Introductory Chapter: New Understandings of Asthma

1. Introduction

Asthma is a heterogeneous disease characterized by chronic airway inflammation and airway hyperresponsiveness, and the main lesion site is bronchi. It is a threat to public health worldwide and affects people of all ages. According to relevant data, it is conservatively estimated that there are at least 300 million asthma patients in the world, and 380,000 people die of asthma every year. Asthma has become a serious public health problem, bringing great pressure to individuals, families and the society. At the same time, the incidence of asthma is also one of the fastest rising diseases in the world. Data show that the overall prevalence of asthma in both adults and children has been increasing worldwide for the past 20 years. At present, the prevalence of asthma varies greatly among countries in the world, ranging from 0.3–17%, and the incidence of asthma varies in different regions and genders within the same country. Generally speaking, the incidence of asthma is higher in developed countries than in developing countries and higher in urban areas than in rural areas [1, 2].

The mechanism of asthma is complicated, and its pathogenesis has not been fully understood. Currently, asthma is considered to be a heterogeneous disease with the combined effects of gene and environment [3]. Asthma is a polygenic disease, and hundreds of asthma susceptibility gene loci have been found, which are related to the molecular mechanism and pathophysiological manifestations. Epigenetics regulate asthma between environmental and genetic factors through DNA methylation, histone modification, and regulation of non-coding RNA [4]. At the same time, the complex role of airway and gut microbiome in the development and severity of asthma has also been recognized [3].

2. New understandings of asthma in definitions, phenotypes and treatments

In recent years, thanks to the continuous explorations and understandings of the pathogenesis of asthma, as well as high-quality clinical trials and real-world data, the recommended treatment strategies of various countries are updated frequently, and new drugs for asthma treatment keep emerging. The field of asthma treatment develops rapidly.

First, the definition of asthma is constantly being updated. The 2021 update of GINA no longer distinguishes between intermittent and mild persistent asthma and refers to both as mild asthma. The preferred treatment for mild asthma is updated to low-dose ICS/formoterol on demand [5]. However, the Spanish Asthma Management Guidelines (GEMA) [6], published in 2021, differ from GINA in their definition and treatment guidelines for mild asthma, which retain intermittent asthma and can be treated with one of three options: SABA, or low dose ICS/formoterol, or low dose ICS/salbutamol, and GEMA continues to recommend daily maintenance of low dose ICS as the preferred treatment for mild persistent asthma. The definition and treatment strategies for mild asthma are still controversial, and more evidence and research is needed to gain more agreement. Therefore, GINA 2022 recommends that the term ‘mild asthma’ should generally be avoided in clinical practice, but if it was used, patients should be alerted to the risk of acute attacks of severe asthma and the need for ICS-containing treatment.

Second, with the deepening understanding of the mechanism of asthma, the phenotypes of asthma are also changing. More and more clinicians believe that asthma cannot be simply divided into allergic type and non-allergic type. In many asthmatic patients, chronic airway inflammation is driven by Th2 or ILC2 cells that produce IL-4, IL-5, and IL-13, and these type 2 cytokines and promote typical features of the disease, such as eosinophilia accumulation, hypersecretion of mucus, bronchial hyperresponsiveness, increased IgE production and susceptibility to exacerbation. However, only half of asthmatics have this type 2 high feature, whereas type 2 low asthma is more associated with obesity, high neutrophils and a lack of response to corticosteroids, the main drug used to treat asthma [7]. So that, in recent years, the phenotype of asthma has evolved into endotype: type 2 high (essentially eosinophilic type) and type 2 low (non-eosinophilic, sometimes neutrophilic, and metabolic). The therapeutic targets of different endogenous inflammatory pathways have become the new focus of drug research and development for asthma.

Finally, asthma treatments are constantly being updated. Among them, the emergence of new targets in both type 2 high and type 2 low inflammatory pathways has led to more strategies for treatment. In the year of 2022, GINA added TSLP target antibody into the treatment program. Up to now, there have been four types of target drugs approved internationally. Three biological antibodies have been produced to target IL-5, Mepolizumab, an IgG1 antibody directed against IL-5 [8], cells expressing the IL-5 receptor alpha chain such as eosinophils and basophils [9, 10]. The target of IL-4RA inhibition is Dupilumab, which was first used in eosinophilic asthma and is also effective in non-eosinophilic asthma patients [11]. Currently, IL-9 inhibitors have not been shown to be effective in patients with moderate to severe asthma [12]. Omalizumab, a biologic agent targeting IgE, has been widely used in the clinic, but only about 70% of children and adults treated with Omalizumab showed a good response to treatment [13]. Epithelium-derived inflammatory cytokines include IL-1, IL-33, IL-25 and TSLP, among which biologics targeting IL-33 and TSLP are more advanced, and results of the clinical trials have only been published for TSLP. Tezepelumab (AMG 157/MEDI9929) is a humanized monoclonal antibody to TSLP that can be applied to both type 2 high and type 2 low severe asthma [14]. At present, in addition to the development of new drugs and clinical trials, several issues still need to be addressed in biotarget therapy, including the length of time that severe patients need to be treated with biologic agents; the risk assessment of immunogenicity of monoclonal antibodies, and more data are needed in special populations.

3. Summary

With the continuous exploration of the pathogenesis of asthma and the development and analysis of various clinical trials, the diagnosis and treatment of asthma, as well as the development of drugs, are constantly updated and improved. This book summarized recent researches on the diagnosis and treatment of asthma and its mechanisms. In the future, with more comprehensive and in-depth explorations of inflammatory pathways in asthma and evidence-based supports from high-quality clinical studies, the treatment of asthma will continue to make great strides forward for the benefit of asthma patients.