Acupoint Plaster Application Combined with Omalizumab for Severe Allergic Asthma: A Randomized Controlled Trial

Summary

This randomized controlled trial indicated that adding acupoint plaster application to omalizumab may improve symptom control, inflammatory profiles, and immune status in severe allergic asthma, but did not significantly affect conventional pulmonary function.

Abstract

Some patients with severe allergic asthma remain poorly controlled despite guideline‑recommended therapy. This prospective randomized controlled trial evaluated whether adding acupoint plaster therapy to omalizumab provides additional benefits in asthma control, inflammatory biomarkers, immune function, and pulmonary function. Fifty‑six adults with severe allergic asthma were randomized 1:1 to receive either omalizumab plus acupoint plaster (experimental group) or omalizumab alone (control group), with 28 patients per group. Outcomes were assessed at 8 and 16 weeks, including co‑primary endpoints (asthma control test (ACT) score and traditional Chinese medicine (TCM) symptom score) and secondary endpoints (rescue medication use, mini asthma quality of life questionnaire (mini‑AQLQ), peripheral blood eosinophils, fractional exhaled nitric oxide (FeNO), T‑cell subsets, and pulmonary function). Analyses were performed on an ITT basis using multiple imputation. At both time points, the experimental group showed greater improvements in co‑primary endpoints than the control group. At 16 weeks, the experimental group also demonstrated greater improvements in eosinophils, FeNO, percentage of CD4⁺ T lymphocytes (CD4⁺%), percentage of CD8⁺T lymphocytes (CD8⁺%), CD4⁺/CD8⁺ ratio. No significant differences were observed in pulmonary function parameters. Two participants (7.7%) in the experimental group experienced mild local skin reactions, with no serious adverse events reported. This exploratory study suggests that adding acupoint plaster to omalizumab may confer additional clinical, inflammatory, and immunological benefits in severe allergic asthma, with a favorable safety profile. However, these findings warrant confirmation in larger, blinded, multi‑center studies with extended follow‑up.

Introduction

Bronchial asthma is a chronic airway inflammatory disorder characterized by variable respiratory symptoms and fluctuating airflow limitation¹. Allergic asthma remains the predominant phenotype and accounts for a substantial share of severe disease worldwide². Despite receiving guideline-recommended treatment with inhaled corticosteroids/ long‑acting beta₂-agonists (ICS/LABA) therapy, an estimated 5–10% of patients progress to severe asthma with persistent symptoms, impaired lung function, and recurrent exacerbations³. The disease burden has continued to grow in China, where allergic asthma constitutes the majority of severe cases⁴.

Omalizumab, a recombinant humanized anti‑immunoglobulin E (IgE) monoclonal antibody, has been widely used in the treatment of difficult‑to‑control allergic asthma and has been shown to effectively reduce the frequency of acute exacerbations and improve symptom control⁵. However, real‑world data indicate that allergic asthma is often accompanied by elevations in multiple biomarkers, and biological agents targeting a single IgE pathway may not be sufficient to achieve comprehensive disease control. Despite adequate treatment, a considerable proportion of patients still experience residual airway inflammation or incomplete symptom resolution⁶. This treatment gap highlights the need to explore adjunctive therapeutic strategies that act beyond the IgE‑mediated pathway⁷.

Among external therapies in Traditional Chinese Medicine (TCM), acupoint plaster application has been used clinically for chronic respiratory disease for many decades⁸. Recent clinical reports of sanfu plaster suggest reductions in symptom frequency and improved disease stability in patients with bronchial asthma⁹. Clinical and experimental studies have suggested that acupoint plaster therapy may influence immune balance, including T-lymphocyte subsets and other markers of adaptive immunity, thereby complementing anti-IgE therapy¹⁰. Mechanistic studies indicate that herbal acupoint formulations may attenuate Th2-associated cytokine signaling¹¹ or suppress group-2 innate lymphoid cell (ILC2) activation¹². Emerging evidence suggests that acupoint application may provide adjunctive benefits in chronic airway diseases by modulating inflammatory and immune responses, which has prompted interest in its use as a complementary strategy for asthma management¹³. A network meta-analysis further supports the symptomatic benefit of acupuncture-related interventions in asthma¹⁴. Evidence from other respiratory disorders further indicates that acupoint plaster therapy may contribute to improvements in respiratory function under some conditions¹⁵. However, the integrative evaluation of acupoint plaster combined with biologic therapy remains scarce¹⁶. This randomized trial, therefore, tested whether adding standardized acupoint plaster therapy to omalizumab yields additional improvements in symptom control, type-2 inflammatory biomarkers, lung function, and immune parameters in adults with severe allergic asthma.

Protocol

Ethics statement

The study protocol was approved by the Ethics Committee of Chengdu Hospital of Integrated Traditional Chinese and Western Medicine (Approval No. 2024KT019). The trial was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. All the materials used in this study are listed in the Table of Materials.

Study design and participants

This was a prospective, randomized, open-label, parallel-group, single-center trial conducted between June 2024 and December 2024. Eligible patients with severe allergic asthma were enrolled. Diagnosis and severity were based on national and international asthma guidelines^1,17. The inclusion and exclusion criteria were as follows:

Inclusion criteria

Eligible participants were adults aged 18–65 years with physician-diagnosed severe allergic asthma who exhibited typical symptoms, including wheeze, breathlessness, chest tightness, and cough. Variable airflow limitation was confirmed by spirometry, and allergic sensitization was documented by either a positive skin prick test or elevated serum allergen-specific IgE levels. All participants had been receiving a stable medium-to-high dose inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) regimen for at least 3 months, and all participants’ total serum IgE levels fell within the approved dosing range for omalizumab.

Exclusion criteria

Participants were excluded if they had received any biologic therapy, including anti-IgE, anti-interleukin-5 (IL-5)/IL-5 receptor, or anti-interleukin-4 receptor α (IL-4Rα) agents, within the previous 12 months; required maintenance oral corticosteroid therapy; or had experienced an acute asthma exacerbation within the preceding 4 weeks. Additional exclusion criteria included a history of smoking, pregnancy or lactation, severe hepatic, renal, or cardiovascular disease, skin diseases at the intended acupoint sites, or known hypersensitivity to any of the herbal components.

Sample size

The sample size was calculated based on the primary outcome, the change in Asthma Control Test (ACT) score from baseline to week 16. Assuming a clinically meaningful between-group difference of 2.5 points and a standard deviation (SD) of 3.0 (derived from previous pilot data^6,7,14), a two-sided alpha of 0.05, and 80% power required 23 participants per group. To account for an anticipated attrition rate of approximately 15%, enrollment of 26 participants per group was required, yielding a total sample size of 52.

Randomization and grouping

A computer-generated simple random sequence (1:1) was prepared by an independent team member (YT), who was not involved in recruitment, intervention delivery, or assessment. Allocation was concealed in sequentially numbered, opaque, sealed envelopes (SNOSE). After eligibility confirmation and consent, a second team member (YY) opened the next envelope and assigned the participant to it. Because of the visible and tactile nature of acupoint plaster application, blinding of participants and clinicians was not feasible. Outcome assessors and data analysts were also not blinded. The lack of blinding and sham-control is acknowledged as a limitation and discussed in the discussion section.

Background and concomitant therapy

Throughout the 16‑week intervention period, all participants maintained a fixed background asthma therapy comprising regular inhaled budesonide/formoterol (320/9 μg, one inhalation twice daily). For acute exacerbations, all participants were allowed to use the same budesonide/formoterol formulation (320/9 μg) as rescue medication on an as‑needed basis, with a maximum of 8 inhalations per day, and each use was meticulously recorded. Montelukast (10 mg once daily) was permitted as a concomitant medication, and its use remained stable from baseline through the entire follow-up period. All participants had no history of biologic agent use within the previous 12 months, no oral corticosteroid use within the previous 4 weeks prior to study enrollment, and no modifications to the baseline asthma regimen during the 16‑week trial period.

Omalizumab administration

Omalizumab was administered subcutaneously to all participants. Dose (75–600 mg per administration, divided into 1–4 injections as required) and dosing interval (every 2 or 4 weeks) were determined from baseline total serum IgE and body weight using the approved dosing table for adults and adolescents (≥12 years), per product labeling. The maximum recommended dose was 600 mg every 2 weeks. Participants whose baseline IgE or weight fell outside the approved ranges in the table were excluded. Injections were administered by designated registered nurses into the lateral deltoid muscle (alternating arms). Participants were observed for at least 2 h after the first dose, and for 30 min after each subsequent dose. If a dose is missed, it may be administered at the original dose within 3 days of the scheduled time. Any delay exceeding 3 days requires review and assessment by the study physician.

Preparation of the acupoint plaster

The herbal formulation was based on the classical prescription Bai-Jie-Zi-Gao (white mustard seed paste). The formula comprised four herbal components with the following specifications: Asarum heterotropoides var. mandshuricum, commonly known as Xi Xin, was used in the form of root and rhizome at a dose of 10 g. Euphorbia kansui, known as Gan Sui, was included as root material at 10 g. Sinapis alba L., referred to as Bai Jie Zi (white mustard seed), was stir-fried and used as seed material at 20 g. Corydalis yanhusuo W.T. Wang, known as Yan Hu Suo, was incorporated as tuber material at 20 g. All herbal materials were obtained from a single Good Manufacturing Practice-certified supplier and authenticated by a qualified Traditional Chinese Medicine pharmacist according to the Pharmacopeia of the People's Republic of China (2020 edition). Voucher specimens were retained for reference.

All herbs were obtained from a single GMP-certified supplier and authenticated by a qualified TCM pharmacist in accordance with the Pharmacopeia of the People's Republic of China (2020 edition). Voucher specimens were retained. Each batch was ground to a fine powder (< 100 mesh, ~150 µm) under controlled humidity. Fresh ginger (Zingiber officinale Roscoe) rhizome was washed, peeled, and pressed; the juice was filtered through sterile gauze and used within 4 h. Powder and ginger juice were mixed at a ratio of 1 g powder: 1 mL juice to form a homogeneous paste of moderate viscosity. Approximately 1.5 g of paste per acupoint (≈10 g total per session) was spread evenly onto disposable adhesive patches (60 × 70 mm) to a thickness of 2 mm, as verified with a calibrated thickness gauge. Patches were stored at 4 °C, protected from light, and used within 8 h of preparation.

Acupoint application procedure

Acupoints were selected per the WHO Standard Acupuncture Point Locations in the Western Pacific Region¹⁸. The points used were bilateral Feishu (BL13), bilateral Dingchuan (EX-B1), bilateral Fengmen (BL12), bilateral Zhongfu (LU1), and the midline points Tanzhong (CV17) and Tiantu (CV22). A schematic of acupoint locations is provided in Figure 1A–B. All applications were performed by a certified TCM practitioner with ≥5 years of clinical experience. Participants were seated upright with the back exposed. The skin at each acupoint was cleaned with 75% ethanol and allowed to dry. Patches were applied between 09:00 and 11:00 to align with circadian and traditional timing for acupoint therapies. Sessions were delivered three times weekly (Monday/Wednesday/Friday) for 16 consecutive weeks. Patches were retained until the participant reported localized warmth or mild flushing, typically within 1–2 h. The objective criteria for patch removal were: local erythema; stinging or burning sensation reported by the participant; elapsed time of 2 h, whichever occurred first (Figure 1C).

Safety monitoring of acupoint plaster

A skin tolerance test was performed before the first session by applying a small amount of the prepared paste to the inner forearm for 30 min; participants with marked local reactions were excluded. Contraindications included pregnancy, broken or inflamed skin at application sites, severe atopic dermatitis, and known allergy to any formulation component. A patch was considered to have detached early if it dislodged within 30 min of application; in such cases, the patch was reapplied once if the skin was intact. Local skin reactions were graded on a four-level scale: Grade 1, transient erythema or itching resolving <2 h; Grade 2, persistent erythema lasting >2 h without blistering; Grade 3, small blisters (<5 mm) or moderate burning; Grade 4, large blisters, ulceration, or systemic allergic features. Grade 1 reactions were managed by observation; Grade 2 by withholding the next session and topical care; Grade 3–4 reactions prompted study-physician evaluation, treatment, and protocol-specified discontinuation. Adverse events were collected through treatment sites, scheduled visits, telephone follow-up, and participant diaries. Each event was graded for severity (mild/moderate/severe), duration, action taken, and relationship to the study intervention (unrelated, unlikely, possibly, probably, definitely related), and assessed by an independent investigator using prespecified criteria.

Outcome assessment

Assessments were performed at baseline (week 0), week 8, and week 16. An asthma exacerbation was defined as an acute worsening of wheezing, dyspnea, cough, or chest tightness that exceeded the patient's usual day‑to‑day variation and required an increase in asthma medication. To minimize confounding from differential rescue therapies, all participants used as-needed budesonide/formoterol (320/9 μg) as the rescue medication throughout the study, and each exacerbation episode and corresponding inhalations were meticulously documented. The amount of rescue medication use was calculated as the total number of as‑needed inhalations of budesonide/formoterol (320/9 μg) within the 8 weeks preceding each study visit.

The study employed two co-primary outcomes to assess treatment efficacy. The first was the asthma control test (ACT) score¹⁹, a validated patient-reported instrument that evaluates asthma control over the preceding four weeks. The second co-primary outcome was the Traditional Chinese Medicine (TCM) symptom score, which assesses four cardinal respiratory symptoms: cough, expectoration, wheeze, and dyspnea. Each symptom is scored on a scale from 0 to 3, yielding a total score ranging from 0 to 12, with higher scores indicating greater symptom severity. Detailed scoring criteria are provided in the appendix table.

Secondary outcomes encompassed multiple domains of asthma assessment. Quality of life was evaluated using the mini asthma quality of life questionnaire (mini-AQLQ)²⁰, a validated 15-item instrument. The frequency of rescue medication use, defined as the number of as-needed budesonide/formoterol inhalations, was systematically recorded. Type 2 inflammatory biomarkers included peripheral blood eosinophil count and fractional exhaled nitric oxide (FeNO). Pulmonary function was comprehensively assessed through multiple parameters: Forced expiratory volume in 1 s (FEV1), FEV₁ percent predicted (FEV1% predicted), the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), and peak expiratory flow (PEF). Immunological status was evaluated by measuring the percentages of CD4⁺ T lymphocytes (CD4⁺%) and CD8⁺ T lymphocytes (CD8⁺%), and the CD4⁺/CD8⁺ ratio, using flow cytometry.

Safety outcomes were monitored throughout the study period and included assessment of local skin reactions at acupoint application sites, monitoring of vital signs, and routine laboratory tests covering hematology, hepatic, and renal function parameters.

Technical procedures

All blood samples, FeNO measurements, and pulmonary function assessments were conducted in the morning following an overnight fast. Venous blood was drawn by trained phlebotomists and processed within 2 h by the hospital's clinical laboratory, which is accredited to standard. FeNO was measured before spirometry to avoid airway perturbation, using a chemiluminescence-based analyzer at an exhalation flow of 50 mL/s. Two acceptable measurements within 10% of each other were averaged. Daily calibration and ambient NO checks were documented. Spirometry was performed by certified pulmonary function technologists according to ATS/ERS standards, with daily volume and flow calibration. Acceptability and repeatability criteria were applied; the best of three technically acceptable maneuvers was retained.

Statistical analysis

Data were analyzed according to the intention-to-treat principle, and missing data were handled using multiple imputation. Continuous variables are presented as mean±standard deviation (SD), and categorical variables as number (percentage). Baseline continuous variables were compared using the independent-samples t test, and categorical variables using the chi-square test or Fisher’s exact test, as appropriate. Repeated continuous outcomes were analyzed using linear mixed-effects models with fixed effects for group, time, and group-by-time interaction. Between-group comparisons at week 8 and week 16 were performed using independent-samples t tests, with mean differences, 95% confidence intervals, and Cohen’s d reported. Rescue medication use was analyzed using negative binomial regression and is presented as incidence rate ratios (IRRs) with 95% CIs. All tests were two-sided, and p < 0.05 was considered statistically significant.

Results

Participant flow and follow-up

A total of 64 patients were screened; 56 met eligibility criteria and were randomized in a 1:1 ratio, with 28 participants assigned to each group. During follow-up, two participants in the treatment group discontinued the intervention after week 8 for personal reasons. Therefore, 54 participants completed the 16-week follow-up (26 in the treatment group and 28 in the control group). All randomized participants were included in the ITT analysis. T...

Discussion

This randomized controlled trial evaluated whether acupoint plaster application could provide additional benefit when added to omalizumab in adults with severe allergic asthma. The main findings were that the combination therapy was associated with greater improvement in asthma control, TCM symptom burden, rescue medication use, eosinophilic inflammatory indices, and peripheral T-cell immune profiles than omalizumab alone. In contrast, conventional spirometric parameters showed significant improvement over time in both g...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
75% medical alcohol	Shandong Lierkang Medical Technology Co., Ltd.	1202050004	100 mL/bottle
Acupoint Patches	Sichuan Sanhe Medical Materials	WZ102000982	Disposable, 60 mm x 70 mm
Bai Jie Zi	Sichuan Jingxin Traditional Chinese Medicine Decoction Pieces Co., Ltd.	CHUAN20160145	stir-frying, 500 g/bag
BD Multitest 6-Color TBNK Kit	BD Biosciences	662967	BD Multitest 6-Color TBNK
Dilution solution for blood cell analysis	Mindray	DWX-50101	Used for diluting samples for complete blood count (CBC) testing
DuraClone IM T Cell Subsets Tube	Beckman Coulter	B53328	10-color/10 types of monoclonal antibody premixed tubes
FeNO Analyzer	Sunvou Medical Electronics Co.,Ltd	Sunvou-CA2122	For exhaled nitric oxide test
Flow cytometry	BD Biosciences	FACSCelesta	Flow Cytometry Analysis Platform
Fully Automated Blood Analyzer	Mindray	BC7500CST	Five-part blood cell analyzer
Fully Automatic Biochemical Analyzer	Roche	Cobas 8000	Suitable for comprehensive biochemical tests including liver function and renal function assays
Gan Sui	Beijing Qijing Yinpian Co., Ltd.	PC81627	root, 500 g/bag
ginger	Ito-Yokado Supermarket	N/A	For preparing ginger juice
Hemolysin for blood cell analysis	Mindray	M-68FD	For lyzing red blood cells and releasing white blood cells
Liver function biochemical quality control reagents	Zhongsheng Beikong	Biochemical composite quality control samples	For liver function testing
Omalizumab	Novartis	SJ20170042	Anti-IgE monoclonal antibody
Renal function biochemical quality control reagents	Zhongsheng Beikong	Biochemical composite quality control samples	For renal function Tests
Spirometer	Yeager	Master screen	For lung function test
SPSS Statistics	IBM	Version 25.0	Statistical software
Staining solution for blood cell analysis	Mindray	WNR-800A	For leukocyte classification staining
Xi Xin	Sichuan Guoqiang Traditional Chinese Medicine Decoction Pieces Co., Ltd.	YJY002439729	root and rhizome, 500 g/bag
Yan Hu Suo	Sichuan Guoqiang Traditional Chinese Medicine Decoction Pieces Co., Ltd.	YJY002439815	tuber, 500 g/bag