Utilizing chest CT to assess the impact of omalizumab treatment on airway remodeling in refractory asthma

doi:10.21203/rs.3.rs-3339444/v1

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Research Article

Utilizing chest CT to assess the impact of omalizumab treatment on airway remodeling in refractory asthma

https://doi.org/10.21203/rs.3.rs-3339444/v1

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Background

To evaluate the benefits of omalizumab treatment in patients through real-world clinical follow-up data and assess the impact of omalizumab treatment on airway remodeling using chest CT.

Methods

This is a single-center prospective cohort study conducted in the Department of Respiratory and Critical Care Medicine of our hospital from May 2021 to December 2022, focusing on refractory asthma patients who received omalizumab treatment during this period. A comparison was made between the pre-treatment and post-treatment laboratory indicators, pulmonary function parameters, airway parameters, and mucous plug scores obtained from chest CT.

Results

This study included a total of 61 patients with refractory asthma treated with omalizumab. The study found that: ①regardless of whether the treatment lasted for a full four months or not, it significantly improved patient asthma control scores and reduced hospitalization costs and length of stay (p < 0.05). ②After four months of treatment, patients showed a decrease in FENO levels and central airway resistance (Rc) (p < 0.05) as measured by airway resistance examination. Pulmonary ventilation function examination revealed significant improvements (p < 0.05) in MEF75, MEF50, MEF75/25, PEF, and FEV1/FVC. ③After four months of omalizumab treatment, the ratio of wall thickness and outer radius (T/D) and wall area percentage (WA%) of the bronchial wall decreased significantly (p < 0.05). ④After medication, the expression of airway mucous plugs decreased. The mucous plug score was negatively correlated with several indicators of large and small airway function.

Conclusions

Omalizumab treatment can remodel the airways in refractory asthma patients, reducing airway wall thickness, decreasing the percentage of airway wall area, and reducing the expression of airway mucous plugs, thereby improving airflow limitation. Utilizing chest CT provides a novel and intuitive assessment of the efficacy of omalizumab treatment, offering a new perspective for the analysis of omalizumab treatment efficacy.

Trial registration:

This study was registered in Chinese Clinical Trial Registry, the number is ChiCTR2100046343.

Omalizumab

Asthma

Airway wall parameters

Mucus plug score

Computed tomography of chest

Bronchial asthma is a heterogeneous disease characterized by chronic airway inflammation involving various cells and cellular components such as eosinophils, mast cells, T lymphocytes, and neutrophils. Asthma is a common chronic respiratory disease, and its global prevalence has been increasing over the years[1]. Currently, there are approximately 300 million asthma patients worldwide, with refractory asthma patients accounting for 5–10% of them[2]. Despite the use of traditional treatment modalities, including high-dose inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic drugs, the symptom control of asthma patients remains suboptimal. Therefore, a novel biological agent, omalizumab, a humanized monoclonal antibody against human immunoglobulin E (IgE), has been introduced for asthma treatment[3, 4].

Omalizumab is a recombinant humanized monoclonal antibody[3], classified as an anti-IgE targeted biological agent. It selectively binds to IgE, reducing the levels of free IgE in the body. By inhibiting the binding of IgE to high-affinity receptors (FcεRI) on mast cells, basophils, and dendritic cells, it further suppresses cellular activation and the release of inflammatory factors. Omalizumab also decreases FcεRI receptor expression on inflammatory cells, blocking allergen-induced inflammatory responses, thereby improving asthma symptoms. Omalizumab is the world's first approved targeted drug for the treatment of moderate to severe asthma, and numerous clinical studies have shown that it improves Asthma Control Test (ACT) scores, reduces the frequency of acute exacerbations, and shortens hospitalization duration[5, 6].

Bronchial asthma, as a common chronic airway inflammatory disease, is characterized by recurrent airway inflammation, leading to structural changes in the airway walls and increased mucus secretion. In some patients, reversible airflow limitation can progress towards irreversible changes. Therefore, early intervention targeting recurrent airway inflammation within the patients' airways will mitigate airway remodeling, thus providing effective treatment for asthma patients. Some basic studies have found that the application of anti-IgE treatment significantly improves the level of airway remodeling in asthmatic mice, characterized by reduced collagen fiber deposition in lung tissue, decreased thickness of airway smooth muscles, and alleviated blood vessel proliferation[7]. However, evidence for these changes in airway structure is currently lacking in clinical assessment, and efforts are currently being made to optimize several techniques for achieving appropriate diagnosis of remodeling. Assessment tools can be categorized into two types: invasive and non-invasive methods[8]. Invasive techniques provide us with information about bronchial structural changes obtained directly from pathological tissue[9], measuring histological alterations in bronchial layers, as well as inflammation and fibroblast infiltration. The development of non-invasive techniques aims to mitigate the drawbacks of invasive methods, measuring markers associated with airway remodeling, such as cytokines and inflammatory mediators[10]. The majority of studies assess the level of airway remodeling through bronchoscopic mucosal biopsies. However, these invasive procedures are difficult to apply widely in clinical settings.

This study utilized imaging software, 3D Slicer[11], to reconstruct the bronchial wall structure and automatically measure bronchial wall parameters. A comparative analysis was performed to investigate the changes in bronchial wall thickness, bronchial lumen area, and other related parameters in asthma patients before and after treatment with omalizumab. The aim was to understand the impact of omalizumab treatment on the patients' airway structure. Additionally, a retrospective analysis of mucous plug expression within the patients' airways was conducted to indirectly assess the effect of omalizumab in reducing airway inflammation, thus providing a novel and intuitive evaluation of the efficacy of omalizumab treatment.

This is a single-center, prospective, cohort study on the treatment of refractory asthma with omalizumab. The study has been approved by our hospital's Medical Ethics Committee with the approval number [2021] Ethics No. (K26-1). The study subjects are refractory asthma patients admitted to the Respiratory and Critical Care Medicine Department of our hospital between May 2021 and December 2022, who voluntarily received treatment with omalizumab from Novartis Pharmaceuticals. These patients have been using two or more controller medications and undergoing standardized treatment for more than 6 months, but have not achieved ideal control.

Inclusion criteria: (1) Age ≥ 18 years, any gender; (2) Serum total IgE > 60 IU/ml; (3) Willingness to use omalizumab for treatment; (4) No severe heart, lung, brain, liver, kidney, blood system, or other diseases; (5) Life expectancy of at least 1 year.

Exclusion criteria: (1) Women who are planning pregnancy, breastfeeding, or pregnant; (2) Use of immunomodulators or other immune therapies within 1 month before enrollment; (3) Experiencing acute exacerbations of bronchial asthma; (4) Presence of severe liver, kidney, cardiovascular, autoimmune, psychiatric diseases, or diabetes; (5) Asthma patients with poor allergen avoidance, treatment compliance, inhalation technique, or affected by other diseases leading to uncontrolled asthma; (6) Unconsciousness or inability to cooperate.

Study Design

Patient baseline data are collected before medication, and the treatment plan is determined based on the patient's weight and baseline serum total IgE level. Subsequently, patients are required to return to the hospital monthly for omalizumab treatment. Following guideline recommendations, we conducted a comprehensive assessment of patients in the fourth month of treatment, including their hospitalization information, clinical laboratory changes, ACT scores, lung function, FENO, bronchial wall parameter measurements in chest CT, and mucus plug scores. If severe adverse reactions occur during treatment, it should be promptly terminated (Fig. 1).

Pulmonary Function

We used a pulmonary function instrument manufactured by Jaeger, Germany, to perform spirometry and impulse oscillometry according to the guidelines for pulmonary function testing. We also used a RuiBreath medical nitric oxide detector to measure the fractional exhaled nitric oxide content in patients' breath, assessing the severity of airway inflammation. Baseline data were collected before medication, and during the first four months of treatment, pulmonary function indicators and FENO were rechecked monthly to monitor changes.

Airway Measurement

All patients underwent chest CT scans before medication. The scan was performed using a 64-channel high-resolution spiral CT with patients in the supine position, and a full lung scan was conducted from the lung apices to the bases at the end of a deep inhalation. The scan parameters were set to 120kV voltage, 150mA current, and a reconstruction layer thickness of 1mm. We used 3D Slicer software for the measurement of bronchial wall-related parameters in chest CT scans. 3D Slicer is an open-source medical imaging visualization and processing software developed with support from the National Institutes of Health (NIH) in the United States. After importing the chest CT images into 3D Slicer software, image reconstruction, registration, landmark selection, and measurements were performed. On the reconstructed cross-sectional images, various bronchial segmental and subsegmental wall parameters were measured, ensuring that each bronchial image was approximately perpendicular to the bronchial axis. The software automatically extracted the airway centerlines and measured airway-related parameters (Fig. 2). The measured parameters included internal radius (IR), outer radius (OR), wall thickness (WT), wall area (WA), etc. Subsequently, standardized airway indices were calculated, such as wall area percentage (WA%), square root of WA, ratio of wall thickness and outer radius (T/D), luminal area (Ai), cross-sectional area (Ao), internal perimeter (Pi), etc. All data were corrected based on the patient's body surface area (BSA) to ensure accuracy and minimize measurement errors. To ensure data reliability, all image data analyses were performed by two physicians, and the average values were used for further processing.

Airway mucus

Two physicians conducted a retrospective analysis of patients' chest CT scans using the Neusoft PACS/RIS imaging diagnostic system and independently scored mucus plug obstruction. The final score was determined by taking the average of their assessments.

The radiological characteristics of mucus plug obstruction[12]are as follows: Mucus plugs typically appear as main axes consistent with the course of bronchial walls, pointing towards the hilum. They may present as short rod-like, nodular, or branched structures with slightly higher density shadows, with CT values around 18–65 Hounsfield Units (HU). Due to the absence of blood supply, mucus does not enhance after contrast-enhanced scans.

The definition of mucus plug obstruction is when one or more subsegmental airways are filled with mucus, leading to airway occlusion. Mucus scoring is performed for all 18 lung segments, and each segment is assigned a score of 0 or 1 based on the presence or absence of mucus plugs. The total mucus plug score for the patient is calculated by summing the scores of all lung segments (Fig. 3).

Statistical Analysis

The statistical analysis was performed using SPSS 24.0 software (IBM, Armonk, NY, USA). For data that followed a normal distribution, the results were presented as mean ± standard deviation (Mean ± SD), and paired sample t-test was used for comparisons before and after medication. For data that did not follow a normal distribution, the results were presented as median (interquartile range), and the two-related samples nonparametric Wilcoxon signed-rank test was used for comparisons before and after medication. A significance level of p < 0.05 was considered statistically significant. Correlation analysis was conducted using the Spearman test. Statistical analysis and graphing were performed using GraphPad Prism 8 software.

General Information and Clinical Characteristics

In this study, a total of 61 cases of refractory asthma patients treated with omalizumab were ultimately included. Among them, 29 patients received treatment for a full four months, while 32 patients discontinued treatment before four months. These patients had poor asthma control (supplement Table 1).

Table 1

Characteristics of the subjects
Characteristic	Total(n = 29)
Sex, female/male(n/n)	17/12
Age(years)	45.34 ± 12.69
BMI (kg/m2)	22.22 ± 3.94
Course(years)	3.00(0.75,12.50)
Family history of asthma, n (%)	2(6.90)
Allergen test positive, n (%)	15(51.72)
Comorbidity of allergic diseases, n (%)	17(58.62)
Allergic rhinitis, n (%)	17(58.62)
Chronic rhinosinusitis, n (%)	5(17.24)
Allergic dermatitis, n (%)	1(3.45)
Allergic purpuras, n (%)	1(3.45)
Smoking status, n (%) Never smoker	23(79.31)
Ex smoker	2(6.90)
Current smoker	4(13.79)
ACT score	17.00(14.25,18.75)

Among the study participants, 32 patients discontinued treatment before completing four months, and among them, 14 cases received medication only once, yielding no usable data for before-and-after comparisons. Hence, they were excluded from further analysis. The remaining 18 patients with a treatment duration of less than four months, a comparison of pre- and post-treatment data revealed improvements in ACT scores and a reduction in the number of hospitalization days. Furthermore, there was a significant decrease in both pre- and post-treatment hospitalization costs as well as out-of-pocket expenses after medical insurance reimbursement(p < 0.001). Analysis of patient laboratory indicators revealed a significant increase in serum total IgE levels compared to before medication (p = 0.003). Lung function examination results collected before and after medication showed a decreasing trend in FENO levels after treatment, though no significant statistical differences were observed (supplement Table 2).

Table 2

Comparison of clinical test indexes before and after four months of medication
	Before medication N = 29	After medication N = 29	p
BMI(kg/ m²)	22.22 ± 3.94	22.45 ± 3.36	.437
ACT score	17.00(14.25, 18.75)	21.00(20.00, 23.00)	.001*
ICS(ug/d)	0.64(0.64, 0.80)	0.64(0.64, 0.80)	.813
Hospitalization days(d)	5.00(2.50, 8.50)	2.00(1.00, 2.50)	.001*
Hospitalization expenses(RMB)	11457.61 ± 4069.98	6685.21 ± 1617.30	.001*
Out-of-pocket expenses(RMB)	2106.50(1802.75, 2665.08)	1655.00(1573.00, 1902.50)	.001*
IgE(IU/ml)	364.60(134.85, 857.60)	673.40(427.15, 1441.50)	.027*
WBC(x10⁹/L)	6.47(5.59, 7.61)	6.30(5.63, 7.39)	.962
PLT(x10⁹/L)	228.00(203.00, 277.50)	227.00(197.00, 247.00)	.006*
EOS(x10⁹/L)	0.33(0.17, 0.58)	0.25(0.15, 0.44)	.141
EOS%	5.00(2.50, 6.70)	3.80(2.10, 7.90)	.272
NLR	1.80(1.42, 2.49)	1.87(1.42, 2.53)	.639
ELR	0.18(0.10, 0.31)	0.12(0.07, 0.29)	.194
ENR	0.09(0.04, 0.14)	0.08(0.04, 0.14)	.183
PLR	121.98(100.53, 137.06)	112.44(98.08, 146.26)	.265
Triglyceride(mmol/L)	1.18(0.94, 2.05)	0.96(0.68, 1.41)	.268
Total cholesterol(mmol/L)	4.23(3.78, 5.35)	4.74(3.60, 5.32)	.188
LDL-C(mmol/L)	2.54(2.07, 3.02)	2.76(1.60, 3.60)	.326
CRP(mg/L)	0.10(0.07, 0.91)	0.10(0.07, 2.48)	.980
Albumin(g/L)	41.67 ± 3.07	40.54 ± 3.05	.057
PaO2(mmHg)	85.68 ± 13.56	87.60 ± 16.21	.554
PaCO2(mmHg)	39.50 ± 2.53	40.51 ± 3.94	.257
IL-2(pg/ml)	1.32(1.09, 1.72)	1.14(1.08, 1.39)	.081
IFN-γ(pg/ml)	1.50 ± 0.59	1.40 ± 0.50	.722
TNF-α(pg/ml)	1.71 ± .80	1.75 ± .47	.901
IL-4(pg/ml)	1.17(1.00, 1.74)	0.96(0.71, 1.35)	.339
IL-6(pg/ml)	2.76(2.08, 4.68)	2.78(1.94, 3.34)	.531
IL-10(pg/ml)	1.97(1.49, 2.18)	2.12(1.78, 2.45)	.776
IL-17(pg/ml)	2.92(1.56, 4.70)	1.98(0.91, 3.78)	.266
Total T lymphocytes(%)	75.18(69.47, 77.32)	73.12(69.80, 79.83)	.524
Helper-induced T lymphocytes(%)	57.99(49.42, 65.95)	58.20(53.10, 64.10)	.489
Treg cells(%)	7.31 ± 1.77	6.79 ± 1.88	.091
1)* Statistically significant difference p＜0.05

Subsequently, we conducted further analysis in refractory asthma patients treated with omalizumab for 4 months. Among the patients treated for a full four months, there were 29 cases. The male-to-female ratio was 17:12, with a mean age of 45.34 ± 12.69. The median duration of the disease was 3.00(0.75, 12.50) years. All patients underwent allergen testing, and the positive rate was 51.72%. More than half of the patients had coexisting allergic conditions, including allergic rhinitis, chronic sinusitis, allergic dermatitis, and allergic purpura. All patients had poor asthma control, with a median ACT score of 17.00(14.25, 18.75) (Table 1). Then we compared the clinical data of the patients before treatment and four months after treatment.

The application of omalizumab for 4 months can improve clinical symptoms and save medical resources

After 4 months of medication, patients' ACT scores increased from 17.00(14.25,18.75) to 21.00(20.00,23.00) (p < 0.001). Furthermore, post-medication, patients' average hospitalization expenses, average out-of-pocket expenses, and median hospitalization days were significantly lower than before medication, with values of 11457.61 ± 4069.98 vs 6685.21 ± 1617.30 CNY (p < 0.05), 2106.50 (1802.75, 2665.08) vs 1655.00 (1573.00, 1902.50) CNY (p < 0.05), and 5.00 (2.50, 8.50) vs 2.00 (1.00, 2.50) days (p < 0.05), respectively. The median serum total IgE levels of patients before and after medication were 364.60 (134.85, 857.60) IU/ml and 673.40 (427.15, 1441.50) IU/ml, respectively (p < 0.05). After medication, the median eosinophil count showed a slight decrease compared to before medication, but the difference was not statistically significant (Table 2).

The application of omalizumab for 4 months can enhance lung Function

The results of lung function showed significant improvement in lung function indicators in addition to subjective symptom improvement. For large airway airflow limitation indicators, FEV1/FVC, absolute value and predicted percentage of peak expiratory flow (PEF) significantly increased after four months of medication compared to baseline (p < 0.05). Evaluation of small airway function indicators, including MEF75, MEF50, and MEF75/25, also showed significant improvements in absolute values and predicted percentage after four months of medication(p < 0.05). The results of airway resistance examination demonstrated that Rc significantly decreased after medication, with values of 0.29 ± 0.10 vs. 0.25 ± 0.10[Kpa/(L/s)] before and after medication, respectively(p < 0.05). Regarding airway inflammation indicator FENO, it significantly decreased after medication compared to baseline, with statistical differences (Table 3, Supplement Table3).

Table 3

Comparison of pulmonary function indexes before and after four months of medication
	Before medication N = 29	After medication N = 29	p
FENO(ppb)	46.00(25.50, 82.00)	16.00(12.00, 30.00)	.003*
R central[Kpa/(L/s)]	0.29 ± 0.10	0.25 ± 0.10	.018*
R peripheral[Kpa/(L/s)]	0.33(0.25, 0.46)	0.25(0.20, 0.30)	.074
R5[Kpa/(L/s)]	0.51(0.40, 0.73)	0.40(0.36, 0.56)	.188
R20[Kpa/(L/s)]	0.41 ± 0.10	0.40 ± 0.11	.883
R5-R20[Kpa/(L/s)]	0.06(0.02, 0.21)	0.05(0.03, 0.10)	.887
X5[Kpa/(L/s)]	-0.16(-0.24, -0.11)	-0.10(-0.15, -0.07)	.016*
X20[Kpa/(L/s)]	0.04(-0.11, 0.06)	0.06(0.02, 0.08)	.102
Resonant frequency(L/s)	15.52(11.42, 27.56)	13.61(9.14, 17.33)	.715
SR eff(Kpa*s)	1.35(1.10, 1.94)	1.04(0.84, 1.38)	.216
RV(L)	2.09(1.74, 2.86)	1.71(1.35, 2.54)	.340
RV % TLC	36.49 ± 9.08	34.20 ± 9.83	.239
TLC(L)	5.59 ± 0.96	5.66 ± 0.81	.421
FRC pl % pred	86.52 ± 31.18	94.29 ± 26.89	.400
Vc max(L)	2.91 ± 0.28	3.14 ± 0.59	.405
MEF 75(L/s)	4.99 ± 1.69	5.83 ± 1.55	.004*
MEF 50(L/s)	2.61 ± 1.16	3.08 ± 1.20	.023*
MEF 25(L/s)	0.61(0.40, 0.94)	0.88(0.51, 1.70)	.129
MMEF 75/25(L/s)	2.17 ± 1.11	2.51 ± 1.11	.045*
FEV 1% FVC	76.09 ± 10.45	78.63 ± 8.64	.042*
FEV3% FVC	91.99(89.47, 95.60)	95.52(91.30, 97.36)	.376
PEF(L/s)	6.94 ± 1.73	7.73 ± 1.87	.003*
FEV 1(L)	2.59 ± 0.66	2.83 ± 0.65	.005*
FVC(L)	3.41 ± 0.74	3.61 ± 0.78	.011*
MEF 75%pred	76.63 ± 24.34	88.27 ± 22.02	.013*
MEF 50%pred	59.80 ± 25.08	69.95 ± 24.41	.033*
MEF 25%pred	34.52(26.36, 60.94)	50.77(30.24, 74.29)	.174
MMEF 75/25%pred	57.06 ± 25.88	65.70 ± 24.77	.054
FEV 1% FVC %pred	90.81 ± 12.39	93.89 ± 10.22	.037*
PEF %pred	93.26 ± 17.29	101.70 ± 18.40	.019*
1)* Statistically significant difference p＜0.05

The application of omalizumab for 4 months can alleviate airway constriction

From the radiological perspective, we analyzed the benefits of a four-month medication on patients using 3D Slicer technology to measure airway wall-related data. Among the 29 patients who completed the four-month medication, four patients had missing pre-or post-medication chest CT data, leading to their exclusion. Consequently, we collected data from 25 patients before and after medication. The changes in WT/BSA before and after medication did not show significant statistical differences. However, T/D significantly decreased after medication compared to before, with values of 0.51 ± 0.05 vs. 0.50 ± 0.04 (p < 0.05). WA exhibited a decreasing trend after medication, but the difference was not statistically significant. Conversely, post-medication WA% showed a significant statistical decrease (p < 0.05). (Table 4, Fig. 4)

Table 4

Comparison of bronchial wall thickness under CT before and after four months of medication
	Before medication N = 25	After medication N = 25	p
IR/BSA(mm)	1.28 ± 0.45	1.32 ± 0.43	.577
OR/BSA(mm)	2.59 ± 0.74	2.60 ± 0.77	.908
WT/BSA(mm)	1.25(1.13, 1.48)	1.25(1.13, 1.48)	.673
T/D(%)	0.51 ± 0.05	0.50 ± 0.04	.040*
WA%/BSA(%)	44.63 ± 5.74	43.67 ± 5.02	.014*
Pi/BSA(mm)	7.79(5.86, 9.40)	7.79(6.31, 9.81)	.724
WA/BSA(mm)	3.75(3.53, 4.67)	3.65(2.96, 4.87)	.745
Ai/BSA(mm²)	10.45(5.69, 15.87)	10.61(6.23, 17.19)	.838
Ao/BSA(mm²)	34.57(23.62, 62.28)	34.51(22.27, 63.85)	.990
1)* Statistically significant difference p＜0.05

In further exploring the correlation analysis of bronchial wall parameters, we compared patients' T/D and WA% with baseline clinical data (Supplement Table4). We observed a positive correlation between Platelet to Lymphocyte Ratio (PLR) and WA% (r = 0.400, p = 0.031). Then we conducted a correlation analysis between bronchial wall parameters and lung function indicators (Supplement table5) and found that as WA% increased, the total airway resistance (R tot) (r = 0.479, p = 0.028), the specific resistance effective as a percentage of predicted value (SR eff %pred) (r = 0.568, p = 0.007), and the effective airway resistance (R eff) (r = 0.510, p = 0.018) also increased(Fig. 5).

The application of omalizumab for 4 months can reduce airway mucus plug scores expression

For the 25 patients who had both pre- and post-medication chest CT images, a comparison was made. At baseline, the median mucus plug score for patients before medication was 1.00 (0.00, 6.50), whereas after medication, the median mucus plug score was 0.00 (0.00, 3.00) (p < 0.05). This indicates a significant decrease in mucus plug scores after the four-month treatment with omalizumab (Table 5, Fig. 6)

In the further exploration of factors related to patients' baseline mucus plug expression, we conducted Spearman correlation analysis to associate mucus plug scores with baseline clinical data (Supplement table6). The results showed that mucus plug scores were positively correlated with the eosinophils to neutrophil ratios (ENR) (r = 0.435, p = 0.018), IL4 expression (r = 0.723, p = 0.005), and fractional exhaled nitric oxide (FENO) levels (r = 0.468, p = 0.028), which are indicators of airway inflammation (Supplement table7). Regarding the correlation analysis of patients' lung function test parameters, we found that mucus plug scores were positively correlated with airway resistance parameters (R eff, SR eff, R tot) with correlation coefficients of 0.449, 0.444, and 0.454, respectively (p < 0.05). They were also negatively correlated with X5, X10, X15, X20, X25, and X35 (p < 0.05). Small airway function indicators (MEF75, MEF50, MEF75/25) showed negative correlations with mucus plug scores (p < 0.05). Most large airway function indicators (PEF, FEV1, FVC) were negatively correlated with mucus plug scores (p < 0.05) (Fig. 7).

In this study, we divided patients into those who received treatment for a full four months and those who received treatment for less than four months. We compared the changes in clinical test indicators and lung function test results before and after treatment for both groups to evaluate the benefits of different treatment durations. The study results showed that regardless of whether treatment lasted for a full four months or not, omalizumab therapy significantly reduced hospitalization days, lowered total hospitalization costs, and out-of-pocket expenses, while also significantly improving patients' asthma-related subjective symptom scores. These findings are consistent with results from other domestic and international studies [13, 14].

From the clinical laboratory results, we observed that the serum total IgE levels of patients increased after medication, approximately doubling compared to the baseline. This phenomenon is consistent with previous studies, where researchers found that a twofold increase in serum total IgE levels after 4 weeks of medication indicated a better treatment response[15], however the specific reasons are not yet clear.

From the perspective of lung function to explore the possible reasons for the improvement of subjective symptoms in patients before and after medication, we used the forced oscillation technique to measure the airway resistance of patients, which significantly decreased. The X5 value increased, and common large airway indicators, including FEV1, FVC, FEV1/FVC, and PEF, significantly increased compared to before medication. Small airway function indicators also showed significant improvement. Additionally, we found that after four months of treatment, the FENO level of patients decreased, which indicating significant suppression of airway inflammation. Previous studies have shown that FENO levels are associated with clinical deterioration [16], suggesting that the decrease in FENO levels might be one of the reasons for the improvement in respiratory distress and wheezing symptoms in asthma patients after receiving omalizumab treatment.

Asthma patients' airway inflammation is a crucial pathogenic and developmental mechanism[17], where mast cells and their secreted mediators play a key role in immune regulation during asthma airway remodeling[18]. Although asthma was previously considered a reversible airflow limitation, long-term stimulation of chronic airway inflammation may lead to irreversible airway structural remodeling in some patients[19]. Airway remodeling is characterized by smooth muscle hypertrophy or hyperplasia, mucus gland hyperplasia, vascular proliferation, deposition of extracellular matrix in the submucosal and adventitial layers, as well as collagen and protein deposition beneath the epithelium[20–22], collectively leading to increased airway hyperresponsiveness and airflow obstruction [23].

A recent randomized open-label study[24] conducted in Spain included patients with severe asthma receiving oral corticosteroids, omalizumab was added to the standard treatment. The study utilized transmission electron microscopy to assess the degree of airway remodeling in bronchial biopsies. In the omalizumab group, a significant reduction in basement membrane thickness and decreased cell interstice were observed. The study suggests that omalizumab could markedly decrease the usage of oral corticosteroids and is associated with bronchial epithelial repair. Bronchoscopy and bronchial biopsy are currently common techniques used to assess the extent of airway remodeling in asthma patients, but these methods are invasive and carry risks. With advancements in high-resolution CT (HRCT) technology[25–27], it has made significant progress in characterizing airway structure in asthma patients. HRCT scans of the chest can display the ratio of bronchial wall thickness to bronchial diameter, which is associated with subepithelial fibrosis in bronchial pathology [28]. Previous research has found that asthma patients exhibit an increased ratio of bronchial wall thickness to outer diameter compared to normal individuals, allowing a more visual and intuitive display of airway remodeling levels[11]. Additionally, other studies have shown a correlation between increased persistent peripheral airway resistance and increased bronchial wall thickness in asthma patients[29]. The British research team[30] utilized chest CT to measure bronchial wall parameters and found that bronchial wall thickness is associated with peripheral airways resistance and reactance. In vitro studies, treatment with omalizumab can inhibit fibroblast aggregation in the lungs and decrease subepithelial and basement membrane thickening[31]. Building on these studies, we conducted a measurement of bronchial wall-related parameters in chest CT scans before and after four months of omalizumab treatment to determine if there were structural changes in the airways of patients. The study results showed a significant decrease in T/D and WA% after treatment. Furthermore, we conducted a correlation analysis between these parameters and lung function indicators, revealing that larger bronchial wall area and narrower bronchial lumen were associated with higher R tot, SR eff, and R eff. Omalizumab treatment led to an increase in bronchial lumen area, improving airflow limitation caused by airway narrowing, providing a new perspective for evaluating the efficacy of omalizumab treatment. Omalizumab acts by targeting free IgE in the blood, interrupting IgE-mediated allergic inflammatory cascades, inhibiting the expression and production of pro-inflammatory factors associated with airway remodeling, thereby improving airway remodeling[32]. These research findings corroborate the effectiveness of omalizumab treatment from an imaging perspective, providing new information for better understanding the therapeutic effects and mechanisms of asthma.

Research[33] has revealed that mucus plugging is an overlooked key feature of asthma-related airway diseases. Mucus plugging not only physically obstructs airways but also contributes to disease progression through sustained inflammation. Consequently, mucus plugging can serve as an immunogenic stimulus even in the absence of allergens or current treatment approaches. In clinical follow-up observations, a certain proportion of asthma patients were found to have mucus plugs in the airways. However, repeated mucus plug formation can gradually exacerbate airway remodeling [12, 34].The accumulation of pathological mucus is a key characteristic of fatal asthma, and post-mortem studies clearly demonstrate extensive mucous obstruction in the airways[35]. Another research team used hyperpolarized ³He magnetic resonance imaging to evaluate the relationship between ventilation in each bronchopulmonary segment and CT-detected mucus plugs, and innovatively found that CT-detected airway mucus plugs could cause ventilation defects in lung segments[36]. This provides a deeper understanding of the impact of increased mucus plug secretion in asthma airways on the frequency of acute exacerbations and decline in lung function. Another study in benralizumab found[37] that ¹²⁹Xe ventilation significantly improved in participants with uncontrolled asthma and in those with significant mucus plugging after a single dose of benralizumab.

We scored the mucus plugs on the chest CT and correlated the mucus plug scores with baseline clinical data. We found that blood ENR levels were positively correlated with mucus plug expression and significantly positively correlated with the Th2-type cytokine IL-4. IL-4 is an important effector cytokine that promotes the differentiation of mast cells and eosinophils[38], stimulates B cell differentiation and proliferation, thereby promoting B cell synthesis and secretion of IgE. Further analysis revealed that mucus plug expression was positively correlated with airway resistance parameters R eff, SR eff, and R tot (p < 0.05), and negatively correlated with X5, X10, X15, X20, X25, and X35 (p < 0.05). Small airway function indicators were all negatively correlated with mucus plug scores (p < 0.05). Most of the large airway function indicators PEF, FEV1, and FVC absolute values were negatively correlated with mucus plug scores (p < 0.05). Our study found that changes in mucus plugs in chest CTs of typical persistent asthma patients were associated with airflow limitation. These findings are consistent with related studies abroad and further confirm the role of mucus plugs in asthma airflow limitation[34, 39].

However, there is currently insufficient clinical research on the impact of anti-IgE therapy on mucus plug expression. In this study, we used a novel method to compare the changes in mucus plug scores before and after omalizumab treatment to evaluate its effect on mucus plug formation. Based on basic research[7]in an asthma mouse model, Masson staining of lung tissue pathology slides showed a reduction in collagen fiber deposition and a significant reduction in goblet cell hyperplasia and mucus secretion after anti-IgE treatment. A study conducted in South Korea[40] discovered that anti-IgE antibody therapy can suppress the development of airway hyperresponsiveness, eosinophilic inflammation, and airway remodeling. These results provide a theoretical basis for the imaging changes before and after omalizumab treatment, but further pathological data are needed to assist in verification and evaluation.

In summary, the findings from various aspects, including patients' subjective symptoms, clinical laboratory indicators, lung function test results, and chest CT images, have verified the efficacy of omalizumab treatment in controlling the disease and effectively improving asthma symptoms and airway remodeling.

However, this study also has certain limitations. It is a single-center prospective cohort study, and during clinical follow-up, there were data missing and patients lost to follow-up, which caused some bias in the research results. The assessment time point in this study was 4 months, and there is still a lack of long-term follow-up data after prolonged medication. Further data at 1 year and even after discontinuation of treatment are needed. As omalizumab treatment has just been introduced into clinical practice in China, the patients treated with omalizumab at our research center are insufficient, making patient recruitment challenging and resulting in a small study size with a limited sample. To validate the research findings, it is necessary to expand the sample size and conduct larger-scale, multi-center, long-term prospective clinical studies.

Omalizumab treatment can remodel the airways of patients with severe asthma, reducing airway wall thickness, decreasing the proportion of airway wall area, and reducing the expression of airway mucus plugs, thus improving airflow limitation. This airway remodeling is associated with the expression of inflammatory factors in the body and affects patients' lung function. By using chest CT, we can novelly and visually assess the efficacy of omalizumab treatment, providing a new perspective for the analysis of its effectiveness.

Ai	Luminal area
Ao	Cross sectional area
ACQ	Asthma control questionnaire
ACT	Asthma control test
BSA	Body surface area
CRP	C-reactive protein
EOS	Eosinophils
ELR	Eosinophils to lymphocyte ratios
ENR	Eosinophils to neutrophil ratios
FENO	Fractional exhaled nitric oxide
Fres	Resonant frequency
FVC	Forced vital capacity
FEV1	Forced expiratory volume in one second
FEV1/FVC	Forced expiratory volume in one second to Forced vital capacity
FEV3/FVC	Forced expiratory volume in three second to Forced vital capacity
GETE	Global assessment of treatment effectiveness
IL-2	Interleukin 2
IL-4	Interleukin 4
IFN-γ	Interferon γ
ICS	Inhaled corticosteroids
IR	Internal radius
IgE	Immunoglobulin E
IL-6	Interleukin 6
IL-10	Interleukin 10
IL-17	Interleukin 17
LABA	Long-acting beta-agonist
LAMA	long-acting muscarine anticholinergic
MEF75	Forced expiratory flow from 25% FVC
MEF50	Forced expiratory flow from 50% FVC
MEF25	Forced expiratory flow from 75% FVC
MMEF	Maximal mid-expiratory flow
NLR	neutrophil to lymphocyte ratios
OR	Outer radius
Pi	Internal perimeter
PLR	Platelet to lymphocyte ratios
PEF	Peak expiratory flow
Rc	Central airway resistance
Rp	Peripheral airway resistance
R eff	Resistance effective
RV	Residual volume
R tot	The total airway resistance
R5	Resistance at 5 Hz
R20	Resistance at 20 Hz
R35	Resistance at 35 Hz
SR eff	Specific resistance effective
T/D	Ratio of wall thickness and outer radius
TNF-α	Tumor necrosis factor alpha
Treg	Regulatory cells
TLC	Total lung capacity
VC	Vital capacity
Vc max	Maximal vital capacity
WA%	Wall area percentage
WT	Wall thickness
WA	Wall area
X5	Reactance at 5 Hz
X10	Reactance at 10 Hz
X20	Reactance at 20 Hz
X35	Reactance at 35 Hz
Z5	Respiratory impedance at 5 Hz
%pred	The percentage of predicted value

Funding

This work is supported by the Zhuhai Science and Technology Project (ZH22036201210072)

Ethics statement and consent to participate

Ethics committee approval by our hospital's Medical Ethics Committee with the approval number [2021] Ethics No. (K26-1). Written consent for publication was obtained from all of the patients.

Acknowledgements

None

Conflicts of interest

There are no conflicts of interest.

*Corresponding Author:

Jing Liu, PhD. Fifth Affiliated Hospital of Sun Yat-sen University, 52 East Meihua Rd., Zhuhai City 519000, China. Phone: +86(0)7562528538; Fax: +86(0)7562528733

E-mail: [email protected] (Jing Liu)

Meizhu Chen, Fifth Affiliated Hospital of Sun Yat-sen University, 52 East Meihua Rd., Zhuhai City 519000, China. Phone: +86(0)7562528538; Fax: +86(0)7562528733

E-mail: [email protected] (Meizhu Chen)

Authors' contributions

HL S, ZH C, QQ L designed the study, analyzed and interpreted the data and contributed in writing the manuscript; DH M, HL S, TB N, performed chest CT assessment; QQ L,FF S, YY H, J W, ZG W, KQ W, MZ C were responsible for patient enrollment and follow-up. J L and MZ C contributed to the conception of the study and final approval of the version to be published. All authors read and approved the final manuscript.

Consent for publication

Written informed consent was obtained from the patient for publication.

Availability of data and materials

Data will be made available on request.

Competing interests

Not applicable

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No competing interests reported.

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Utilizing chest CT to assess the impact of omalizumab treatment on airway remodeling in refractory asthma

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Background

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Pulmonary Function

Airway Measurement

Airway mucus

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The application of omalizumab for 4 months can improve clinical symptoms and save medical resources

The application of omalizumab for 4 months can enhance lung Function

The application of omalizumab for 4 months can alleviate airway constriction

The application of omalizumab for 4 months can reduce airway mucus plug scores expression

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