Systematic literature review of the epidemiology and clinical burden of chronic rhinosinusitis with nasal polyposis

Figures & data

Table 1. Detailed criteria for inclusion/exclusion of studies for epidemiology SLR.

Criteria	Inclusion criteria	Exclusion criteria
Population	Patients aged ≥18 years old with chronic rhinosinusitis with nasal polyposis (CRSwNP)	Only patients aged <18 years All other diseases
Intervention/Comparators	Epidemiology and burden of illness studies were not restricted by treatment	None
Outcomes	Prevalence in key regions^a Incidence in key regions^a Key comorbidities (e.g. asthma, allergic rhinitis) Morbidity (e.g. exacerbations, symptoms, severity) Mortality risk Percentage of patients who require surgery, and the frequency of surgery and repeated surgery Risk factors Percentage of patients with high EOS OCS burden and pattern (including OCS use and consequences of OCS use)	Outcomes not related to the epidemiology of CRSwNP
Study design	Any study type (e.g. prospective and retrospective cohort studies, survey studies, case-control studies) Articles published 1 January 2008, to 8 February 2019 Conference abstracts published 1 January 2017, to 7 March 2019	Animal studies, in vitro studies, case reports, expert opinion articles, commentaries, letters Articles published before 1 January 2008 Conference abstracts published before 1 January 2017
Language	Articles in English^b	All non-English articles

^aKey regions included: US, Canada, EU5 (France, Germany, Italy, Spain, United Kingdom), China, Japan, Australia, Brazil.

^bCitation retrieval was not limited by language. Records were categorized based on language during title-and-abstract screening stage, and non-English abstracts were excluded. English abstracts with non-English articles were excluded at the full-text screening stage.

Abbreviations. CRSwNP, chronic rhinosinusitis with nasal polyposis; EOS, eosinophil; EU5, European Union 5; HTA, health technology agency; N/A, not applicable; OCS, oral corticosteroid; SLR, systematic literature review; US, United States.

Table 2. Detailed criteria for inclusion/exclusion of studies for clinical burden SLR.

Criteria	Inclusion criteria	Exclusion criteria
Population	Patients aged ≥18 years old with CRSwNP	Only patients aged <18 years old
Intervention	Any treatment for CRSwNP	Treatments not for CRSwNP
Comparators	Any treatment for CRSwNP	Treatments not for CRSwNP
Outcomes	The current SoC for CRSwNP Clinical outcomes of different therapies, including consequences of OCS use	Outcomes not related to the clinical burden of CRSwNP
Study design	RCTs Non-randomized studies: Observational studies (e.g. case-control, cross-sectional, longitudinal, and cohort studies) Single-arm studies Pilot studies Articles published 1 January 2008 to 16 February 2019 Conference abstracts published 1 January 2017 to 16 February 2019	Animal studies, in vitro studies, case reports, expert opinion articles, commentaries, letters Articles published before 1 January 2008 Conference abstracts published before 1 January 2017
Language	Articles in English^a	All non-English articles

^aCitation retrieval was not limited by language. Records were categorized based on language during title-and-abstract screening stage, and non-English abstracts were excluded. English abstracts with non-English articles were excluded at the full-text screening stage.

Abbreviations. CRSwNP, chronic rhinosinusitis with nasal polyposis; OCS, oral corticosteroid; RCTs, randomized controlled trials; SLR, systematic literature review; SoC, standard of care.

Figure 1. PRISMA diagram: Epidemiology. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; y/o, years old.

Table 3. Most commonly reported comorbidities for patients with CRSwNP^a.

Comorbidity	Study	Country	Time frame	Study design	Population	Total study population (n)	CRSwNP population (n)	CRSwNP age, years (mean ± SD)	Percentage of patients with CRSwNP and comorbidity (%)	Description
Asthma	^14	Korea	2010–2012	Cross-sectional survey	CRS	17,506	Not stated	52.7 ± 0.9	Physician-diagnosed: 6.7 ± 1.5 Self-reported: 9.4 ± 1.6% Past: 3.9 ± 1.0 Current: 5.4 ± 1.4	Asthma
	^37	Japan	2005	Prospective study	CRS	553	309	51.5 ± 18.8	23.1	Asthma
	^67	US	2013–2014	Retrospective case-control study	CRSwNP	21,682	10,841	45.84 ± 11.86	At baseline: 12.4 At follow-up: 20.8	Asthma
	^23	US	2001–2010	Retrospective longitudinal cohort study	CRS	446,480	595	48.4 ± 19.1	23.9	Asthma
	^19	US	1996–2016	Retrospective database analysis	CRS	29,934	9,177	44.8 ± 15.2	30.1	Asthma
	^71	US	2003–2013	Retrospective cross-sectional study	CRS	1,393	488	46	53.6	Asthma
	^74	US	2002–2012	Chart review	CRS	507 + 874	874	50.35 ± 14.4	56	Asthma
	^22	Europe, Asia, Australia	Not stated	Prospective study	CRS	573	Benelux: 125 Berlin: 72 Adelaide: 68 Beijing: 152 Chengdu: 114 Tochigi: 42	Not stated	Benelux: 44.44 Berlin: 36.36 Adelaide: 42.42 Beijing: 13.68 Chengdu: 7.25 Tochigi: 33.3	Asthma
Allergy/Atopy/Atopic dermatitis	^19	US	1996–2016	Retrospective database analysis	CRS	29,934	9,177	44.8 ± 15.2	12.6	Allergy
	^91	US	Not stated	Prospective case series	Adults presenting with inflammatory paranasal sinus disease	514	18–39 years: 203 40–59 years: 213 60+ years: 98	Not stated	18–39 years: 77.4 40–59 years: 74.7 60+ years: 59.1	Environmental allergy
	^40	Belgium	NR	Questionnaire	CRS	1,281	420	Not stated	47.6	Allergy
	^22	Europe, Asia, Australia	Not stated	Chart review	CRS	573	Benelux:125 Berlin: 72 Adelaide: 68 Beijing: 152 Chengdu:114 Tochigi: 42	Not stated	Benelux: 44.44 Berlin: 54.55 Adelaide: 57.58 Beijing: 36.84 Chengdu: 34.78 Tochigi: 33.33	Allergy
	^23	US	2001–2010	Retrospective longitudinal cohort study	CRS	446,480	595	48.4 ± 19.1	4.2	Atopic dermatitis
	^68	Europe	2007–2009	Cross-sectional case-control study	CRS	869	445	46.8 ± 11.2	46.8	Atopy
	^71	US	2003–2013	Retrospective cross-sectional study	CRS	1,393	488	46	66.4	Atopy
Allergic rhinitis	^67	US	2013–2014	Observational, retrospective, case-control study	CRSwNP	21,682	10,841	45.84 ± 11.86	At baseline: 25.6 At follow-up: 53.3	Allergic rhinitis
	^74	US	2002–2012	Chart review	CRS	507 + 874	874	50.35 ± 14.4	76	Allergic rhinitis
	^68	Europe	2007–2009	Cross-sectional case-control study	CRS	869	445	46.8 ± 11.2	∼2/3 participants	Allergic rhinitis
	^14	Korea	2010–2012	Cross-sectional survey	General adult population	17,506	Not stated	52.7 ± 0.9	17.4	History of allergic rhinitis
	^23	US	2001–2010	Retrospective longitudinal cohort study	CRS	446,480	595	48.4 ± 19.1	42.7	Allergic rhinitis

^aStudies with populations ≥500 included.

Abbreviations. AERD, aspirin-exacerbated respiratory disease; AFRS, allergic fungal rhinosinusitis; Benelux, Belgium, the Netherlands, Luxembourg; COPD, chronic obstructive pulmonary disorder; CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyposis; GERD, gastroesophageal reflux disease; SD, standard deviation; US, United States

Table 4. Drugs most commonly used for CRSwNP^a.

Treatment	Study	Country	Time frame	Study design	Population	Total study population (n)	CRSwNP population (n)	CRSwNP age, years (mean ± SD)	Percentage who received prior treatment (%)	Treatment description
Intranasal corticosteroids	^68	Europe	2007–2009	Cross-sectional case-control study	CRS	869	445	46.8 ± 11.2	90.4	Ever having received medical treatment for their sinus condition – intranasal corticosteroids
	^15	US	2014–2015	Cross-sectional survey	General adult population	1189	1.1%	Not stated	92.5	Treated with nasal spray in the past 12 mo
	^23	US	2001–2010	Retrospective longitudinal cohort study	CRS	446,480	595	48.4 ± 19.1	7–24 mo before CRS diagnosis: 0.3 (1.0) 0–6 mo before CRS diagnosis: 0.3 (0.6)	Overall nasal steroid use Number of orders (by physician), mean (SD)
Oral corticosteroids	^68	Europe	2007–2009	Cross-sectional case-control study	CRS	869	445	46.8 ± 11.2	61.3	Ever having received medical treatment for their sinus condition – OCS
	^67	US	2013–2014	Retrospective case-control study	CRSwNP	21,682	10,841	45.84 ± 11.86	At baseline: 29.2 At follow-up: 61.6	OCS prescription
	^71	US	2003–2013	Retrospective cross-sectional study	CRS	1393	488	Not stated	23.4	% having taken oral steroids
	^15	US	2014–2015	Cross-sectional survey	General adult population	1189	1.1%	Not stated	71.2	Taken oral steroids for nasal or sinus symptoms in the past 12 mo
	^23	US	2001–2010	Retrospective longitudinal cohort study	CRS	446,480	595	48.4 ± 19.1	7–24 mo before CRS diagnosis: 0.4 (0.9) 0–6 mo before CRS diagnosis: 0.2 (0.7)	Overall systemic steroid use Number of orders, mean (SD)
Antibiotics	^67	US	2013–2014	Retrospective case-control study	CRSwNP	21,682	10,841	45.84 ± 11.86	At baseline: 28.5 At follow-up: 29.9	Macrolide prescription
	^68	Europe	2007–2009	Cross-sectional case-control study	CRS	869	445	46.8 ± 11.2	54.9	Ever having received medical treatment for their sinus condition – antibiotics
	^23	US	2001–2010	Retrospective longitudinal cohort study	CRS	446,480	595	48.4 ± 19.1	7–24 mo before CRS diagnosis: 1.5 (2.4) 0–6 mo before CRS diagnosis: 0.9 (1.7)	Overall antibiotic use Number of orders, mean (SD)
Antihistamines	^68	Europe	2007–2009	Cross-sectional case-control study	CRS	869	445	46.8 ± 11.2	33.6	Ever having received medical treatment for their sinus condition – antihistamines

^aStudies with populations ≥500 included.

Abbreviations. CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyposis; CRSwNP, chronic rhinosinusitis with nasal polyposis; mo, months; OCS, oral corticosteroids; SD, standard deviation.

Figure 2. PRISMA diagram for RCTs: Clinical Burden. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCTs, randomized clinical trials.

Figure 3. PRISMA diagram for RWE studies: Clinical Burden. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RWE, real-world evidence.

Table 5. RCTs and RWE studies investigating biologics^a.

Reference	Biologic	Study type	NCT# (study name)	Phase	N	Population
Bachert, 2019^86	Dupilumab	placebo-controlled, multicenter RCT	NCT02898454 (SINUS-52)	3	448	Adults with severe CRSwNP previously treated with systemic corticosteroids and/or NP surgery, on daily mometasone furoate
Han, 2019^85	Dupilumab	placebo-controlled, multicenter RCT	NCT02912468 (SINUS-24)	3	276	Adults with severe CRSwNP, with or without comorbid asthma, on daily mometasone furoate
Bachert, 2016^87	Dupilumab	placebo-controlled, multicenter RCT	NCT01920893	2	60	Adults with CRSwNP refractory to intranasal corticosteroids
Bachert, 2017^90	Mepolizumab	placebo-controlled, multicenter RCT	NCT01362244	2	107	Adult patients with severe recurrent bilateral nasal polyposis requiring surgery
Gevaert, 2011^91	Mepolizumab	placebo-controlled, single-center RCT	NR	NR	30	Adult patients with severe nasal polyposis (grade 3/4 or recurrent after surgery) refractory to corticosteroid therapy
Tuttle, 2018^92	Mepolizumab	retrospective study	N/A	N/A	14	Patients with AERD
NLM, 2009^93	Omalizumab	placebo-controlled, single-center RCT	NCT01066104	2	27	Adult outpatients with CRSwNP, without uncontrolled moderate-to-severe asthma
Gevaert, 2013^94	Omalizumab	placebo-controlled, 2-center RCT	NR	NR	24	Adult CRSwNP patients with comorbid asthma for >2 years
Bidder, 2018^95	Omalizumab	prospective cohort study	N/A	N/A	37	CRSwNP patients with severe allergic asthma

^aOnly biologics RCTs with results available at the time of the literature search are listed in this table. Ongoing Phase III studies identified by the literature search for omalizumab in CRSwNP: POLYP 1 and POLYP 2; ongoing Phase III study identified for mepolizumab in severe bilateral nasal polyposis: SYNAPSE; ongoing Phase III study identified for benralizumab in severe nasal polyposis: OSTRO.

Abbreviations. AERD, aspirin-exacerbated respiratory disease; CRSwNP, chronic rhinosinusitis with nasal polyposis; NP, nasal polyposis; NR, not reported; N/A, not applicable; RCT, randomized controlled trial; RWE, real-world evidence.

Figure 4. Clinical outcomes scores for dupilumab versus placebo from SINUS-24 and SINUS-52 Phase III RCTs.

Figure 5. Mepolizumab clinical trial results.

Figure 6. Omalizumab clinical trial and RWE study results.

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