Effects of omalizumab on lung function in patients with moderate-to-severe allergic asthma: a systematic review and meta-analysis

Abstract

Background:

With the rise of targeted treatments for asthma, treatment with omalizumab is a new option.

Objectives:

To assess the improvement of pulmonary function with additional omalizumab treatment in patients (⩾6 years old) with moderate-to-severe allergic asthma.

Data sources and methods:

Observational studies of randomized controlled trials of add-on omalizumab for the treatment of patients with moderate-to-severe allergic asthma, published from the establishment till August 2022, were retrieved from WAN FANG DATA, PubMed, CNKI, Embase, Cochrane, and Web of Science databases. Data extraction and quality evaluation were performed on the literature that met the inclusion criteria, using RevMan 5.3 to analyze the data.

Results:

A total of 11 randomized controlled clinical trials were included, involving a total of 3578 patients with asthma, 1856 patients in the omalizumab group, and 1722 patients in the control group. The improvement in Forced expiratory volume in 1 s as a percentage of predicted normal and Forced expiratory volume in 1 s was more pronounced in the omalizumab-treated group [MD = 3.91, 95% confidence interval (CI): 1.89–5.94, p = 0.0002; MD = 0.09, 95% CI: 0.05–0.13, p < 0.0001], while the improvement in Morning Peak expiratory flow rate was not statistically different between the two groups (MD = 3.64, 95% CI: −22.17–29.45, p = 0.78).

Conclusion:

Additional omalizumab treatment showed some improvement in lung function in patients with moderate-to-severe asthma.

Trial registration:

PROSPERO ID:CRD42022378498.

Plain language summary

Improvement of lung function in asthmatic patients with additional omalizumab

In this paper, by screening clinical trials related to the treatment of patients with moderate and severe asthma with omalizumab plus, we extracted indicators related to lung function for meta-analysis and found that in patients with moderate to severe asthma, the addition of omalizumab can improve lung function to a certain extent and delay the worsening of lung function.

Introduction

Bronchial asthma (asthma) is a chronic inflammatory disease of the airways, characterized by repeated episodes of wheezing, shortness of breath, chest tightness, and dyspnea. It is also accompanied by hyperresponsiveness and reversible airflow limitation.^1,2 According to the survey, globally, the incidence and mortality of asthma show a trend of the increasing year by year, with the disease remaining poorly controlled. In a European study of 8000 asthma patients, only 20.1% achieved control, 34.8% achieved partial control, and 45.1% failed to achieve effective control. ² Asthma is a distinctly heterogeneous disease and can be clinically classified into many phenotypes. One important phenotype is allergic asthma, which accounts for 71.0% of severe asthma. ³ The current guidelines suggest prescribing low-dose inhaled corticosteroid (ICS) + long-acting beta-agonists (LABAs) for patients with moderate asthma and moderate-dose ICS + LABA for those with severe asthma. In cases where patients do not respond well to these treatments, the addition of antibodies such as anti-IgE (Immunoglobulin E) or anti-IL-5 (Interleukin-5) may be considered, depending on the clinical phenotype. However, in reality, some patients are unable to achieve effective clinical control even after receiving formal treatment and even appear hormone dependent.^4,5 The demand for medical resources is much greater for patients with moderate-to-severe asthma than for those with mild asthma, and the medical costs for severe patients also amount to more than half of the total costs for asthma patients.^6,7 Poorly controlled asthma symptoms and recurrent attacks not only endanger the health of the patient but also have a serious impact on the patient’s daily life and work. Prolonged hormone therapy also produces some adverse effects, such as femoral head necrosis, respiratory infections, immunosuppression, metabolic disorders, and so on. Omalizumab, the first biologically targeted therapy for asthma, reduces serum-free IgE levels and inhibits its binding to effector cells (Dendritic cells, basophils, etc.) by specifically binding to IgE to form complexes,^8,9 thereby inhibiting inflammatory cell activation and mediator release to block the inflammatory cascade that triggers asthma attacks.^10–13 The efficacy and safety of omalizumab in patients with moderate-to-severe asthma have been demonstrated in some studies, which have improved clinical symptoms and reduced the rate of acute exacerbations and hospitalizations, but there is still some controversy over whether it can improve lung function of patients. Therefore, this study aims to investigate the effectiveness of omalizumab in improving lung function in patients with moderate-to-severe asthma by searching the relevant literature for meta-analysis.

Methods

Information sources and study selection

Search strategy and inclusion and exclusion criteria were developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements. ¹⁴ Computer retrieval of the databases WAN FANG DATA, PubMed, CNKI, Embase, Cochrane, and Web of Science was conducted from the time of creation to August 2022, with the search strategy “(((Omalizumab OR Xolair) AND (asthma OR Asthmas OR Bronchial Asthma OR Asthma, Bronchial)) AND (Pulmonary Function OR Lung Function)) AND randomized controlled trial,” respectively expanded with English and Chinese subject words, no language restrictions, and finally 320 kinds of literature were collected.

Inclusion criteria: (1) Study type: a clinically randomized controlled trial with additional omalizumab for moderate-to-severe asthma, whether published or not. (2) Study population: Patients of all races, nationalities, and genders, aged ⩾6 years, with disease duration ⩾1 year, and diagnosed with moderate-to-severe asthma by the Global Initiative for Asthma Control or asthma-related guidelines such as ATS; patients who failed to achieve clinical symptom control goals despite conventional therapies such as inhaled medium to high dose ICS/ICS + LABA/ICS + LABA + other asthma treatment drugs. (3) Intervention: Conventional therapy + subcutaneous omalizumab in the test group. The dose of omalizumab was determined according to the patient’s baseline total serum IgE (IU/ml) and body mass (kg) levels. The appropriate dose and frequency of administration (every 2 or 4 weeks) were determined according to the dosing schedule, with each dose ranging from 75 to 600 mg; the control group was treated with conventional therapy or conventional therapy + subcutaneous placebo, with placebo administered as omalizumab for the same duration (⩾16 weeks). (4) Report at least one of the following outcome indicators: Forced expiratory volume in 1 s as a percentage of predicted normal (FEV1%), Morning Peak expiratory flow rate (mPEF), and Forced expiratory volume in 1 s (FEV1). (5) Year of publication: database builds to August 2022.

Exclusion criteria: (1) Previous use of omalizumab, pregnant and lactating women, patients with hypersensitivity to omalizumab, and patients with other cardiopulmonary or immune system disorders that may affect the results of the trial. (2) Nonclinical randomized controlled trials, self-crossover controlled trials, and uncontrolled clinical trials. (3) Conference abstracts, reviews, and Cochrane systematic reviews that are still in the proposal and title stages. (4) Studies without any of the outcome indicators of the study’s nascent population or literature for which the full text was not available. (5) Types of studies such as reviews, Meta-analyses, and systematic reviews. (6) Repeatedly published literature.

Data extraction and quality evaluation

Two researchers screened the studies independently. By reading the title and abstract, the remaining literature was read in full after excluding those that were clearly irrelevant to the study, and data were extracted from those studies that met the inclusion criteria. The extracts included the authors of the literature, the year, the number of patients included in the study, the specific interventions in the trial and control groups, the duration of the trial, the outcome indicators, and so on in the same statistical table, which were then cross-checked and in case of disagreement, discussed or third-party assistance was sought in deciding whether to include the study. Quality and bias were evaluated according to the criteria recommended in the Cochrane Handbook. ¹⁵ Seven aspects were evaluated to check whether: the correct random method was used, blinding was used, there was selective bias, the random allocation scheme was concealed, there were missing data reported, study results were selectively reported, and there were other sources of bias.

Statistical analyses

Statistical analysis was performed with RevMan 5.3 software, using Mean Deviation (MD) or Standard Mean Difference (SMD) and 95% confidence intervals (CIs) as statistics. Determine whether there is heterogeneity in each study, and calculate the I² value to test the heterogeneity. If I² is less than 50% and p ⩾ 0.1, it indicates that there is little heterogeneity among the results of various studies and a fixed-effects model is chosen for the analysis. Conversely, I² > 50%, p < 0.1, indicates significant heterogeneity between studies. If there is clinical heterogeneity (such as age and sex), subgroup analysis or descriptive analysis may be used. If only statistical heterogeneity was present, a random-effects model could be use for combined analysis.

Results

Study selection

An initial search of 320 references from various databases was conducted according to the search strategy. Additionally, 29 references in the relevant systematic evaluation and meta-analysis categories were manually searched to minimize publication bias. A total of 134 articles were excluded due to duplication. In addition, 185 articles were removed based on a review of their titles and abstracts. These exclusions were made for reasons such as reviews, conference evaluations, non-randomized controlled trials, and lack of relevance to the topic. The remaining 30 articles were carefully read in their entirety. Three articles were excluded for post hoc analysis and evaluation, three articles for inconsistency of study participants, six articles for not providing target outcomes, and seven articles for not including specific study data. A total of 11 studies were included in this meta-analysis. The study screening process is shown in Figure 1. Basic features included in the study are listed in Table 1.

Figure 1.

Study screening flow diagram.

Table 1.

Basic characteristics of the included studies.

Author	Year	Treatment time (week)	Control interventions	Number of people (Experimental group/control group)	IgE levels (IU/ml, average)		Baseline ICS dose equivalent (µg/day, average)		Report ending	Age (years)
					Experimental	control	Experimental	Control
Busse, W 16	2001	28	Conventional treatment a  + placebo	525 (268/257)	172.5	186.3	570.0	568.0	①	(12–74)
Garcia 17	2013	16	Conventional treatment b  + placebo	41 (20/21)	153.0	160.0	2710.0	2667.0	① + ③	(18–70)
Ayres 18	2004	52	Conventional treatment c	312 (206/106)	167	NR	2000.0	2000.0	① + ③	(12–73)
Ohta 19	2009	16	Conventional treatment b  + placebo	315 (151/164)	216.4	246.7	1174.8	1163.1	② + ③	(20–75)
Chanez 20	2010	16	Conventional treatment a  + placebo	31 (20/11)	202.0	253.3	3712.0	3272.0	②	⩾18
Li 21	2016	24	Conventional treatment b  + placebo	609 (310/299)	271.5	279.4	NR	NR	①	(18–75)
Hanania 22	2013	48	Conventional treatment b  + placebo	673 (344/329)	NR	NR	NR	NR	①	(12–75)
Humbert 23	2004	28	Conventional treatment d  + placebo	409 (209/210)	197.6	189.6	2359.0	2301.0	③	(12–75)
Qian 24	2021	16	Conventional treatment e	130 (65/65)	224.52	230.47	NR	NR	①	(6–12)
Xiaoning 25	2022	26	Conventional treatment f	114 (55/59)	433.9	430.8	NR	NR	①	(12–17)
Busse, WW 26	2011	60	Conventional treatment b  + placebo	419 (208/211)	NR	NR	NR	NR	①	(6–20)

^aBeclomethasone dipropionate.

^bInhaled corticosteroid + long-acting β2-agonist.

^cBeclomethasone dipropionate + long-acting β2-agonist.

^dICS + LABAs or ICS + LABAs + one additional asthma controller medication or ICS + LABAs + OCS.

^eBudesonide and Formoterol powder inhalation.

^fBudesonide suspension.

① Represents FEV1%

② Represents mPEF

③ Represents FEV1

FEV1, Forced expiratory volume in 1 s; FEV1%, Forced expiratory volume in 1 s as a percentage of predicted normal; ICS, low-dose inhaled corticosteroid; LABA, long-acting beta-agonist; mPEF, Morning Peak expiratory flow rate; NR, not mentioned; OCS, oral corticosteroid.

Evaluation of quality

Of the 11 studies finally included, only 4 described the method of randomization^19,20,24,25 the rest only mentioned ‘randomization’. A total of eight had placebo as the control group and were blinded; Qian ²⁴ used conventional treatment as the control group and were single-blinded; the remaining two used conventional treatment as the control group and used open labels. All studies described the reasons and data processing of lost follow-up and quit, except for Xiaoning ²⁵ and Busse ²⁶ there was no lost follow-up and quit in the study. Their risk of bias evaluation is shown in Figures 2 and 3, and the results of the modified Jadad score are shown in Table 2.

Figure 2.

Risk assessment of bias in included studies.

Figure 3.

Included studies quality assessment.

Table 2.

Modified Jadad scores.

Study	Year	Randomization	Concealed	Blind	Withdrawals and lost visits	Score	Grade
Busse, W 16	2001	Unclear	Unclear	Appropriate	Yes	5	High quality
Garcia 17	2013	Unclear	Unclear	Appropriate	Yes	5	High quality
Ayres 18	2004	Unclear	Unclear	Appropriate	Yes	3	Low quality
Ohta 19	2009	Appropriate	Clear	Appropriate	Yes	7	High quality
Chanez 20	2010	Appropriate	Clear	Appropriate	Yes	7	High quality
Li 21	2016	Unclear	Unclear	Appropriate	Yes	5	High quality
Hanania 22	2013	Unclear	Unclear	Appropriate	Yes	5	High quality
Humbert 23	2004	Unclear	Unclear	Appropriate	Yes	5	High quality
Qian 24	2021	Appropriate	Unclear	Unclear	Yes	5	High quality
Xiaoning 25	2022	Appropriate	Unclear	Inappropriate	–	4	High quality
Busse, WW 26	2011	Unclear	Unclear	Appropriate	–	5	High quality

Rating 1–3 as low quality, 4–7 as high quality.

FEV1%

A total of eight studies reported FEV1% values or changes from baseline in patients with asthma after treatment.^{16–18,21,22,24–26} However, Hanania ²² divided the experimental and control groups into six subgroups based on low/high FeNO, low/high Eosinophil, and low/high Periostin, so these six subgroups were analyzed first for heterogeneity, and the results showed no significant heterogeneity (I² = 0%, p = 1.00), so a fixed effect model for analysis (MD = 1.71, 95% CI: −0.83–4.24, p = 0.19), indicating that these biomarkers were not influential factors (Figure 4). Therefore, they were considered separate data for inclusion and statistical analysis. The results showed moderate heterogeneity among the eight studies (I² = 64%, p = 0.0007) and a random-effects model was selected for meta-analysis. The improvement in FEV1% in patients with omalizumab treatment was more significant; the difference was statistically significant compared to the control group (MD = 3.91, 95% CI: 1.89–5.94, p = 0.0002), see Figure 5. Sensitivity analysis was performed using a piece-wise exclusion method, and it was found that after excluding the studies by Xiaoning ²⁵ and Busse, ²⁶ there was no heterogeneity among the remaining six studies (I² = 0%, p = 0.58), and the improvement in FEV1% in the omalizumab group was still greater than that in the control group (MD = 3.64, 95% CI: 2.19–5.09, p < 0.00001), and the two analyses. The conclusions obtained had the same trend, indicating that the findings were more reliable. The reasons for the heterogeneity may be related to the different basal IgE levels of patients and individual differences.

Figure 4.

Change in FEV1% from baseline for each subgroup of patients.

FEV1%, Forced expiratory volume in 1 s as a percentage of predicted normal.

Figure 5.

Patient FEV1% levels after treatment.

FEV1%, Forced expiratory volume in 1 s as a percentage of predicted normal.

MPEF

Data were obtained from the 16-week studies by Ohta ¹⁹ and Chanez, ²⁰ which monitored the value of the change in mPEF from baseline to the end of treatment in patients. There was moderate heterogeneity between these two studies (I² = 65%, p = 0.09) and a random-effects model was chosen for analysis, with no statistically significant difference between the omalizumab group and the control group (MD = 3.64, 95% CI: −22.17–29.45, p = 0.78), see Figure 6.

Figure 6.

Change in mPEF from baseline after treatment (L/min).

mPEF, Morning Peak expiratory flow rate.

FEV1

Four studies by Garcia, ¹⁷ Ayres, ¹⁸ Ohta ¹⁹ and Humbert ²³ reported changes in FEV1 values after treatment or from baseline in patients. After statistical analysis, the results showed little heterogeneity between the four studies (I² = 45%, p = 0.14) and therefore a fixed-effects model was chosen for analysis. Compared with the control group, the FEV1 value in the omalizumab group improved significantly, with statistical significance (MD = 0.09, 95% CI: 0.05–0.13, p < 0.0001), as shown in Figure 7.

Figure 7.

FEV1 values after treatment (L).

FEV1, Forced expiratory volume in 1 s.

Discussion

In recent years, with the continuous advancement of basic research on asthma and in-depth study on asthma phenotype, it has become clear that elevated serum IgE levels and their specificity are a dominant component of asthma triggers and an important feature of allergic asthma. ²⁷ Individualized targeted therapy has irreplaceable importance in the treatment of asthma. The effectiveness and safety of omalizumab in the treatment of moderate-to-severe allergic asthma have been confirmed by the results of several randomized controlled clinical studies in China and abroad. Omalizumab reduces hormone use in nearly half of the patients, ²⁸ halves the rate of severe acute exacerbations, and reduces emergency department visits and hospital admissions.^23,29 It allows most patients to lose daytime symptoms and not wake up at night, ³⁰ improving their quality of life. ²³ In addition, lung function is an important indicator for the evaluation of asthma control; FEV1 and PEF can reflect the severity of airway obstruction, which are the most commonly used assessment indicators to determine asthma control. ² Lung function is also closely related to patients’ daily work and quality of life. However, the paucity of randomized clinical trials on lung function in asthma patients and the inconsistent findings have prompted us to look at the effect of this drug on lung function and its improvement in patients to see if it might provide a better option for asthma patients who require high-dose hormone therapy over a long period, and our study provides an evidence-based basis for this.

The results of this study showed that after at least 16 weeks of treatment, the improvement in FEV1% and FEV1 was more pronounced in the omalizumab group compared to the control group, and the same trend was observed in both adult and children patients. There was not any statistically significant difference between the two groups regarding the improvement of patients’ mPEF. Despite both Li ²¹ Least Squares Mean Treatment Difference (LSMTD = 11.53 L/min; p = 0.022) and Humbert ²³ (p = 0.042) indicating that there was a statistically significant difference between the two groups for the improvement of mPEF, there were no specific data to include in the analysis. Therefore, only two studies, Ohta ¹⁹ and Chanez, ²⁰ were included, which could have given rise to statistically insignificant results. We guessed that maybe omalizumab also improved mPEF to some extent. In the real world, a study conducted on 65 patients receiving omalizumab therapy reported a statistically significant increase in FEV1% levels from baseline values of (55.6 ± 10.6)–(76.63 ± 10.34) at the fourth year of follow-up. ³¹ In some retrospective studies, such as the Paganin, ³² 207 patients with asthma treated with omalizumab were reported. Some improvement in FEV1% was Predicted and Forced Vital Capacity (FVC) was found at 6 months in patients who responded to treatment and this improvement persisted at 12 and 24 months. Furthermore, the administration of omalizumab has demonstrated the ability to effectively reverse airway obstruction in severe allergic asthma patients. ³³ Additionally, obese patients with severe asthma have also exhibited improvements in lung function. ³⁴ Similarly, in a 9-year follow-up study of asthma patients treated with omalizumab, a significant increase in FEV1 values compared to baseline and a sustained improvement in quality of life were found. ³⁵ Some studies have also shown insignificant improvements in lung function with omalizumab treatment, and studies by Chanez ²⁰ and Hanania, ²² included in this article, similarly concluded that omalizumab did not have a statistically significant improvement in lung function index FEV1% and mPEF in patients. We suspect that this may be related to the poor control of the patient’s asthma and the irreversible damage to the airways caused by recurrent attacks, or that there may be individual differences in the patients, leading to inconsistent test results. In summary, we believe that additional omalizumab treatment may improve lung function to some extent in patients with moderate-to-severe asthma.

Limitations of the study: (1) Based on the search strategy developed, only selected databases were searched and studies without full text and complete data were not included, resulting in the inclusion of incomplete studies. (2) Two open-label studies and one low-quality study were included, which may have exaggerated the treatment effect and created a risk of bias when assessing the results. (3) Studies such as Garcia ¹⁷ and Chanez ²⁰ included small sample sizes (N < 50), which may result in large data errors, and only two studies were included for improvements in patients’ mPEF, reducing the reliability of this finding. (4) The type, dosage, and frequency of administration of conventional therapeutic agents used by patients at baseline were inconsistent and may have affected the treatment effect. (5) The small number of included studies and the lack of publication bias analysis may have exaggerated the differences between the two groups, resulting in a possible overestimation of the improvement in lung function in asthmatic patients with omalizumab. (6) Most of the included studies are short-term observations and lack long-term follow-up data. Therefore more high-quality data from long-term clinical studies are needed to increase the reliability of the conclusions of this article.

Omalizumab has played an invaluable role in the treatment of asthmatic patients and in improving their life and work since it came on the market. There is also more evidence that additional omalizumab treatment can improve lung function in patients with moderate-to-severe asthma,^36–39 delaying the deterioration of lung function and reducing the financial burden on patients and their families. However, the clinical evidence on the use of omalizumab is still limited. In some countries, including China, many doctors are adopting a wait-and-see approach due to the shorter time it has been available on the market and the more expensive price of omalizumab. The drug is not yet widely used and some patients are also unaware of it. This study aims to enhance the knowledge of doctors and patients regarding the significance of omalizumab in treating moderate-to-severe asthma. It can contribute to increasing the clinical options and medication base. The indications of omalizumab withdrawal, whether there are adverse reactions after discontinuation, and whether and how to reduce the dose of omalizumab after symptom improvement remain to be solved. Consequently, it is imperative to conduct a comprehensive evaluation of the clinical symptoms exhibited by patients with moderate-to-severe asthma, as well as their economic circumstances, adherence to treatment, and willingness to comply. This assessment will facilitate the development of an individualized treatment plan that maximizes the patient’s potential to benefit from the intervention.

Conclusion

This study found that in patients with moderate-to-severe asthma, the addition of omalizumab can improve lung function to a certain extent and delay the worsening of lung function.