and secondary consequences of CRSwNP can significantly affect HR-QoL.10 Patient-reported outcome measure should capture this range of factors and may include both disease-specific and generic QoL questionnaires (Figure 1). Treatment of CRSwNP should aim to control symptoms and improve HR-QoL. The standard of care (SoC) for CRSwNP includes intranasal and sys- temic corticosteroids as well as endoscopic sinus surgery (ESS),2,3
which have been effective in many patients, especially continuous treatment with topical corticosteroids and potentially short courses of oral corticosteroids.20-22 However, in approximately one-third of patients with CRSwNP, the condition is not well-controlled with SoC.22 Although some patients show symptom and QoL improvement, for others, especially those with severe symptoms, SoC treatment provides only short-term efficacy and NPs frequently recur after surgery.22,23 Nasal polyp recurrence can result in additional surgeries, with attendant increased risks for patients with CRSwNP. The rate of revision ESS is higher in pa- tients with CRSwNP versus CRSsNP (3.5% vs 1.6%, respec- tively).2 In a recently published multicenter, randomized controlled trial (RCT) comparing patients given ESS and medical treatment (n ¼ 118) with those who received medical treatment alone (n ¼ 116), more than half of all patients had uncontrolled disease at 12 months with either treatment approach, using HR-QoL as the primary outcomemeasure.24This important study provides important evidence of the unmet need for treatment.
Biologics offer a new therapeutic option for patients,25 and significant QoL impairment is a key criterion for the indication of biologic treatment in CRSwNP.2,26 The QoL impact of CRSwNP was well-reviewed before the advent of biologics,27-31
but examining their effect on QoL and comparing them with current care pathways provides a fresh perspective. Furthermore, as new treatments and efficacy data emerge,32 their potential to improve outcomes in CRSwNP should be continually evaluated. In this clinical commentary review, we evaluate QoL data from interventional clinical trials and real-world studies published in the past 11 years in adults with CRSwNP and comorbidities, to guide evidence-based decision-making regarding established and emerging treatments.
SEARCH STRATEGY AND RESULTS We conducted a systematic primary and secondary Medline
and PubMed search for data on QoL and CRSwNP published between January 2010 and March 2021. Five separate searches captured key QoL data. Detailed search, inclusion, and exclusion criteria are described in Figure E1 (in this article’s Online Re- pository at www.jaci-inpractice.org).
Searches yielded 695 entries in total; 43 studies were selected for analysis. Asthma was the most common comorbidity of CRSwNP, reported in 81% of the selected studies. Most studies were RCTs (56%) or prospective cohort studies (30%). The most common PROM used was the Sino-Nasal Outcome Test (SNOT)-22 (65%), followed by the 36-Item Short Form (SF- 36) (19%), Rhinosinusitis Disability Index (14%), and visual analog scale (11%).
Impact of CRSwNP on QoL Patients with CRSwNP can experience a complex range of
symptoms beyond those related to the nose and paranasal si- nuses. Here, we discuss the QoL impact of the various symp- toms, consequences, and comorbid conditions, and examine the utility of targeted biologic treatment.
Key CRSwNP symptoms and their consequences
Nasal symptoms. Chronic nasal congestion or obstruction, rhinorrhea, and facial pain or pressure are key clinical features of CRSwNP. Although these symptoms can be used to assess dis- ease severity and intervention success, few studies have directly linked nasal symptoms in CRSwNP to QoL. However, their severity as assessed by PROMs (eg, SNOT-22, SNOT-20) cor- relates with reduced QoL.10,33 Impact on QoL varies by CRS subtype; patients with AERD are most severely affected.33
Olfactory dysfunction. Olfactory dysfunction is a common diagnostic criterion for CRSwNP and a key predictor of reduced QoL.11,34,35 Loss of smell, or a change in its sense, is commonly reported using disease-specific PROMs such as SNOT-22 (Figure 1). Specific tests assessing olfactory function, such as the University of Pennsylvania Smell Identification Test (UPSIT) are also used to assess disease status in people with CRSwNP.36 Patients who experience anosmia report reduced enjoyment of food, difficulty cooking, difficulty assessing per- sonal hygiene, and failure to smell smoke and rotten food.35 The impact of olfactory dysfunction on QoL is increasingly being recognized. Anosmia, hyposmia, and parosmia have received new attention during the COVID-19 pandemic37-39 and are widely reported to have a substantial detriment to QoL.36,40,41 This
Social impact‡
Fatigue/tiredness/energy levels
Extra-rhinologic symptoms†
Other nasal symptoms*
Disease-specific questionnaires General health assessment questionnaires
SNOT-22 RSDICSS RQLQ SF-36 EQ-5D GWBS
FIGURE 1. Anatomy of chronic rhinosinusitis with nasal polyps, with key symptoms and quality of life (QOL) consequences, as captured by common patient-reported outcome measures. Only key symptoms and health-related QoL items are depicted. General health, general pain, duration, severity, confusion, emotional control and stability, and the need for medication are not shown. Disease-specific measures cover health-related QoL, whereas general measures assess broader QoL aspects. *Includes sneezing, the need to blow nose, the need to rub nose, itchy nose, and thick nasal discharge. †Includes eye and ear symptoms, thirst, cough, and dizziness. zIncludes any interference with social activities or relationships. xIncludes activities of daily living, mobility, exertion self-care, and recreational activities. CSS, chronic sinusitis survey; EQ-5D, EuroQoL 5-Dimension; GWBS, general well-being scale; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; SF-36, Short Form-36 Health Survey; SNOT-22, Sino-Nasal Outcome Test.
J ALLERGY CLIN IMMUNOL PRACT JUNE 2022
1436 MULLOL ETAL
may prove important in raising awareness regarding the CRSwNP burden.37,42
Reduced sleep quality and sleep disorders. Over 75% of patients with CRSwNP experience reduced sleep quality. Worse sleep quality correlates with more severe disease.43 Sleep impairments include snoring, fragmented sleep, daytime sleepi- ness, and obstructive sleep apnea.44,45 However, research sug- gests that NPs themselves in CRS do not worsen or increase the risk for sleep problems. Instead, sleep problems associated with CRSwNP may have multifactorial causes, including underlying inflammatory processes.43
Mental health and psychological well-being. Chronic rhinosinusitis with NPs can affect psychological well-being and mental health.17 Patients can experience reduced concentration, frustration, sadness, depression, anxiety, phobia, hopelessness, and embarrassment11,12,35 in addition to preoperative anxiety.46
It was also reported that patients with CRSwNP and anosmia have decreased QoL and increased depression and anxiety.11
Utility of PROMs to assess QoL Quality of life assessments are important for understanding
patient-oriented health outcomes, particularly for chronic conditions such as CRSwNP.47 Table I lists PROMs commonly used to assess QoL in patients with CRSwNP. Figure 1 shows key symptoms and HR-QoL consequences of CRSwNP, as well as the PROMs that capture them. Patient-reported outcome measures may be general or disease-specific, and some have validated minimal clinically mean- ingful differences (MCIDs). They cover a range ofHR-QoL domains
including physical, mental, psychological, practical, and social. Although there is no standardized PROM for CRSwNP, SNOT-22 has emerged as one of the most comprehensive and widely accepted measures.68 Sino-Nasal Outcome Test-22 captures a range of symptoms (Figure 1).2,48 However, trials often report overall HR-QoL scores but not individual symptoms. Quality of life and symptom measures have been found to correlate in a number of studies.33 Nonetheless, to support the use of QoL measures in assessing clinical outcomes, more research is needed to evaluate the relationship between objective outcome measures and PROMs. In our search, six of 14 biologics studies reported only total PROM scores without providing domain-level HR- QoL results. Although this is informative, it does not identify the most burdensome aspects of disease.
Chronic rhinosinusitis with NP comorbidities further
decrease patient QoL Chronic rhinosinusitis with NPs is often associated with
comorbidities that further decrease QoL.18 Nasal polyps are commonly linked to immunologic or inflammatory respiratory conditions such as allergic rhinitis and asthma. Chronic rhino- sinusitis with NPs and asthma often share the same type 2 immunopathology, and epithelial barrier dysfunction is present in both conditions. Furthermore, 40% to 67% of patients with CRSwNP have asthma.18 Patients with both conditions can present with more severe symptoms of CRSwNP, asthma, or both18 and have higher rates of NP recurrence and revision surgeries as well as higher dependence on corticosteroids than do patients who have asthma alone.72
TABLE I. Key PROMs used to assess quality of life QoL in patients with chronic rhinosinusitis with nasal polyps
PROM
domains; range for output scores)
Time to
General health assessment questionnaires
EuroQoL-5D The EuroQoL is composed of a descriptive system: five questions, each with five levels of severity per question (no problem to extreme problem); converted to a maximum score of 1 indicating best health state; plus 0-100 VAS to assess general health
<2 Mobility, self-care, usual activity (eg, severity of problems in work, study, family, and leisure activities), pain/discomfort, anxiety/ depression, general health
MCID of 0.04 (EuroQoL-5D descriptive system) and 8 (EuroQoL-VAS) in CRS
48,49
General Well-being Schedule
The General Well-being Schedule 18-item version is the most commonly used and is composed of 14 items rated on a 6-point Likert scale, with four items rated on a 10- point Likert scale. Total score ranges from 0 to 110
Not specified Anxiety, depression, positive well-being, self- control, vitality, general health
Positive well-being (scores of 73-110), moderate distress (scores of 61-72), and severe distress (scores of 0-60)
50,51
SF-36 SF-36 is composed of 36 questions across eight domains; each domain has a 0-100 scale (0 is the worst and 100 is the best score); generates an overall physical and mental summary score out of 100
5-10 Mental and physical composite measures; eight subdomains: vitality, physical functioning, role: physical or physical, bodily pain, general health, role: emotional, and social functioning, mental health
MCID of 2 points for PCS and 3 points for mental composite score; 8 points for each individual domain in chronic rhinosinusitis with nasal polyps
17,47,48,52
SF-12 Shortened version of SF-36; SF-12 is composed of 12 questions across eight domains; each domain has a 0-100 scale (0 is the worst and 100 is the best score).
Another shortened version of the SF-36 is the SF-6D, designed also to assess cost- effectiveness, with total scores on a scale of 0-1
5-10 Vitality, physical functioning, bodily pain, general health, physical, emotional, and social role functioning, mental health
Not specifically defined for CRS; estimated between 10-12.5 points for other respiratory indications. General (not indication- specific) MCID for SF-6D is 0.3
53-55
VAS for symptom severity or pain
VAS is a sliding scale (usually 0-10 cm) with word anchors at each end representing extreme feelings, with higher scores indicating greater severity
Not specified VAS to assess symptom severity (eg, VAS total symptom score), individual symptoms scores, or VAS pain used to capture pain severity (minimum to maximum)
Score of >5 cm is considered to affect QoL or represent uncontrolled symptoms. Scores of >2 to 5 cm represent partially controlled symptoms, and <2 cm, well-controlled symptoms
2,56
Asthma Quality of Life Questionnaire†
The Asthma Quality of Life Questionnaire is composed of 32 questions across four domains; each item is measured on a 7- point Likert scale (1-7), with higher scores indicating better QoL
Not specified Symptom types, activity limitation, emotional function, environmental exposure
Minimal important change score in overall score of 0.5 (change of 1.0 is considered moderate and change of 2.0 is considered large) in asthma
57
CSS The CSS is composed of six questions across two domains; 0-100 scale per question; divided into CSS-S (severity-based) and CSS-D (duration-based), with higher scores indicating better QoL
5 Symptom types, medication used MCID for CSS-D: 0.5 SD of pretreatment mean score; 9.75
48,58,59
(continued)
A C T
V O LU
M E 10
6 M U LLO
domains; range for output scores)
Time to
Nasal Obstruction Symptom Evaluation Survey
The Nasal Obstruction Symptom Evaluation Survey is 5 questions on a Likert scale with values of 0-4; total score is converted to a number from 0 (no nasal obstruction) to 100 (severe nasal obstruction)
Not specified Nasal obstruction and sleep quality (although association with CRS QoL was found to be limited)
MCID is 5.3 points or w40% improvement in nasal obstructive score; not fully validated in CRS
47,60
Rhinosinusitis Quality of Life Questionnairez
The Rhinosinusitis Quality of Life Questionnaire is composed of 17 questions across three domains, with different Likert scales used for each domain; total score ranges from 0 to 100 with higher scores indicating lower QoL
7 Symptom frequency, symptom bothersomeness, symptom impact
MCID between 3.8 and 6.1; not specifically validated in CRS
48,61,62
RQLQ The RQLQ is composed of 31 questions across seven domains; 0-6 scale for each question. Total score range is 0-6, with higher scores indicating lower QoL. Mini RQLQ is a shortened version, containing 14 questions across five domains.
Not specified Activity, sleep, nonehay fever, practical, nasal, eye, emotions
MCID 0.62 Mini RQLQ 0.7 (not specifically validated in
CRS)
58,63,64
Rhinosinusitis Disability Index
The Rhinosinusitis Disability Index is composed of 30 questions on a 5-point Likert scale; total score ranges from 0 to 120, with lower scores indicating better outcomes
5-10 Physical, functional, emotional MCID 10.35 48,65
RSOM-31 The RSOM-31 is composed of 31 questions across seven domains; total score ranges from 0 to 155 (superseded by SNOT-22, which was derived from RSOM-31); lower scores indicate better outcomes
15-20 Nasal, eye, sleep, ear, general symptoms, practical problems, emotional consequences
MCID >30% change 66,67
SNOT-22 SNOT-22 is composed of 22 questions across five domains; total score ranges from 0 to 110; lower scores indicate better outcomes
7 Discrete rhinologic, extrarhinologic, ear/facial, psychological, and sleep symptoms associated with CRS
MCID 8.9 points Brazilian version MCID >14 points
48,68,69
SNOT-20 SNOT-20 is composed of 20 questions across four domains; total score is from 0 to 100 (superseded by SNOT-22); total scores can be divided by 20
Lower scores indicate better outcomes
5 Rhinologic, ear, facial symptoms, psychological and sleep function
MCID 16 points; if divided by 20, >0.5 is considered a significant change
48,70,71
CRS, chronic rhinosinusitis; CSS, Chronic Sinusitis Survey;MCID, minimal clinically important difference; PCS, physical composite score; PROM, patient-reported outcome measure; QoL, quality of life; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; RSOM, Rhinosinusitis Outcome Measure;…
Chronic Rhinosinusitis With Nasal Polyps: Quality of Life in the Biologics Era
Joaquim Mullol, MD, PhD a , Antoine Azar, MD
b , Kathleen M. Buchheit, MD
c , Claire Hopkins, DM
d , and
Jonathan A. Bernstein, MD e Barcelona, Spain; London, United Kingdom; Baltimore, Md; Boston, Mass; and Cincinnati, Ohio
Chronic rhinosinusitis (CRS) affects up to 12% of the general population and is traditionally divided into two main phenotypic subsets, based on the presence of nasal polyps (CRSwNP) or their absence. It is well-established that many patients with CRSwNP report poor quality of life (QoL), which is further compromised by comorbidities (eg, asthma, bronchiectasis, aspirin-exacerbated respiratory disease). Chronic rhinosinusitis CRS with nasal polyps is managed with a combination of medical therapy and surgical interventions, and biologics are emerging as a promising new treatment option for patients with inadequate response to the standard of care. A range of patient-reported outcome measures have been used to assess QoL for patients with CRSwNP in clinical trials, including
aClinical and Experimental Respiratory Immunoallergy, Hospital Clinic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Centro Investigación Biomédica En Red Enfermedades Respiratorias, Barcelona, Spain
bDivision of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Md
cAERD Center, Allergy and Immunology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass
dGuy’s and St Thomas NHS Foundation Trust, London, United Kingdom eDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
Editorial support (in the form of writing assistance, including development of the initial draft based on author direction, assembling tables and figures, collating authors’ comments, grammatical editing, and referencing) was provided by Ewa Kilinska, MSc, of Fishawack Communications Limited, part of Fishawack Health, UK, and was funded by Novartis Pharmaceuticals Corp.
J. Mullol has participated in advisory boards for, has received research grants from, or participated in speakers’ bureaus for AstraZeneca, Genentech, GlaxoSmithK- line, Glenmark, Menarini, Mitsubishi Tanabe Pharma, MSD, Mylan-Meda Phar- maceuticals (Viatris), Novartis, Procter & Gamble, Regeneron Pharmaceuticals, Inc, Sanofi-Genzyme, UCB Pharma, and Uriach Group. A. Azar has served as principal investigator for X4 and AstraZeneca, principal investigator and consultant for Grifols, Sanofi, and Regeneron Pharmaceuticals, and consultant for Optinose, Horizon, and CSL. K.M. Buchheit has served on advisory boards for AstraZeneca, Regeneron Pharmaceuticals, Sanofi, and GlaxoSmithKline and has served as a speaker for GlaxoSmithKline. C. Hopkins has served on advisory boards for AstraZeneca, Sanofi-Regeneron, and GlaxoSmithKline. J.A. Bernstein has served as a principal investigator, consultant, and speaker for Sanofi-Regen- eron, Novartis, Genentech, and Astra Zeneca; consultant and speaker for Opti- nose; and member of JTF Guideline and CRS work group.
Received for publication August 6, 2021; revised March 4, 2022; accepted for publication March 8, 2022.
Available online March 16, 2022. Corresponding author: Joaquim Mullol, Hospital Clinic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Universidad de Barcelona, Centro Investigación Biomédica En Red Enfermedades Respiratorias, Barcelona 08036, Catalonia, Spain. E-mail: [email protected].
2213-2198 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.jaip.2022.03.002
1434
disease-specific questionnaires (eg, Sino-Nasal Outcome Test-22) and generic ones (eg, Short Form-36). Significantly impaired QoL has been identified as a criterion for the indication to use biologics in patients with CRSwNP. This review summarizes clinical evidence (2010-2021) on QoL outcomes with currently available treatments for CRSwNP and assesses the improvement in QoL after biologic treatments, especially for patients with comorbidities reported in interventional studies (randomized controlled trials and real-world experience). 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). (J Allergy Clin Immunol Pract 2022;10:1434-53)
Key words: Nasal polyposis; Patient-reported outcomes; Loss of smell; Asthma; Nonsteroidal anti-inflammatory drugeexacerbated respiratory disease; Aspirin-exacerbated respiratory disease
INTRODUCTION Chronic rhinosinusitis (CRS) is a highly prevalent inflam-
matory condition of the paranasal sinuses and nasal cavities,1-3
which affects 5% to 12% of the general population and can have a profound impact on quality of life (QoL).2,3 Chronic rhinosinusitis can be divided into two major phenotypes based on nasal polyps (NPs), which are inflammatory swellings of the nasal sinus mucosa or cavity: their presence (CRSwNP) or absence (CRSsNP).1 Approximately 20% of patients with CRS have CRSwNP.4 Whereas CRSwNP more commonly affects men, women often experience more severe inflammation and are more likely to have comorbidities.5 The pathogenesis of CRSwNP is not fully understood, but it results in chronic inflammation involving eosinophil infiltration, local IgE forma- tion, and cytokine production.1 Chronic rhinosinusitis with NPs has traditionally been associated with type 2 inflammation; however, this inflammatory pattern is not unique to CRSwNP. Recently, there has been increased focus has on disease charac- terization based on pathophysiologic endotypes rather than clinical phenotypes. This had laid the groundwork for individ- ualized treatment strategies as new options targeting specific immunologic processes have become available.6
Chronic rhinosinusitis with NPs is diagnosed through nasal endoscopy, computed tomography scans, and the Lund-Mackay score, whereas QoL is assessed through patient-reported outcome measures (PROMs).2,3,7,8 Validated PROMs serve a vital role in assessing patient-perceived health, QoL, and functional status linked to treatment.8
MULLOL ETAL 1435
CRS- C
hronic rhinosinusitis
CRSsNP- C
CRSwNP- C
ESS- E
Health-related QoL (HR-QoL) is a multidimensional concept and includes physical, psychological, and social domains. Physical symptoms of CRSwNP include nasal congestion, rhinorrhea or postnasal drainage, facial pressure or pain, and anosmia.9,10 Sec- ondary consequences include sleep impairment, anxiety, and depression.11-13 The largest QoL impairments are often experi- enced by patients with comorbidities including asthma, nonste- roidal anti-inflammatory druge or aspirin-exacerbated respiratory disease (N-ERD/AERD), chronic obstructive pulmonary disease, bronchiectasis, and obstructive sleep apnea, or those with rare CRS subtypes such as allergic fungal rhinitis.2,3,14-19 Both symptoms and secondary consequences of CRSwNP can significantly affect HR-QoL.10 Patient-reported outcome measure should capture this range of factors and may include both disease-specific and generic QoL questionnaires (Figure 1). Treatment of CRSwNP should aim to control symptoms and improve HR-QoL. The standard of care (SoC) for CRSwNP includes intranasal and sys- temic corticosteroids as well as endoscopic sinus surgery (ESS),2,3
which have been effective in many patients, especially continuous treatment with topical corticosteroids and potentially short courses of oral corticosteroids.20-22 However, in approximately one-third of patients with CRSwNP, the condition is not well-controlled with SoC.22 Although some patients show symptom and QoL improvement, for others, especially those with severe symptoms, SoC treatment provides only short-term efficacy and NPs frequently recur after surgery.22,23 Nasal polyp recurrence can result in additional surgeries, with attendant increased risks for patients with CRSwNP. The rate of revision ESS is higher in pa- tients with CRSwNP versus CRSsNP (3.5% vs 1.6%, respec- tively).2 In a recently published multicenter, randomized controlled trial (RCT) comparing patients given ESS and medical treatment (n ¼ 118) with those who received medical treatment alone (n ¼ 116), more than half of all patients had uncontrolled disease at 12 months with either treatment approach, using HR-QoL as the primary outcomemeasure.24This important study provides important evidence of the unmet need for treatment.
Biologics offer a new therapeutic option for patients,25 and significant QoL impairment is a key criterion for the indication of biologic treatment in CRSwNP.2,26 The QoL impact of CRSwNP was well-reviewed before the advent of biologics,27-31
but examining their effect on QoL and comparing them with current care pathways provides a fresh perspective. Furthermore, as new treatments and efficacy data emerge,32 their potential to improve outcomes in CRSwNP should be continually evaluated. In this clinical commentary review, we evaluate QoL data from interventional clinical trials and real-world studies published in the past 11 years in adults with CRSwNP and comorbidities, to guide evidence-based decision-making regarding established and emerging treatments.
SEARCH STRATEGY AND RESULTS We conducted a systematic primary and secondary Medline
and PubMed search for data on QoL and CRSwNP published between January 2010 and March 2021. Five separate searches captured key QoL data. Detailed search, inclusion, and exclusion criteria are described in Figure E1 (in this article’s Online Re- pository at www.jaci-inpractice.org).
Searches yielded 695 entries in total; 43 studies were selected for analysis. Asthma was the most common comorbidity of CRSwNP, reported in 81% of the selected studies. Most studies were RCTs (56%) or prospective cohort studies (30%). The most common PROM used was the Sino-Nasal Outcome Test (SNOT)-22 (65%), followed by the 36-Item Short Form (SF- 36) (19%), Rhinosinusitis Disability Index (14%), and visual analog scale (11%).
Impact of CRSwNP on QoL Patients with CRSwNP can experience a complex range of
symptoms beyond those related to the nose and paranasal si- nuses. Here, we discuss the QoL impact of the various symp- toms, consequences, and comorbid conditions, and examine the utility of targeted biologic treatment.
Key CRSwNP symptoms and their consequences
Nasal symptoms. Chronic nasal congestion or obstruction, rhinorrhea, and facial pain or pressure are key clinical features of CRSwNP. Although these symptoms can be used to assess dis- ease severity and intervention success, few studies have directly linked nasal symptoms in CRSwNP to QoL. However, their severity as assessed by PROMs (eg, SNOT-22, SNOT-20) cor- relates with reduced QoL.10,33 Impact on QoL varies by CRS subtype; patients with AERD are most severely affected.33
Olfactory dysfunction. Olfactory dysfunction is a common diagnostic criterion for CRSwNP and a key predictor of reduced QoL.11,34,35 Loss of smell, or a change in its sense, is commonly reported using disease-specific PROMs such as SNOT-22 (Figure 1). Specific tests assessing olfactory function, such as the University of Pennsylvania Smell Identification Test (UPSIT) are also used to assess disease status in people with CRSwNP.36 Patients who experience anosmia report reduced enjoyment of food, difficulty cooking, difficulty assessing per- sonal hygiene, and failure to smell smoke and rotten food.35 The impact of olfactory dysfunction on QoL is increasingly being recognized. Anosmia, hyposmia, and parosmia have received new attention during the COVID-19 pandemic37-39 and are widely reported to have a substantial detriment to QoL.36,40,41 This
Social impact‡
Fatigue/tiredness/energy levels
Extra-rhinologic symptoms†
Other nasal symptoms*
Disease-specific questionnaires General health assessment questionnaires
SNOT-22 RSDICSS RQLQ SF-36 EQ-5D GWBS
FIGURE 1. Anatomy of chronic rhinosinusitis with nasal polyps, with key symptoms and quality of life (QOL) consequences, as captured by common patient-reported outcome measures. Only key symptoms and health-related QoL items are depicted. General health, general pain, duration, severity, confusion, emotional control and stability, and the need for medication are not shown. Disease-specific measures cover health-related QoL, whereas general measures assess broader QoL aspects. *Includes sneezing, the need to blow nose, the need to rub nose, itchy nose, and thick nasal discharge. †Includes eye and ear symptoms, thirst, cough, and dizziness. zIncludes any interference with social activities or relationships. xIncludes activities of daily living, mobility, exertion self-care, and recreational activities. CSS, chronic sinusitis survey; EQ-5D, EuroQoL 5-Dimension; GWBS, general well-being scale; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; SF-36, Short Form-36 Health Survey; SNOT-22, Sino-Nasal Outcome Test.
J ALLERGY CLIN IMMUNOL PRACT JUNE 2022
1436 MULLOL ETAL
may prove important in raising awareness regarding the CRSwNP burden.37,42
Reduced sleep quality and sleep disorders. Over 75% of patients with CRSwNP experience reduced sleep quality. Worse sleep quality correlates with more severe disease.43 Sleep impairments include snoring, fragmented sleep, daytime sleepi- ness, and obstructive sleep apnea.44,45 However, research sug- gests that NPs themselves in CRS do not worsen or increase the risk for sleep problems. Instead, sleep problems associated with CRSwNP may have multifactorial causes, including underlying inflammatory processes.43
Mental health and psychological well-being. Chronic rhinosinusitis with NPs can affect psychological well-being and mental health.17 Patients can experience reduced concentration, frustration, sadness, depression, anxiety, phobia, hopelessness, and embarrassment11,12,35 in addition to preoperative anxiety.46
It was also reported that patients with CRSwNP and anosmia have decreased QoL and increased depression and anxiety.11
Utility of PROMs to assess QoL Quality of life assessments are important for understanding
patient-oriented health outcomes, particularly for chronic conditions such as CRSwNP.47 Table I lists PROMs commonly used to assess QoL in patients with CRSwNP. Figure 1 shows key symptoms and HR-QoL consequences of CRSwNP, as well as the PROMs that capture them. Patient-reported outcome measures may be general or disease-specific, and some have validated minimal clinically mean- ingful differences (MCIDs). They cover a range ofHR-QoL domains
including physical, mental, psychological, practical, and social. Although there is no standardized PROM for CRSwNP, SNOT-22 has emerged as one of the most comprehensive and widely accepted measures.68 Sino-Nasal Outcome Test-22 captures a range of symptoms (Figure 1).2,48 However, trials often report overall HR-QoL scores but not individual symptoms. Quality of life and symptom measures have been found to correlate in a number of studies.33 Nonetheless, to support the use of QoL measures in assessing clinical outcomes, more research is needed to evaluate the relationship between objective outcome measures and PROMs. In our search, six of 14 biologics studies reported only total PROM scores without providing domain-level HR- QoL results. Although this is informative, it does not identify the most burdensome aspects of disease.
Chronic rhinosinusitis with NP comorbidities further
decrease patient QoL Chronic rhinosinusitis with NPs is often associated with
comorbidities that further decrease QoL.18 Nasal polyps are commonly linked to immunologic or inflammatory respiratory conditions such as allergic rhinitis and asthma. Chronic rhino- sinusitis with NPs and asthma often share the same type 2 immunopathology, and epithelial barrier dysfunction is present in both conditions. Furthermore, 40% to 67% of patients with CRSwNP have asthma.18 Patients with both conditions can present with more severe symptoms of CRSwNP, asthma, or both18 and have higher rates of NP recurrence and revision surgeries as well as higher dependence on corticosteroids than do patients who have asthma alone.72
TABLE I. Key PROMs used to assess quality of life QoL in patients with chronic rhinosinusitis with nasal polyps
PROM
domains; range for output scores)
Time to
General health assessment questionnaires
EuroQoL-5D The EuroQoL is composed of a descriptive system: five questions, each with five levels of severity per question (no problem to extreme problem); converted to a maximum score of 1 indicating best health state; plus 0-100 VAS to assess general health
<2 Mobility, self-care, usual activity (eg, severity of problems in work, study, family, and leisure activities), pain/discomfort, anxiety/ depression, general health
MCID of 0.04 (EuroQoL-5D descriptive system) and 8 (EuroQoL-VAS) in CRS
48,49
General Well-being Schedule
The General Well-being Schedule 18-item version is the most commonly used and is composed of 14 items rated on a 6-point Likert scale, with four items rated on a 10- point Likert scale. Total score ranges from 0 to 110
Not specified Anxiety, depression, positive well-being, self- control, vitality, general health
Positive well-being (scores of 73-110), moderate distress (scores of 61-72), and severe distress (scores of 0-60)
50,51
SF-36 SF-36 is composed of 36 questions across eight domains; each domain has a 0-100 scale (0 is the worst and 100 is the best score); generates an overall physical and mental summary score out of 100
5-10 Mental and physical composite measures; eight subdomains: vitality, physical functioning, role: physical or physical, bodily pain, general health, role: emotional, and social functioning, mental health
MCID of 2 points for PCS and 3 points for mental composite score; 8 points for each individual domain in chronic rhinosinusitis with nasal polyps
17,47,48,52
SF-12 Shortened version of SF-36; SF-12 is composed of 12 questions across eight domains; each domain has a 0-100 scale (0 is the worst and 100 is the best score).
Another shortened version of the SF-36 is the SF-6D, designed also to assess cost- effectiveness, with total scores on a scale of 0-1
5-10 Vitality, physical functioning, bodily pain, general health, physical, emotional, and social role functioning, mental health
Not specifically defined for CRS; estimated between 10-12.5 points for other respiratory indications. General (not indication- specific) MCID for SF-6D is 0.3
53-55
VAS for symptom severity or pain
VAS is a sliding scale (usually 0-10 cm) with word anchors at each end representing extreme feelings, with higher scores indicating greater severity
Not specified VAS to assess symptom severity (eg, VAS total symptom score), individual symptoms scores, or VAS pain used to capture pain severity (minimum to maximum)
Score of >5 cm is considered to affect QoL or represent uncontrolled symptoms. Scores of >2 to 5 cm represent partially controlled symptoms, and <2 cm, well-controlled symptoms
2,56
Asthma Quality of Life Questionnaire†
The Asthma Quality of Life Questionnaire is composed of 32 questions across four domains; each item is measured on a 7- point Likert scale (1-7), with higher scores indicating better QoL
Not specified Symptom types, activity limitation, emotional function, environmental exposure
Minimal important change score in overall score of 0.5 (change of 1.0 is considered moderate and change of 2.0 is considered large) in asthma
57
CSS The CSS is composed of six questions across two domains; 0-100 scale per question; divided into CSS-S (severity-based) and CSS-D (duration-based), with higher scores indicating better QoL
5 Symptom types, medication used MCID for CSS-D: 0.5 SD of pretreatment mean score; 9.75
48,58,59
(continued)
A C T
V O LU
M E 10
6 M U LLO
domains; range for output scores)
Time to
Nasal Obstruction Symptom Evaluation Survey
The Nasal Obstruction Symptom Evaluation Survey is 5 questions on a Likert scale with values of 0-4; total score is converted to a number from 0 (no nasal obstruction) to 100 (severe nasal obstruction)
Not specified Nasal obstruction and sleep quality (although association with CRS QoL was found to be limited)
MCID is 5.3 points or w40% improvement in nasal obstructive score; not fully validated in CRS
47,60
Rhinosinusitis Quality of Life Questionnairez
The Rhinosinusitis Quality of Life Questionnaire is composed of 17 questions across three domains, with different Likert scales used for each domain; total score ranges from 0 to 100 with higher scores indicating lower QoL
7 Symptom frequency, symptom bothersomeness, symptom impact
MCID between 3.8 and 6.1; not specifically validated in CRS
48,61,62
RQLQ The RQLQ is composed of 31 questions across seven domains; 0-6 scale for each question. Total score range is 0-6, with higher scores indicating lower QoL. Mini RQLQ is a shortened version, containing 14 questions across five domains.
Not specified Activity, sleep, nonehay fever, practical, nasal, eye, emotions
MCID 0.62 Mini RQLQ 0.7 (not specifically validated in
CRS)
58,63,64
Rhinosinusitis Disability Index
The Rhinosinusitis Disability Index is composed of 30 questions on a 5-point Likert scale; total score ranges from 0 to 120, with lower scores indicating better outcomes
5-10 Physical, functional, emotional MCID 10.35 48,65
RSOM-31 The RSOM-31 is composed of 31 questions across seven domains; total score ranges from 0 to 155 (superseded by SNOT-22, which was derived from RSOM-31); lower scores indicate better outcomes
15-20 Nasal, eye, sleep, ear, general symptoms, practical problems, emotional consequences
MCID >30% change 66,67
SNOT-22 SNOT-22 is composed of 22 questions across five domains; total score ranges from 0 to 110; lower scores indicate better outcomes
7 Discrete rhinologic, extrarhinologic, ear/facial, psychological, and sleep symptoms associated with CRS
MCID 8.9 points Brazilian version MCID >14 points
48,68,69
SNOT-20 SNOT-20 is composed of 20 questions across four domains; total score is from 0 to 100 (superseded by SNOT-22); total scores can be divided by 20
Lower scores indicate better outcomes
5 Rhinologic, ear, facial symptoms, psychological and sleep function
MCID 16 points; if divided by 20, >0.5 is considered a significant change
48,70,71
CRS, chronic rhinosinusitis; CSS, Chronic Sinusitis Survey;MCID, minimal clinically important difference; PCS, physical composite score; PROM, patient-reported outcome measure; QoL, quality of life; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; RSOM, Rhinosinusitis Outcome Measure;…
Related Documents
