Use of Allergen Immunotherapy in China: Current Status and Research Progress

Abstract

Allergic diseases, including allergic rhinitis (AR), asthma, food allergies and drug allergies, are significant health issues globally and in China. AR affects 10%–40% of the global population [1], and 18.6%–52.9% across regions in China [2]. The prevalence of asthma has kept rising to 4.2% in China by 2015 [3]. This rampancy is also observed in other allergic diseases, together straining the public health systems around the world.

Allergen immunotherapy (AIT) alleviates IgE-mediated allergic diseases by inducing immune tolerance through a controlled and progressive exposure to allergens. Despite its eye-catching outcomes in China, AIT still faces hurdles in its wider replication, such as lack of individualisation, poor patient compliance and inadequate understanding among clinicians and patients. This paper provides a view on the current status, progress and future directions of AIT in China.

Since its discovery in 1911, AIT has already been established as a mainstay for treating allergic diseases in Western countries. In China, AIT was first copied in the 1960s by the allergy department (established in 1956 and the only one then) at Peking Union Medical College Hospital. However, the expansion of AIT was slow until the approval of standardised allergen extracts in the late 1990s and early 2000s. In recent years, the application of AIT has been accelerated due to increasing recognition from medical professionals and demand from patients. The release of Chinese AIT guidelines has bolstered basic, clinical and translational research. PubMed data show that the number of AIT-related studies involving Chinese scholars has doubled since 2018. Hot research keywords include sublingual immunotherapy (SLIT), subcutaneous immunotherapy (SCIT), efficacy and safety, biomarkers, immunoregulation and omalizumab. Increasing research fruits have been published in top journals (Figure 1).

More recently, Chinese scholars have set out on the journey to explore new delivery routes in AIT, such as oral immunotherapy, intracervical lymphatic immunotherapy, intratonsillar immunotherapy, as well as the combined application of biologics in AIT. Mechanistical research has even turned the lens to the association of gut microbiota with AIT outcomes. The roles of follicular helper T cells and regulatory T cells in allergic diseases and AIT have also been further elucidated. In summary, Chinese scholars have caught up with the global pace in the research on AIT.

Supported by the results from mechanistical research and the experience from frontline clinicians, Chinese AIT guidelines have been released. In 2017, the first edition of the Chinese Guideline on Allergen Immunotherapy for Allergic Rhinitis [4] was published by the Chinese Society of Allergy (CSA) and the Chinese Allergic Rhinitis Collaborative Research Group (C²AR²G), providing evidence-based recommendations and filling a gap in AR immunotherapy guidance. This guideline covered essential aspects of AIT, such as indications, allergen selection, dosing and adverse effect management. In 2022, the guideline was refreshed [5], depending on clinical experience gained during the COVID-19 pandemic and unique Chinese practices and strategies, such as cluster and rush immunotherapies. Besides, the updated guideline also addresses AIT in paediatric AR and concurrent medication use, providing comprehensive guidance. The 2022 edition reaffirmed the efficacy of AIT in relieving symptoms, reducing medications, improving quality of life and preventing AR progression into asthma, while emphasising its safety and contraindications. These changes demonstrate the alignment between Chinese and international standards in AR immunotherapy.

Similarly, the AIT guideline for allergic asthma in China has also seen continual optimisation. In early guidelines (e.g., the 2016 edition), AIT was cautiously suggested, due to limited evidence. Supported by clinical data in China, the 2019 edition endorsed AIT as a personalised therapy, marking a pivotal shift in understanding. By 2024, AIT had been recognised as a disease-modifying treatment, particularly for mild-to-moderate allergic asthma, thanks to its potential to curb disease progression and reduce medication dependence.

Compared with international guidelines, such as those from EAACI [6] and the AAAAI/ACAAI Joint Task Force [7], the Chinese AIT guidelines exhibit several differences. In Chinese guidelines, AIT is recommended as the first-line treatment for AR patients with obvious allergen-related symptoms, adopting a more open attitude without setting too many preconditions. In contrast, EAACI suggests considering AIT mainly for patients with moderate-to-severe AR symptoms that are inadequately controlled by regular and appropriate pharmacotherapy, and/or allergen avoidance. AAAAI/ACAAI's stance on indications is similar to that of EAACI, both being more conservative and emphasising disease severity and a poor response to pharmacotherapy as prerequisites for AIT. Consistently, all three guidelines consider uncontrolled or severe asthma an absolute contraindication. However, the Chinese guideline lists additional absolute contraindications to SCIT, such as children younger than 5 years of age and older adults older than 65 years of age, current use of β-receptor antagonists, uncontrolled systemic autoimmune disease, active malignant neoplasia, and commencing SCIT during pregnancy. EAACI proposes contraindications related to active systemic autoimmune disorders and active malignant neoplasia, and recommends against initiating AIT during pregnancy. The AAAAI/ACAAI Joint Task Force prefers a risk–benefit assessment for initiating AIT. Additionally, a low patient adherence discounts the efficacy of AIT in China, with many patients discontinuing the treatment abruptly. To address this challenge, the Chinese guideline offers details about how to continue AIT after missed doses, an area that is relatively underexplored in other guidelines (Figure 2).

The application of AIT in China is still impeded by multiple factors, including poor patient compliance (often due to the psychological burden of long-term therapy), high costs, inconvenient procedures, potential adverse reactions and lack of confidence in outcomes. For instance, the non-compliance rate is about 16.27% in patients receiving SLIT, mainly due to unmet therapeutic expectations [8]. Moreover, current diagnostic tools may not always be accurate enough to identify specific allergens, thus failing the workout of an optimal strategy. There is also a shortage of specialised institutions and practitioners. According to the data from the Chinese College of Allergy and Asthma (CCAA) in 2022, out of 502 hospitals surveyed nationwide, only 90 hospitals had a special allergy department, staffed by just 350 professionals in total, resulting in a 1:4 million ratio in the general Chinese population. Inadequate standardisation of allergen vaccines, often extracted from natural sources with variable quality and efficacy, is another key challenge. The biological activity and immunogenicity of vaccines should be standardised for improving the efficacy and reducing the adverse reactions of AIT. Additionally, the long-term (3–5 years) AIT treatment brings significant financial and labour burdens.

AIT will surely become a powerful weapon combatting allergic diseases in China. Research focus will be laid on new delivery routes, like epicutaneous, oral, intracervical lymphatic and intratonsillar immunotherapy, which have shown potential to enhance the safety and ease the operation of AIT. Novel adjuvants, nanotechnology and standardised recombinant allergen vaccines can be expected as AIT boosters. The spectrum of AIT-treated diseases should be broadened to cover food allergy, a disease attracting more attention. New allergen vaccines should be invented to cover more common allergens, such as pollens, moulds, animal dander and so on. Emerging bioinformatic and molecular technologies will help create genetically engineered allergens that induce immune tolerance without allergic reactions. Digitalisation and AI technology will revolutionise the management of allergic diseases [9]. Digital healthcare platforms can provide personalised education and collect real-time feedback. AI models can assist in the quest for new biomarkers, thus facilitating the individualisation of AIT. Policies should be made to increase reimbursement and reduce the financial burden on patients receiving AIT, promote the innovation of new vaccines and delivery systems, train AIT specialists and establish more specialised allergy departments or centres in China.

Song Li: conceptualization of the review topic, literature search and data collection, and drafting of the manuscript. Zhi-Ling Zhu: co-conceptualization of the review topic, literature search and data collection, and preparation of figures. Lei Cheng: supervision of the project, critical revision of the manuscript for important intellectual content, provision of essential resources and support, and final approval of the version to be published. Each author has contributed significantly to the research and preparation of this manuscript and has approved the final version for submission.

The authors declare no conflicts of interest.