Effects of omalizumab combined with budesonide formoterol on clinical efficacy, pulmonary function, immune function, and adverse reactions in children with moderate and severe allergic asthma

Abstract

Objective: To evaluate the clinical efficacy and safety of combining omalizumab with budesonide formoterol to treat children with moderate and severe allergic asthma, and investigate the effect of this combination therapy on pulmonary and immune functions.

Methods: The data of 88 children with moderate and severe allergic asthma, who were admitted to our hospital between July 2021 and July 2022, were included in the study. The patients were randomly assigned either to control group (n = 44; received budesonide formoterol inhalation therapy) or experimental group (n = 44; received omalizumab subcutaneous injection + budesonide formoterol inhalation therapy) using computer-generated randomization. The clinical efficacy, asthma control (measured using childhood Asthma-Control Test [C-ACT] score), pulmonary function (forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow), immune function (cluster of differentiation 3 cells [CD3⁺ cells], cluster of differentiation 4 cells [CD4⁺ cells], immunoglobulin G, immunoglobulin A, and immunoglobulin E), and adverse reactions were observed and compared between both groups.

Results: After treatment, the experimental group had improved levels of pulmonary function and immune function indexes, higher C-ACT scores, and a higher overall response rate than the control group (P < 0.05). In addition, the incidence of adverse reactions was not significantly different between both groups (P > 0.05).

Conclusion: The combination of omalizumab with budesonide formoterol for treating moderate and severe allergic asthma in children demonstrated promising clinical efficacy and improved their pulmonary and immune functions, leading to more rational asthma control. The combined regimen demonstrated satisfactory clinical safety and deserved clinical promotion.

Introduction

Asthma is a common and serious chronic respiratory disease found in children. It is difficult to treat clinically because of its high incidence and detrimental impacts on the physical and mental development of children, to a certain extent, and could disrupt normal life and learning processes.^1,2 Allergic asthma is a specific form of asthma characterized by coughing as the only or the main clinical manifestation, but may be accompanied by chest tightness and a runny nose, which may relapse frequently.^3,4 Clinical studies have indicated that the disease primarily involves certain cells, including eosinophils, T lymphocytes, and mast cells. Repeated respiratory tract infections can increase the frequency of asthma attacks, which can subsequently lead to the development of chronic bronchitis and even pulmonary interstitial fibrosis, thereby aggravating the disease severity and creating additional challenges for its clinical management. Thus, these factors may have a detrimental impact on the children’s treatment outcomes and prognosis.^5,6

In children, glucocorticoids are commonly used for the clinical treatment of allergic asthma because of their various advantages, including multiple routes of administration, which provide an ideal pharmaceutical onset time and therapeutic effect. However, there are several drawbacks to the single administration of glucocorticoids. It can delay the course of disease cycle, prolong the use of hormonal drugs, and significantly reduce the safety of medication, which could have consequential impacts on the health and development of children. As the understanding of the underlying mechanism associated with the pathogenesis of asthma aggravates in clinical practice, continuous optimization of clinical medication regimen is being pursued.^7,8

Omalizumab, a recombinant DNA-derived humanized monoclonal IgE antibody, has demonstrated promising results in the clinical treatment of allergic asthma in adults.^9,10 However, considering that children with moderate to severe allergic asthma often have unsatisfactory results with conventional medication regimens,^11,12 we integrated conventional inhalation therapy with omalizumab in these children as an attempt to improve treatment efficacy and assess the effects and safety of this regimen. The findings provided a more detailed basis to improve the clinical management of children with such conditions, as demonstrated by the results in the following sections.

Materials and Methods

General data

The study enrolled 88 children with moderate and severe allergic asthma admitted to the hospital between July 2021 and July 2022. They were equally divided into two groups using computer-generated randomization. The study was conducted in accordance with the standards and approved by the hospital ethics committee.

The inclusion criteria for the study were as follows: (1) Children aged 6–11 years; (2) the level of IgE ≥ 35 IU/mL; (3) diagnosis of moderate and severe asthma based on the 2016 version of the “Guidelines for the Diagnosis and Prevention of Bronchial Asthma in Children,” and (4) parents of the children having normal awareness and communication abilities voluntarily consenting to participate in the study and providing signed consent document for confirmation after receiving detailed information about the research purpose and related contents from doctors. Moderate asthma was defined as achieving complete control with asthma medication at level 3, and severe asthma was defined as achieving complete or incomplete control with asthma medication at level 4 or 5. Those with the following criteria were excluded from this study: (1) Children with other types of asthma; (2) children who had contraindications to the prescribed medication; (3) presence of congenital diseases or immune dysfunction; and (4) children with abnormal mental status or mental retardation and could not effectively cooperate with the study requirements.

Treatment methods

The control group was treated with budesonide formoterol (AstraZeneca AB, Sweden; approval number/registration certificate number H20110173; and strength: 80 ug/4.5 ug: 60 inhalations/vial). The drug was administered through inhalation (80 ug/4.5 ug/inhalation; 2 inhalations each time, twice a day). After 12 weeks of medication, the dosage could be reduced to one inhalation per day.

In the experimental group, omalizumab (Novartis Pharma Stein AG, Switzerland; Imported Drug Registration Standards: JS20140060; and strength: 150 mg/vial) was added to the regimen used in the control group. The drug was administered subcutaneously with an initial dose of 150–600 mg administered once per day, followed by additional doses at 14–28 days interval based on the patient’s condition. If a child experienced an acute attack of allergic asthma during the treatment, the stepped treatment was implemented based on the indicated guidelines.

To ensure accuracy of the study results, no other drug than those specified in the study protocol was administered to either group. Both groups continued their respective medication regimen for 16 weeks.

Outcome measures

Prior to and following the treatment, 5 mL of fasting cubital venous blood was drawn from the patients of both groups and centrifuged at 3000 r/min for 10 min to separate the serum and stored at –70°C until further measurement. The contents of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE) were detected using a single immunodiffusion test, and the levels of cluster of differentiation 3 (CD3⁺) and cluster of differentiation 4 (CD4⁺) cells were detected by monoclonal antibody-based immunofluorescence.

After 16 weeks of treatment, the following indicators were observed and compared: (1) Pulmonary function: forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), and fractioned exhaled nitric oxide (FENO); (2) immune functioning: CD3⁺, CD4⁺, and immunoglobulin indicators: IgG, IgA, and IgE; (3) asthma control: Childhood Asthma-Control Test (C-ACT) was used to evaluate the level of asthma control. A score below 19 indicated unsatisfactory asthma control, while a higher score indicated better disease control; (4) treatment effectiveness: evaluated based on indicators referring to (a) marked response (asthma-related manifestations, such as wheezing, cough disappearance, and normal clinical examination results), (b) moderate response (relief from disease-related manifestations, and clinical examination results confirmed substantial lessening of the disease), and (c) no response (disease-related manifestations and clinical examination results did not demonstrate significant change); and (5) adverse reactions: occurrence of drug-related pharyngeal irritation, abdominal pain, fever, headache, and other adverse events during the treatment.

Statistical analysis

Data analysis was performed using the SPSS 24.0 software. Measurement data conforming to normal distribution were expressed as (X̄±s), and independent sample t test was used to compare results of both groups. Measurement data that did not conform to normal distribution were expressed as median (1st quartile - 3rd quartile), and the Mann–Whitney U test was used to compare both groups. Enumeration data were expressed as percentage (%) values and analyzed using the Chi-square (χ²) test for comparison of both groups. P < 0.05 was considered as statistically significant.

Results

Comparison of general data in both groups

Initial analysis comparing general data between control and experimental groups showed no significant differences (P > 0.05), as shown in Table 1.

Table 1 Comparison of general data (n [%], and (x̄±s).

General data	Control group (n = 44)	Experimental group (n = 44)	t/χ2	P
Gender
Male	28 (63.64)	30 (68.18)	0.202	0.653
Female	16 (36.36)	14 (31.82)
Disease severity
Moderate	35 (79.55)	33 (75.00)	0.259	0.611
Severe	9 (20.45)	11 (25.00)
Age (years)	8.39±1.03	8.52±1.12	0.567	0.572
Body mass index (BMI; kg/m2)	18.54±1.75	18.89±1.88	0.904	0.369
Disease duration (years)	3.45±0.55	3.34±0.48	1.000	0.320
Heart rate (beats/min)	82.11±10.25	82.64±10.28	0.242	0.809
Systolic blood pressure (mmHg)	100.50±7.21	100.34±7.30	0.103	0.918
Diastolic pressure (mmHg)	67.80±3.95	68.02±4.13	0.242	0.809

Analysis of pulmonary function indicators in children

There were no significant differences in pulmonary function indexes between both groups prior to treatment.

However, after treatment, all indicators were significantly higher. Comparison analysis performed between both groups established that indicators in the experimental group were higher than those in the control group (P < 0.05) (Table 2).

Table 2 Comparison of pulmonary function indicators in children of both groups (x̄±s).

Indexes	Time point	Control group (n = 44)	Experimental group (n = 44)	t	P
FEV1 (%)	Before treatment	75.10±18.40	75.29±19.37	0.047	0.963
	After treatment	86.19±25.24	98.46±27.33	2.188	0.031
	t	2.355	4.588
	P	0.021	<0.001
PEF (L/s)	Before treatment	2.32±0.34	2.31±0.37	0.132	0.895
	After treatment	4.45±1.27	5.34±1.57	2.924	0.004
	t	10.747	12.460
	P	<0.001	<0.001
FVC (L)	Before treatment	1.50±0.17	1.53±0.21	0.737	0.463
	After treatment	2.31±0.28	2.78±0.32	7.332	<0.001
	t	16.403	21.663
	P	<0.001	<0.001
FENO (ppb)	Before treatment	56.35±5.16	56.41±5.09	0.055	0.956
	After treatment	40.25±4.05	29.16±2.16	16.027	<0.001
	t	16.281	32.690
	P	<0.001	<0.001

Analysis of immune function indicators in children

Prior to treatment, no significant differences were observed in immune function indicators between both groups. However, after treatment, there was a notable increase in CD3⁺, CD4⁺, IgG, and IgA levels whereas IgE levels were notably decreased. In the control group, no substantial difference was observed, compared to the pre-treatment levels, whereas the experimental group exhibited significant differences between the levels of pre- and post-treatment immune function indicators.

Further, group comparison indicated that the levels of CD3⁺, CD4⁺, IgG, and IgA were relatively higher whereas IgE levels were relatively lower in the experimental group, compared to the control group (P < 0.05) (Table 3).

Table 3 Comparison of immune function indicators in both groups (x̄±s).

Indexes	Time point	Control group (n = 44)	Experimental group (n = 44)	t	P
CD3+(%)	Before treatment	43.60±9.40	43.29±9.37	0.155	0.877
	After treatment	44.41±8.51	51.34±7.63	4.022	<0.001
	t	0.424	4.419
	P	0.673	0.000
CD4+(%)	Before treatment	23.55±6.14	24.03±6.05	0.369	0.713
	After treatment	25.28±4.37	31.63±3.20	7.777	<0.001
	t	1.523	7.366
	P	0.132	<0.001
IgG (g/L)	Before treatment	9.30±2.56	9.37±2.49	0.130	0.897
	After treatment	9.73±1.58	11.21±2.70	3.138	0.002
	t	0.948	3.323
	P	0.346	0.001
IgA (g/L)	Before treatment	1.16±0.31	1.18±0.34	0.288	0.774
	After treatment	1.25±0.38	2.25±0.56	9.802	<0.001
	t	1.217	10.834
	P	0.227	<0.001
IgE (g/L)	Before treatment	230.39±21.26	226.53±21.62	0.844	0.401
	After treatment	220.69±21.51	125.10±11.49	26.00	<0.001
	t	2.128	27.480
	P	0.036	<0.001

Analysis of C-ACT score in children

We observed no significant difference in C-ACT scores between both groups prior to treatment. However, significant increase in the levels of indicators was observed after treatment, compared to those prior to treatment. Group comparison demonstrated that the scores of the experimental group were relatively higher than those of the control group (P < 0.05) (Table 4).

Table 4 Comparison of C-ACT scores of both groups prior to and after treatment (x̄±s, score).

Group	Case	Prior to treatment	After treatment	t	P
Control group	44	16.91±2.27	20.03±1.25	7.986	<0.001
Experimental group	44	17.13±2.33	23.34±1.34	15.325	<0.001
t		0.449	11.981
P		0.655	<0.001

Analysis of overall response rate

Analysis of the overall response rate between both groups established that patients in the experimental group had a comparatively higher response rate than those in the control group (P < 0.05). The results were displayed in Table 5.

Table 5 Comparison of overall response rate between both groups (n [%]).

Group	Case	No response	Moderate response	Marked response	Overall response rate
Control group	44	7	21	16	37 (84.09)
Experimental group	44	17	16	11	27 (61.36)
χ2					5.729
P					0.017

Analysis of adverse reactions

Further analysis showed that the incidence of adverse reactions in the experimental group was slightly higher but not significantly different from that observed in the control group (P > 0.05). The detailed results are shown in Table 6.

Table 6 Comparison of incidence of adverse reactions in both groups (n [%]).

Group	Case	Abdominal pain	Pharyngeal irritation	Headache	Fever	Overall incidence
Control group	44	0	1	1	0	2 (4.55)
Experimental group	44	1	1	1	1	4 (9.09)
χ2						0.715
P						0.398

Discussion

In the past, various therapies, such as glucocorticoids, bronchiectasis, and other drugs, were prescribed to treat allergic asthma in children.^13–16 Budesonide formoterol, as a compound preparation, offered the combined effects of both glucocorticoid and β2-agonist, and its clinical application was validated regarding both treatment efficacy and safety.^17,18 However, for moderate and severe allergic asthma, the effectiveness of using single agent could not be assured. If the disease is not treated promptly and effectively, it can persist into adulthood, leading to more severe consequences.^19,20 Therefore, an urgent need is expected to optimize and improve the currently used treatment regimen in clinical practice, aiming to achieve overall improved response rates, increase in clinical benefits of the treatment, and ensure physical health and normal growth and development of affected children.^21,22

Omalizumab is a target drug for treating asthma and can significantly reduce serum-free IgE levels. It has been demonstrated that a higher dose can lead to a stronger control effect.²³ In addition, the drug can target high- affinity IgE receptors on the surface of effector cells to inhibit their binding.^24,25

The findings of this study confirmed that the experimental group had a relatively improved level of pulmonary function and immune function indicators, higher C-ACT score, and a better overall response rate after treatment, compared to the control group (P < 0.05). These results confirmed that the use of omalizumab could effectively elevate pulmonary function in children. By inhibiting IgE-mediated allergic reactions and preventing allergic airway responses, omalizumab ensures better disease control and promotes pulmonary functions.

Pulmonary function indicators serve as a reliable measure for the clinical diagnosis and assessment of therapeutic effects in allergic asthma, whereby improved pulmonary functions indicate efficient asthma control.^26,27 Thus, maintaining optimal immune functions in allergic asthma is key for achieving therapeutic efficacy. Abnormal decrease in the levels of CD3⁺ and CD4⁺ cells indicated compromised immune status.^28,29 CD4⁺cells could affect lymphocyte activity, and their reduction affected IgG and IgA levels, compromising the body’s ability to fight infections, leading to ineffective asthma control. In this regard, omalizumab, through its mechanism of action, can significantly improve immune functioning in children with allergic asthma.^27–30

C-ACT scores represent a key assessment tool for evaluating allergic asthma control. Higher C-ACT scores observed in the experimental group indicated more favorable disease control in allergic asthma children. These results confirmed that the combined use of omalizumab could significantly improve the immune functioning of patients, resulting in improved therapeutic efficacy, lessening of clinical manifestations, and overall treatment effectiveness. Importantly, the incidence of adverse reactions did not differ significantly between both groups (P > 0.05). Collectively, these results indicate that the combination of conventional drugs with omalizumab does not significantly increase the risk of adverse reactions, thereby providing evidence of its potentially high safety profile and promising clinical recommendation.

Conclusion

Omalizumab combined with budesonide formoterol demonstrated excellent clinical efficacy and safety in treating children with moderate and severe allergic asthma. It not only improved pulmonary and immune functions in children but also contributed to effective disease control, thereby establishing significant clinical value.

Additionally, we discovered that physical therapy has a beneficial function in enhancing treatment outcomes in clinical practice. Further, active involvement of children in the treatment, utilizing learning training methods, increasing awareness, and active cooperation with physiotherapist could lead to better results in addressing physical issues. Physical therapy has demonstrated promising effectiveness in improving endurance and functional independence in patients having a range of cardiopulmonary conditions and in pre- and post-operative stages of cardiac or pulmonary surgeries.

Author Contributions

Conceptualization, methodology and software, Fuzhe Chen; validation, formal analysis and investigation Lei Liang; resources and data curation Fangfang Chu; writing— original draft preparation Changlong Lu; writing—review and editing, supervision Chongyu Xu. All authors have read and agreed to the published version of the manuscript.

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