The effect of biologics in lung function and quality of life of patients with united airways disease: A systematic review

Background Increasing evidence supports the united airway disease concept for the management of upper and lower respiratory tract diseases, particularly in patients with asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). However, evidence for a combined approach in asthma and CRSwNP is scarce. Objective In this systematic review, we focused on the role of biologics in the lung function and quality of life in patients with severe asthma and CRSwNP. Methods We conducted a systematic search of 3 electronic databases using 2 search strategies to identify studies published from January 2010 to March 2022. Quality assessment was performed with the Critical Appraisal Skills Programme. Results Of 1030 studies identified, 48 original studies reporting data of benralizumab (12), dupilumab (14), mepolizumab (10), omalizumab (13), and reslizumab (2) were analyzed. Primary diagnosis was mostly asthma or CRSwNP, with only 15 studies, mainly observational, performed in populations with united airway disease. In total, 18 studies reported data on quality of life (mostly 22-item Sino-Nasal Outcome Test score), 8 on lung function (mostly FEV1), and 22 on both outcomes. Significant FEV1 and 22-item Sino-Nasal Outcome Test score improvements were consistently observed after 24-week treatment, and thereafter, mostly in real-world studies that included variable proportions of patients with asthma/CRSwNP. Conclusions The use of biologics in patients with severe asthma and CRSwNP was overall associated with significant improvements in lung function and quality of life. However, we observed a high heterogeneity of populations and outcome measurements across studies. Notwithstanding the need of larger studies, our results reinforce the joint management of asthma and CRSwNP as united airway disease in clinical practice.

Upper and lower respiratory tract diseases have traditionally been managed as independent entities in clinical practice.Nowadays, increasing evidence supports a paradigm shift toward united airways disease (UAD), [1][2][3][4] a concept based on the common pathophysiological and immunologic mechanisms that underlie certain respiratory diseases, 5,6 such as the eosinophilic airway inflammation associated with T H 2 cytokines (IL-4, IL-5, and IL-13) and/or IgE. 1,7The UAD concept is particularly relevant in the context of multimorbidity due to severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), a clinical scenario that is particularly common, severe, and difficult to treat.The prevalence rate of asthma in patients with CRSwNP is estimated to be up to 60% to 70%, whereas severe asthma is associated with nasal polyps in more than 70% of cases. 1,7,8Multimorbidity is associated with worse outcomes and more severe disease, 7,8 leading to an increased use of systemic corticosteroids in both diseases.Moreover, approximately 10% of patients with CRSwNP present aspirin-exacerbated respiratory disease (AERD) or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease. 1,9he symptomatology of UAD refers to that described for both CRSwNP and asthma, but its combination often results in a higher symptom burden, worse asthma control, and poorer lung function and quality of life (QOL). 10Some studies have reported higher rates of nasal polyps recurrence 11 and asthma exacerbation, 12 possibly due to increased airway obstruction and eosinophilic inflammation.4][15] Numerous studies have consistently reported the clinical benefit of biologics in upper and lower respiratory tract diseases.In fact, significant improvements in asthma and sinonasal outcomes and a positive impact on QOL [16][17][18] with dupilumab, omalizumab, and mepolizumab have led to the approval of these drugs in the treatment of asthma and CRSwNP.Reslizumab and benralizumab, which are currently approved for asthma, 15,19 have also shown promising results in patients with CRSwNP. 20,21pplying a multidisciplinary, UAD-based approach to the management of these patients is still a challenge and an unmet need.Given the lack of recommendations for joint management in current clinical practice guidelines, 13,15,19 an evidence-based approach could help decision-making processes.However, the considerable heterogeneity among clinical trials, post hoc analyses, and real-world studies performed in patients with UAD makes it difficult to compare data and findings. 2Moreover, studies in CRSwNP rarely evaluate asthma severity, and few asthma trials take severity of CRSwNP into consideration, hampering the evaluation of treatment response in these populations.With this background, we performed this systematic review to explore and analyze the role of biologics in UAD, specifically, their effect on lung function and QOL in patients with severe asthma and CRSwNP.

METHODS
This systematic review follows the recommendations of the PRISMA guidelines 22 (see Table E1 in this article's Online Repository at www.jaci-global.org)and the Cochrane handbook for systematic reviews. 23The search protocol was registered in the international prospective register of systematic reviews, PROSPERO (CRD42022318548).

Eligibility criteria
Systematic reviews with or without meta-analyses, randomized clinical trials (RCTs) and nonrandomized trials, post hoc studies of RCTs, and observational studies were included.Case reports and series, narrative reviews, letters to the editor, expert consensus, and preclinical studies were excluded.Only studies reporting on lung function and/or QOL in patients with asthma and CRSwNP and/or AERD who were treated with biologics were considered for inclusion.Lung function outcomes included FEV 1 , percentage of FEV 1 predicted, prebronchodilator FEV 1 , postbronchodilator FEV 1 , forced vital capacity, FEV 1 /forced vital capacity, forced midexpiratory flow, and peak expiratory flow.QOL assessments determined by the Asthma Quality of Life Questionnaire (AQLQ), 22-item Sino-Nasal Outcome Test (SNOT-22), mini-AQLQ, St. George's Respiratory questionnaire, short-form 36 questionnaire, and Rhinosinusitis Outcome Measure were included.

Search strategy
The literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science databases; studies in English and Spanish published between January 2010 and March 2022 were considered.A research question was formulated using the PICO structure (P, patient; I, intervention; C, comparator; O, outcome), and strategies were subsequently defined according to expert advice.Two search strategies were developed, on the basis of the following research question: ''What are the clinical outcomes in terms of lung function and/or QOL in patients with UAD (asthma and CRSwNP) who receive biologics?''The interventions included all available biologics (anti-IgE [omalizumab], anti-IL-4Ra [dupilumab], anti-IL-5 [mepolizumab and reslizumab], and anti-IL-5Ra [benralizumab] mAbs), and outcomes related to QOL and/or lung function were included.Search strategies were adapted for each database (see Table E2 in this article's Online Repository at www. jaci-global.org).

Study selection and data collection
The results were screened by 2 independent reviewers.Following the predefined inclusion and exclusion criteria, publications were first selected on the basis of title/abstract, and then after full-text reading.Data on study design, patient characteristics, main outcomes, and additional findings were extracted from the studies and uploaded by one of the reviewers to a standardized Microsoft Excel template, which was then double-checked and validated by the second reviewer.

Methodological quality assessment
We performed a quality assessment of the selected studies using the Critical Appraisal Skills Programme checklists (https:// casp-uk.net/casp-tools-checklists/).Study design, methodology, outcomes, and results were evaluated as described in the specific checklists.

Data synthesis
Study outcomes, specifically those related to lung function and QOL, are presented in tables by biologics.Baseline, posttreatment, and change from baseline values from independent studies are indicated, if available, in the tables.Because of the heterogeneous nature of the studies included in this systematic review, the data were synthesized descriptively.

RESULTS
A total of 1030 studies were retrieved using the 2 search strategies (see Figs E1 and E2 in this article's Online Repository at www.jaci-global.org).After duplicates had been removed, 613 studies were screened, of which 535 were excluded on the basis of title/abstract and 7 after full-text reading.Of the 71 articles selected for inclusion, 56 independent studies were identified.Of these, 48 were original studies and 8 were systematic reviews reporting data already identified in the original articles.Overall, methodological quality of most studies was high to moderately high (see Table E3 in this article's Online Repository at www. jaci-global.org).Characteristics of the original publications are summarized in Fig 1.

Benralizumab
8][29][30][31][32][33][34] Of these, 10 studies considered asthma and 2 RCTs considered CRSwNP as the primary diagnosis of the study population (Table I).][32][33][34] In total, 8 studies included lung function and 9 QOL outcomes; of these, 5 studies reported both. 24,26,27,30,33n patients with severe asthma, the SNOT-22 score decreased significantly after 24 weeks-by 34.8 points in an observational study and by 10.4 points in the post hoc analysis of the ANDHI trial. 26,29The baseline score was higher in the former study, which included only 10 patients. 29The post hoc analysis also reported a significant increase in FEV 1 (320 mL) at week 24. 26Three studies assessed the impact of benralizumab on QOL in patients with severe asthma with CRSwNP (35%-78%).The SNOT-22 score decreased by 22.0 points after 52 weeks (observational study) 28 and by 8.9 points after 24 weeks (RCT). 24In the ANDHI trial, FEV 1 increased by 160 mL after 24 weeks, 24 and an observational study showed significant FEV 1 and AQLQ-score improvements after 4, 16, 24, and 50 weeks. 30ive observational studies reported the impact of benralizumab on lung function in patients with severe asthma with CRSwNP (58%-91%); 2 of them also evaluated the impact on QOL.In a population of 18 patients, FEV5 significantly increased after 24 weeks (700 mL) 31,32 and 52 weeks (800 mL). 31Likewise, FEV 1 improvement was confirmed in a larger population at week 4 (200 mL) and week 24 (400 mL), 33 whereas the increase was only numerical in other studies. 27,34The SNOT-22 score significantly decreased, by approximately 14 points (a minimal clinically important difference is defined as scores >8.9), 35 after 24 weeks. 27,33Two RCTs reported the impact of benralizumab on QOL in patients with severe CRSwNP and asthma (68%-83%).A significant reduction in the SNOT-22 score was observed after  25 and 56 weeks (7.5 points). 20The baseline score and the number of patients were lower in the former study.

Dupilumab
7][48] Of these, 10 studies analyzed CRSwNP, 2 asthma, and 2 AERD as the primary diagnosis (Table II).One observational retrospective study reported data on 100% patients with UAD, 48 whereas the remaining studies included 58% to 87% patients with asthma in the population with CRSwNP.The post hoc analysis of the LIBERTYASTHMA QUEST included 20% patients with CRSwNP. 42Three studies reported data on patients with AERD. 43,45,464][45]48 An observational study showed a significant increase in FEV 1 (300 mL) and a decrease in SNOT-22 scores (39.4 points) in patients with UAD after only 4 weeks. 48The first RCT evaluating dupilumab in patients with severe CRSwNP (58% patients with asthma) reported a numerical FEV 1 increase (200 mL) and a significant reduction (18.1 points) in SNOT-22 scores after 16 weeks. 36,37Dupilumab consistently improved both lung function and QOL in the LIBERTY NP SINUS-24 and SINUS-52 populations (patients with severe CRSwNP, 59% patients with asthma).In the RCT, FEV 1 significantly increased (210 mL) after 24 weeks, and the SNOT-22 score significantly decreased by 21.1 and 17.4 points after 24 and 52 weeks, respectively, in the subgroup of patients with CRSwNP and asthma. 16These improvements were further confirmed in subsequent post hoc analyses. 38,44Additional analyses evaluated the impact of dupilumab on the QOL of the overall CRSwNP population.Two of them showed consistent improvements in the SNOT-22 score after 24 weeks (19.2 points 39 and 36.6% 41 ) and 52 weeks (23.9 points), 39 and another showed that the SNOT-22 score significantly improved 1 or more minimal clinically important difference at week 24, regardless of the number of previous surgeries. 40OL has been shown to improve in patients with CRSwNP (74%-87% patients with asthma) treated with dupilumab versus functional endoscopic sinus surgery. 47However, the post hoc analysis of the liberty ASTHMA QUEST study revealed a significant increase in FEV 1 (160-280 mL) and decrease in SNOT-22 scores (10.3-11.9points) in patients with asthma with CRSwNP (20%) who received dupilumab for 52 weeks. 42n patients with AERD, the SNOT-22 score decreased by 48.0 points after at least 6 months, by 34.4 points at week 4, and by 24.4 points after 24 weeks in an observational study, open-label trial, and post hoc analysis, respectively. 43,45,46Notably, baseline SNOT-22 values varied across studies, and were particularly high in Bertlich et al. 46 Lung function was shown to significantly improve after 4 and 12 weeks in the open-label trial (12%), 45 and at week 24 in the post hoc analysis (260 mL). 43

Mepolizumab
][53][54][55][56] Asthma was the primary diagnosis in 8 studies and CRSwNP in 2 studies (Table III).53]55 Eight studies included data on QOL and 7 on lung function outcomes; 5 of them reported both. 49,50,52,54,55n the 3 mepolizumab studies in patients with UAD, FEV 1 increases were statistically significant in the open-label trial (at week 24 and 48) 50 and in 1 observational study (at week 52), 54 but only numerical in patients dependent on oral corticosteroid. 56NOT-22 scores significantly decreased by 18.0 points at week 48, 50 by 19.8 points at week 24, and by 21.8 points at week 52. 54A significant improvement in QOL was reported in the population with CRSwNP in the 2 observational studies in patients with asthma.With similar follow-up (> _52 weeks), the SNOT-22 score decreased by 17.3 and 27.0 points in the retrospective 51 and prospective studies, 28 respectively.Of note, the baseline SNOT-22 value was lower in the former and sample size was smaller in the latter.
Mepolizumab was associated with significant FEV 1 increases in patients with severe eosinophilic asthma and CRSwNP (80%-90%).In 2 observational studies with similar baseline values, FEV 1 improved after 4 weeks (300 mL) and 24 weeks (400 mL), 52 and 12 months (200 mL), 53 respectively.A significant reduction of 17 to 19 points in the SNOT-22 score was also observed in the former study. 52The study of Harvey et al, 55 which included 34% of patients with CRSwNP, reported substantial improvements in FEV 1 (after 12 months) and AQLQ score (at 12 and 24 weeks) in patients with high (>600 cells/ mL) versus low eosinophils level. 55Mepolizumab treatment resulted in QOL improvement in 2 RCTs that included patients with severe CRSwNP (68%-78% patients with asthma).SNOT-22 scores significantly decreased by 13.2 points after 25 weeks 49 and by 16.5 points after 52 weeks 17 ; the baseline value was lower in the former study.A FEV 1 numerical increase of 160 mL at week 25 was also reported. 49

Reslizumab
Only 2 studies reported outcomes with reslizumab: 1 RCT 57 and 1 post hoc analysis. 21In both studies, asthma was the primary diagnosis, and 30% to 42% and 16% of patients had CRSwNP, respectively (Table III).With similar baseline FEV 1 values, increases of nearly 200 mL after 15 weeks and 327 mL after 52 weeks were reported in the overall population of the RCT and in the population with self-reported CRSwNP in the post hoc analysis, respectively. 21,57A significant improvement in AQLQ score was shown in the latter.

Omalizumab
3][64][65][66][67] Overall, 6 studies analyzed asthma, 5 CRSwNP, and 2 AERD as the primary diagnosis of the study populations (Table IV).One RCT 58 and 4 observational studies (2 prospective 63,66 and 2 retrospective) 62,67 reported data on 100% patients with UAD, whereas the remaining studies included 49% to 61% patients with asthma in the population with CRSwNP, 18,60 and 14% to 82% patients with CRSwNP in the population with asthma. 28,51,61][66] Observational studies reported significant increases in FEV 1 after 52 weeks 66 and 24 weeks 67 in patients with UAD treated with omalizumab.QOL improvement was associated with a significant increase in the AQLQ score (0.8 points) 58 or reduction in the SNOT-22 score (22.0 points) after 16 weeks. 63A decrease in the SNOT-22 score over time was also observed (34.1 and 39.3 points at 24 and 52 weeks, respectively). 62In the 2 studies with patients with severe asthma analyzing the population with CRSwNP, significant improvements in lung function 61 and QOL were observed after 52 weeks. 28he publications associated with POLYP 1 and POLYP 2 trials reported a significant decrease in the SNOT-22 score at week 24 (15.0-16.1 points in the RCT) 18,60 and week 52 (6.1 points [from the 24-week assessment] in the open-label extension) 59 in the population with CRSwNP.In contrast, the reduction in the SNOT-22 score was only numerical in an observational study of patients with asthma with CRSwNP. 51n patients with AERD, 2 observational studies reported significant increases in FEV 1 after 9 and 12 months, as well as improved QOL. 64,65

DISCUSSION
This systematic review provides an updated overview of the role of biologics in lung function and QOL of patients with asthma and CRSwNP from the comprehensive perspective of UAD.Our search retrieved 48 original studies (11 RCTs, 11 post hoc analyses, 3 open-label/extension trials, and 23 observational studies) with an overall moderate to high methodological quality.In total, 18 studies reported data on QOL, 8 on lung function, and 22 on both outcomes.Outcomes of benralizumab and reslizumab were mostly identified in populations with asthma, whereas CRSwNP was predominant in dupilumab and mepolizumab studies, and omalizumab was evenly distributed across populations.Significant improvements in FEV 1 and/or the SNOT-22 score have been described in patients with asthma and CRSwNP and/or AERD who received benralizumab (12 studies), dupilumab (14 studies), mepolizumab (10 studies), omalizumab (13 studies), and reslizumab (2 studies).
Patient populations in terms of multimorbidity (ie, percentage with asthma and CRSwNP) were highly heterogeneous across studies.The primary diagnosis was asthma, CRSwNP, or AERD in 25 studies, 19 studies, and 4 studies, respectively.In asthma studies, most of which were observational and retrospective, the percentage of patients with CRSwNP varied from 14% to 88%.Most studies in patients with CRSwNP, however, were RCTs and post hoc analyses, and included a higher proportion of patients with asthma (range, 55%-92%).Overall, 31% of selected studies (15 of 48) included 100% populations with UAD, although most of them were performed in patients with asthma.Lung function and/or QOL outcomes in patients with UAD were often found in small observational retrospective studies, which highlights the need for clinical trials and larger real-world studies focusing on the UAD concept rather than the comorbidity.
Biologics have shown promise in the management of UAD. 2,68Five biologics have been approved for severe asthma, among which dupilumab, omalizumab, and mepolizumab were also approved for the treatment of severe CRSwNP.These agents reduce exacerbation rates and the daily oral corticosteroid dose, and also improve asthma control and lung function. 16,50,55,61Biologics also improve QOL by ameliorating nasal symptoms associated with CRSwNP, such as loss of smell, and reduce the need for systemic corticosteroids and endoscopic sinus surgery. 16,24,49,58Our study shows that treating patients with UAD with benralizumab, dupilumab, mepolizumab, or omalizumab for at least 24 weeks significantly improves FEV 1 and/or the SNOT-22 score.
Although FEV 1 is currently one of the criterion standards for assessing lung function, 19 several other methods were described in the studies retrieved, such as predicted FEV 1 and prebronchodilator or postbronchodilator FEV 1 .Furthermore, different measurement time points were used (ie, from week 4 to week 52), week 24 being the most frequent.Benralizumab and dupilumab high-quality RCTs specifically reported FEV 1 improvements in patients with asthma and CRSwNP, which was further confirmed in mepolizumab and omalizumab post hoc analyses and observational studies.However, the severity of asthma and CRSwNP, when considered as a comorbid condition, was rarely reported.We observed that clinical trials and real-world studies usually analyze 1 primary disease (severe asthma or severe CRSwNP) plus a comorbid condition.Furthermore, the diagnosis of CRSwNP in studies in patients with severe asthma is based on clinical history, whereas the severity of asthma or its treatment is not commonly reported in CRSwNP studies.It has been described that UAD negatively impacts QOL 7 and these patients have poorer outcomes than those reported in patients with asthma or CRSwNP.Our results showed that QOL in patients with asthma and CRSwNP is frequently measured using the SNOT-22 (35 studies), AQLQ (7 studies), and/or St. George's Respiratory questionnaire (2 studies) scales.Of these, SNOT-22 was reported in most studies, even when asthma was the primary diagnosis.Noticeably, the baseline SNOT-22 score was lower in patients with asthma versus patients with CRSwNP.Significant reductions in the SNOT-22 score were observed across studies after at least 24 weeks of treatment with benralizumab, dupilumab, mepolizumab, or omalizumab, with subsequent improvements in QOL that persisted or increased in the long-term.Although some small observational studies reported greater reductions in SNOT-22 scores, these data need to be confirmed in larger populations.
Given the importance of including both lung function and QOL among the main outcomes of studies in patients with asthma and CRSwNP, future research could focus on analyzing the potential correlation between these outcomes.In total, 22 of the 48 studies evaluated the role of biologics (benralizumab [5], dupilumab [8], mepolizumab [5], omalizumab [3], and reslizumab [1]) in both outcomes.Although some authors acknowledged a potential association between lung function and QOL, 38,42,44,54 none of the studies included in this review analyzed this phenomenon.
Our systematic review had some limitations.Some studies were not designed for UAD analysis because data from CRSwNP were primarily obtained from the clinical history.However, most RCTs including patients with CRSwNP performed a prospective group analysis of populations with or without asthma and, in some cases (eg, dupilumab studies), a statistical comparison is shown.Second, although most studies were observational and/or performed in small populations, results were in line with data observed in the RCTs.Third, analysis of the evidence was challenging due to the high heterogeneity of patient populations and variables across studies, which prevented us from making reliable comparisons.In fact, the effect size was different among some of the included studies, even as to the same end point.Therefore, data should be interpreted with caution.Lastly, although the search strategies were design to find all available UAD evidence, studies that were not classified as such might have been overlooked.

Conclusions
We systematically reviewed the latest evidence on the effect of biologics on lung function and QOL in patients with UAD, focusing on severe asthma and severe CRSwNP and/or AERD.In these patient populations, benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab led to an overall improvement in lung function and QOL.The primary diagnosis in most studies was severe asthma or severe CRSwNP; only 15 studies included 100% patients with UAD.Our results showed the high heterogeneity of populations, scores, measurements, and time points, thereby highlighting the need for unified criteria that will allow researchers to compare data and draw reliable conclusions.Further studies will provide an in-depth understanding of the baseline characteristics of patients with multimorbid conditions and allow a more comprehensive evaluation of the effect of biologics in both diseases under the UAD concept.

DISCLOSURE STATEMENT
This work was funded by Sanofi.Editorial assistance was provided by Celia Miguel-Blanco (Medical Science Consulting; Valencia, Spain).The authors were not compensated for writing the manuscript.The sponsor was not involved in the protocol design, data analysis, or manuscript writing.
Disclosure of potential conflict of interest: J. Dom ınguez-Ortega has received funding for research, and honoraria for consultancy and conferences from AstraZeneca, Chiesi, and GlaxoSmithKline (GSK); honoraria for consultancy and conferences from Bial, Novartis, Sanofi, and Teva; and speaker fees from ALK, LETI Pharma, and Mundipharma.J. Mullol is a member of national or international advisory boards and has received speaker fees or funding for clinical trials and research projects from Allakos, AstraZeneca, Genentech, GSK, Glenmark,

FIG 1 .
FIG 1. Characteristics of studies reporting on lung function (LF), QOL, or both.A, LF (all patients with asthma); B, QOL (all patients with asthma); C, QOL (all patients with CRSwNP); D, LF and QOL (all patients with asthma); E, LF and QOL (all patients with CRSwNP).Percentages on the X-axis indicate the proportion of patients with asthma or CRSwNP.

TABLE III .
Studies reporting lung function and/or QOL with mepolizumab and reslizumab

TABLE III .
(Continued) Chronic rhinosinusitis; IQR, interquartile range; NA, Not assessed; N-ERD, NSAID-exacerbated respiratory disease; NSAID, nonsteroidal anti-inflammatory drug; OBS, observational study; OCS, oral corticosteroid; post-BD, postbronchodilator.*Thisstudy reports other lung function and QOL parameters.Results for patients with both asthma and CRSwNP are presented.àResults of the 20 patients who received mepolizumab are presented.§ High and low eosinophil levels defined as >600 cells/mL and < _600 cells/mL, respectively.|| Results of the 115 patients who received anti-IL-5 biologics (mostly mepolizumab) are presented.

TABLE IV .
Studies reporting lung function and/or QOL with omalizumab