bubble_chart Overview

Asthma (bronchial asthma, asthma) is a chronic airway inflammation involving various cells, particularly mast cells, eosinophils, and T lymphocytes. In susceptible individuals, this inflammation can cause recurrent episodes of wheezing, shortness of breath, chest tightness, and/or coughing, often occurring at night and/or in the early morning, with heightened airway responsiveness to various stimuli. However, symptoms can resolve spontaneously or with treatment. Over the past decade, countries such as the United States, the United Kingdom, Australia, and New Zealand have seen an increasing trend in asthma prevalence and mortality. Worldwide, there are approximately 100 million asthma patients, making it a major chronic disease that poses a serious threat to public health. In China, the prevalence of asthma is about 1%, with rates as high as 3% among children. Estimates suggest there are over 10 million asthma patients nationwide.

bubble_chart Etiology

The disease cause of this condition is relatively complex, and it is generally considered a polygenic genetic disorder influenced by both genetic and environmental factors.

(1) Genetic Factors: The relationship between asthma and heredity has increasingly garnered attention. Based on family data, early studies mostly suggested that asthma is a single-gene genetic disorder, with some scholars proposing it as an autosomal dominant inheritance disease and others as an autosomal recessive inheritance disease. Currently, it is believed that asthma is a polygenic genetic disorder, with a heritability of approximately 70–80%. Polygenic genetic disorders result from the combined effects of multiple pathogenic genes located on different chromosomes. These genes exhibit no clear dominance or recessiveness, each exerting a relatively weak influence on the phenotype but with a cumulative effect. The onset of the disease is significantly influenced by environmental factors. Therefore, the genetic basis of bronchial asthma consists of several pathogenic genes with minor but cumulative effects. The risk of an individual developing the disease due to this genetic foundation is termed susceptibility. The likelihood of an individual being prone to asthma, determined by the combined action of genetic and environmental factors, is termed predisposition. The degree of heritability measures the role of genetic factors in disease onset; the higher the heritability, the greater the role genetic factors play. Numerous studies have shown that the prevalence of asthma among relatives of asthma patients is higher than in the general population, and the closer the kinship, the higher the prevalence. Within a family, the more affected individuals there are, the higher the prevalence among relatives; the more severe the patient's condition, the higher the prevalence among relatives. Wang Mingang et al. investigated the prevalence of asthma among first- and second-degree relatives of asthmatic children and compared it with a control group. In the asthma group, the prevalence among first-degree relatives was 8.2%, and among second-degree relatives, it was 2.9%, with the former significantly higher than the latter. In the control group, the prevalence among first- and second-degree relatives was 0.9% and 0.4%, respectively, both lower than the corresponding rates in the asthma group.

A key feature of asthma is the presence of airway hyperresponsiveness. Studies in humans and animals indicate that certain genetic factors control the airway's response to environmental stimuli. Zhang Xiaodong et al. used the histamine inhalation method to measure airway responsiveness in parents of 40 asthmatic children and 34 normal children. Most parents of asthmatic children exhibited varying degrees of increased airway responsiveness, with PC₂₀ averaging 11.6 mg/ml, whereas the PC₂₀ of normal children's parents was all greater than 32 mg/ml. This suggests that a predisposition to airway hyperresponsiveness exists among relatives of asthma patients, highlighting the significant role of inherited airway hyperresponsiveness in asthma's genetic basis.

Currently, the specific genes related to asthma have not been fully identified, but studies suggest the possible existence of asthma-specific genes, IgE-regulating genes, and immune response genes. The autosomal region 11q12q13 contains asthma-related genes that control IgE responsiveness. In recent years, international research on the genetics of total serum IgE has indicated that the genes regulating total IgE are located on chromosome 5. The control of specific immune responses is not governed by IgE-regulating genes but rather by immune response genes, which exhibit high antigen recognition capabilities. Mouse experiments have confirmed that immune response genes are located in the MHC region of chromosome 17. Studies also suggest that immune response genes exist in the HLA-DR locus on human chromosome 6, regulating immune responses to specific antigens. Therefore, the pathogenesis of asthma involves interactions between IgE-regulating genes and immune response genes. Additionally, the varying sensitivity states of cellular receptors in the nervous and respiratory systems, as well as congenital deficiencies of certain enzymes, may also be influenced by genetic factors. In summary, the relationship between asthma and genetics requires further in-depth research to facilitate early diagnosis, prevention, and treatment.

(II) Triggering Factors The formation and recurrent attacks of asthma are often the result of the combined effects of many complex factors.

1. Inhalants Inhalants can be divided into specific and non-specific types. The former includes dust mites, Mongolian snakegourd root, fungi, animal dander, etc.; non-specific inhalants include sulfuric acid, sulfur dioxide, chlorine ammonia, etc. Occupational asthma-specific inhalants include toluene diisocyanate, phthalic anhydride, ethylenediamine, penicillin, proteases, amylases, silk, animal dander or excretions, etc. Additionally, non-specific ones include formaldehyde and formic acid.

2. Infections The formation and onset of asthma are related to recurrent respiratory infections. In asthma patients, specific IgE for bacteria, viruses, mycoplasma, etc., may exist. Inhalation of corresponding antigens can trigger asthma. After viral infections, the respiratory epithelium may be directly damaged, leading to increased airway reactivity. Some scholars believe that interferons and IL-1 produced by viral infections increase histamine release from basophils. In infancy, respiratory viruses (especially respiratory syncytial virus) infections often manifest as asthma symptoms. Asthma caused by parasites such as roundworms and hookworms can still be observed in rural areas.

3. Food The phenomenon of asthma attacks triggered by dietary factors is often seen in asthma patients, especially in infants and young children who are prone to food allergies, though this tendency decreases with age. The most common allergenic foods include fish, shrimp, crab, eggs, milk, etc.

4. Climate Changes Changes in temperature, humidity, air pressure, and/or ions in the air can induce asthma, making it more prevalent during cold seasons or the transition between autumn and winter.

5. Psychological Factors Emotional agitation, anxiety, anger, etc., in patients can all contribute to asthma attacks. It is generally believed that these factors act through the cerebral cortex and vagus nerve reflexes or hyperventilation.

6. Exercise Approximately 70–80% of asthma patients experience asthma attacks after intense exercise, known as exercise-induced asthma or exercise asthma. In typical cases, bronchospasm is most pronounced 6–10 minutes after exercise and 1–10 minutes after stopping, with many patients recovering spontaneously within 30–60 minutes. There is a refractory period of about one hour post-exercise, during which 40–50% of patients do not experience bronchospasm upon further exercise. Clinical manifestations include cough, chest tightness, shortness of breath, and wheezing, with auscultation revealing wheezing sounds. Some patients may not exhibit typical asthma symptoms after exercise, but bronchospasm can be detected through pre- and post-exercise pulmonary function tests. This condition is more common in adolescents. Pre-treatment with sodium cromoglycate, ketotifen, or aminophylline can alleviate or prevent attacks. Studies suggest that intense exercise leads to hyperventilation, causing the loss of moisture and heat from the airway mucosa and temporarily elevated molar concentration in the respiratory epithelium, resulting in bronchial smooth muscle contraction.

7. Asthma and Medications Some medications can trigger asthma attacks, such as propranolol, which induces asthma by blocking β₂-adrenergic receptors. Approximately 2.3–20% of asthma patients experience asthma triggered by aspirin-like medications, known as aspirin-induced asthma. These patients often have nasal polyps and low tolerance to aspirin, hence the term "aspirin triad." The clinical features include: severe asthma attacks induced by aspirin, with symptoms typically appearing within 2 hours of medication use, occasionally delayed to 2–4 hours. Patients may exhibit cross-reactivity to other antipyretic analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs); childhood asthma patients often develop symptoms before age 2, but most cases occur in middle-aged individuals, predominantly between 30–40 years old; females are more affected than males, with a male-to-female ratio of about 2:3; attacks show no clear seasonal pattern, and the condition tends to be severe and refractory, often requiring corticosteroid dependency; over half of patients have nasal polyps, frequently accompanied by perennial allergic rhinitis and/or sinusitis, with asthma symptoms sometimes worsening or being triggered after nasal polyp removal surgery; skin tests for common inhalant allergens are often negative; total serum IgE levels are usually normal; and there is a lower familial prevalence of allergic diseases. The exact pathogenesis remains unclear, but some propose that bronchial cyclooxygenase in these patients may be influenced by a pathogenic mediator (possibly viral), making it more susceptible to inhibition by aspirin-like drugs, leading to aspirin intolerance. Thus, when such patients take aspirin-like medications, arachidonic acid metabolism is disrupted, prostaglandin synthesis is inhibited, causing an imbalance between PGE₂ and PGF_2α, and increased leukotriene production, resulting in strong and prolonged bronchial smooth muscle contraction.

8. Menstruation, Pregnancy, and Asthma Many female asthma patients experience worsening asthma symptoms 3–4 days before menstruation, which may be related to the sudden drop in progesterone during the premenstrual period. For patients who experience this monthly and have light menstrual flow, timely progesterone injections may sometimes prevent severe premenstrual asthma. The impact of pregnancy on asthma is not consistent—some patients see improvement in asthma symptoms, while others experience worsening, though most show no significant change. The effects of pregnancy on asthma are primarily due to mechanical influences and hormonal changes related to asthma. In the advanced stage of pregnancy, as the uterus enlarges, the diaphragm rises, leading to varying degrees of reduction in residual volume, expiratory reserve volume, and functional residual capacity, along with increased ventilation and oxygen consumption. If asthma is properly managed, it will not adversely affect pregnancy or childbirth.

bubble_chart Pathogenesis

(1) Allergic Reaction The pathogenesis of bronchial asthma is related to allergic reactions, with Type I hypersensitivity being the most widely recognized. Patients often have an atopic constitution and are frequently accompanied by other allergic diseases. When allergens enter the body and stimulate the immune system, high titers of specific IgE are synthesized and bind to high-affinity Fcε receptors (FcεR₁) on the surface of mast cells and basophils. They can also bind to low-affinity Fcε receptors (FcεR₂) on certain B cells, macrophages, monocytes, eosinophils, NK cells, and platelets. However, the affinity of FcεR₂ for IgE is approximately 10–100 times lower than that of FcεR₁. If the allergen re-enters the body, it can cross-link with IgE bound to FcεR, leading to the synthesis and release of various active mediators. This results in bronchial smooth muscle contraction, increased mucus secretion, elevated vascular permeability, and inflammatory cell infiltration. Furthermore, under the influence of these mediators, inflammatory cells can release additional mediators, exacerbating airway inflammation. Based on the timing of asthma onset after allergen inhalation, it can be classified into immediate asthma reaction (IAR), late asthma reaction (LAR), and dual-phase asthma reaction (DAR). IAR occurs almost immediately after allergen inhalation, peaking within 15–30 minutes and gradually resolving within about 2 hours. LAR, on the other hand, has a delayed onset, occurring around 6 hours later, and lasts longer, potentially persisting for several days. Some severe asthma patients are closely associated with LAR, exhibiting more severe clinical symptoms and prolonged impairment of lung function, often requiring treatment with inhaled corticosteroids for recovery. In recent years, the clinical significance of LAR has garnered considerable attention. The mechanism of LAR is complex, involving not only IgE-mediated mast cell degranulation but also primarily driven by airway inflammation, which may include mast cell re-degranulation and the release of slow-reacting mediators such as leukotrienes (LT), prostaglandins (PG), and thromboxanes (TX). Studies have shown that mast cell degranulation is not exclusive to immune mechanisms; non-immunological stimuli such as exercise, cold air, and sulfur dioxide inhalation can also activate mast cells to release granules. Asthma is now considered a chronic inflammatory disease involving interactions among multiple inflammatory cells, as well as the participation of numerous mediators and cytokines. LAR is the result of airway inflammatory reactions, with mast cells serving as the primary effector cells, while eosinophils, neutrophils, monocytes, lymphocytes, and platelets form the secondary effector system. These cells can release a large number of inflammatory mediators, activating airway target organs and causing bronchial smooth muscle spasm, microvascular leakage, mucosal edema, and hyperactive mucus secretion due to neural excitation. Patients exhibit significantly heightened airway reactivity. Clinically, conventional bronchodilators alone are often insufficient for relief, whereas inhaled corticosteroids and sodium cromoglicate can help prevent the occurrence of LAR.

The relationship between bronchial asthma and Type III hypersensitivity remains controversial. Traditional views hold that extrinsic asthma is a Type I hypersensitivity reaction, manifesting as IAR, while intrinsic asthma is a Type III hypersensitivity reaction (Arthus phenomenon), manifesting as LAR. However, research findings indicate that LAR mostly occurs secondary to IAR, with LAR exhibiting significant dependence on IAR. Therefore, not all LAR cases are Type III hypersensitivity reactions.

(II) Airway Inflammation Airway inflammation is a significant advancement in the research field of asthma pathogenesis in recent years. The airway inflammation in bronchial asthma patients involves multiple cells, particularly mast cells, eosinophils, and T lymphocytes, and is a chronic non-specific airway inflammation resulting from the interaction of over 50 inflammatory mediators and more than 25 cytokines. Airway inflammation is a critical determinant of reversible airway obstruction and non-specific bronchial hyperresponsiveness in asthma patients. The airway inflammatory response in asthma occurs in three stages: IgE activation and FcεR initiation, the release of inflammatory mediators and cytokines, and the expression of adhesion molecules facilitating leukocyte trans-membrane migration. When allergens enter the body, B cells recognize and activate the antigen through two pathways: (1) T and B cells recognize different epitopes of the antigen and activate separately; (2) B cells engulf and process the antigen, binding it to the major histocompatibility complex (MHC II), which is recognized by Th cells, leading to the release of IL-4 and IL-5, further promoting B cell activation. The activated B cells produce corresponding specific IgE antibodies, which then cross-link with mast cells and eosinophils, leading to the production and release of inflammatory mediators under the influence of allergens. It is known that mast cells, eosinophils, neutrophils, epithelial cells, macrophages, and endothelial cells can all produce inflammatory mediators. Based on the timing of mediator production, they can be classified into three categories: rapidly released mediators (e.g., histamine), secondarily produced mediators (e.g., PG, LT, PAF), and granule-derived mediators (e.g., heparin). Mast cells are the primary effector cells in airway inflammation. Upon activation, they release mediators such as histamine, eosinophil chemotactic factor (ECF-A), neutrophil chemotactic factor (NCF-A), and LT. Alveolar macrophages may also play a crucial role in initiating asthma inflammation, releasing mediators such as TX, PG, and platelet-activating factor (PAF) upon activation. ECF-A attracts eosinophils and triggers the release of major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), eosinophil-derived neurotoxin (EDN), PAF, and LTC₄. MBP and EPO can cause airway epithelial cell shedding, exposing sensory nerve endings and resulting in airway hyperresponsiveness. MBP and EPO can also activate mast cells to release mediators. NCF-A attracts neutrophils and induces the release of LT, PAF, PGS, oxygen free radicals, and lysosomal enzymes, exacerbating the inflammatory response. LTC₄ and LTD₄ are potent bronchoconstrictors and promote increased mucus secretion and vascular permeability. LTB₄ can attract and aggregate neutrophils, eosinophils, and monocytes, as well as induce mediator secretion. PGD₂, PGF₂, PGF_2α, PGI₂, and TX are all powerful airway constrictors. PAF can constrict bronchi, attract and activate inflammatory cells like eosinophils, and increase microvascular exudation, making it an important mediator in asthma inflammation.In recent years, it has been discovered that endothelin (ET₅) produced by airway epithelial cells and vascular endothelial cells is an important mediator causing airway contraction and remodeling. ET₁ is the strongest bronchial smooth muscle constrictor known to date, with a contraction intensity 100 times that of LTD₄ and neurokinin, and 1,000 times that of acetylcholine. ET also promotes submucosal gland secretion and stimulates the proliferation of smooth muscle and fibroblasts. The pro-inflammatory cytokine TNFα can stimulate airway smooth muscle cells to secrete ET₁, which not only exacerbates smooth muscle contraction but also enhances the self-contractile reactivity of airway smooth muscle. This may lead to airway remodeling caused by abnormal proliferation of airway cells and could be a significant factor in chronic refractory asthma. Adhesion molecules (AMs) are a class of glycoproteins that mediate cell-cell adhesion. A large body of research has confirmed that adhesion molecules play a crucial role in the pathogenesis of asthma. During airway inflammatory responses, adhesion molecules mediate the adhesion of leukocytes to endothelial cells and their transendothelial migration to inflammatory sites.

In summary, the inflammatory response in asthma involves multiple inflammatory cells, mediators, and cytokines, with highly complex interactions that require further investigation.

(3) Airway Hyperresponsiveness (AHR) Airway responsiveness refers to the constrictive reaction of the airways to various chemical, physical, or pharmacological stimuli. Airway hyperresponsiveness (AHR) is defined as an exaggerated airway constrictive response to non-antigenic stimuli that would not normally induce or only elicit a grade I reaction. AHR is one of the key features of asthma. It often shows familial tendencies and is influenced by genetic factors, though extrinsic factors play a more significant role. Currently, airway inflammation is widely recognized as one of the most important mechanisms underlying AHR. When the airways are exposed to allergens or other stimuli, AHR develops due to the involvement of various inflammatory cells, mediators, cytokines, damage to the airway epithelium, and intraepithelial nerves. Some studies suggest that autocrine and paracrine secretion of endothelin by airway stromal cells, as well as interactions between cytokines—particularly TNFα—and endothelin, play a crucial role in the development of AHR. Additionally, AHR is associated with decreased β-adrenergic receptor function, increased cholinergic nerve excitability, and impaired inhibitory function of non-adrenergic non-cholinergic (NANC) nerves. Physical and chemical stimuli such as viral respiratory infections, SO₂, cold air, dry air, hypo- and hypertonic solutions can also elevate airway responsiveness. The degree of AHR is closely related to airway inflammation, though the two are not synonymous. While AHR is now universally acknowledged as a common pathophysiological feature of bronchial asthma, not all individuals with bronchial hyperresponsiveness (BHR) have asthma. Conditions such as long-term smoking, ozone exposure, viral upper respiratory infections, chronic obstructive pulmonary disease (COPD), allergic rhinitis, bronchiectasis, tropical pulmonary eosinophilia, and hypersensitivity pneumonitis can also present with BHR. Therefore, the clinical significance of BHR should be interpreted comprehensively.

(4) Neural Factors The autonomic innervation of the bronchi is highly complex, involving not only the traditionally recognized cholinergic and adrenergic nerves but also the non-adrenergic non-cholinergic (NANC) nervous system. Bronchial asthma is associated with decreased β-adrenergic receptor function and heightened vagal tone, and may also involve increased α-adrenergic nerve reactivity. The NANC inhibitory nervous system is the primary neural pathway responsible for airway smooth muscle relaxation. Its neurotransmitters are not yet fully understood but may include vasoactive intestinal peptide (VIP) and/or peptide histidine methionine. Conversely, airway smooth muscle contraction may result from dysfunction of this system. The NANC excitatory nervous system consists of unmyelinated sensory nerves, with substance P as its neurotransmitter. This substance is found in the chemosensitive C-fiber afferents of the airway vagus nerves. When airway epithelial injury exposes C-fiber afferent nerve endings, inflammatory mediators stimulate local axon reflexes, leading to antidromic conduction along collateral branches of afferent nerves and the release of sensory neuropeptides such as substance P, neurokinins, and calcitonin gene-related peptide. These substances induce bronchial smooth muscle contraction, increased vascular permeability, and enhanced mucus secretion. Recent studies have shown that nitric oxide (NO) is the primary neurotransmitter of human NANC nerves. Endogenous NO has a dual role in the airways: on one hand, it relaxes airway smooth muscle and kills pathogenic microorganisms, playing a crucial role in airway tone regulation and pulmonary immune defense; on the other hand, excessive local NO production can exacerbate airway tissue damage and trigger AHR. The effects of NO depend on its local concentration and target site, suggesting that modulating airway NO production may be beneficial for asthma treatment.

bubble_chart Pathological Changes

The basic pathological changes in the airways include infiltration of mast cells, pulmonary macrophages, eosinophils, lymphocytes, and neutrophils. The airway mucosa exhibits tissue edema, increased microvascular permeability, retention of bronchial secretions, bronchial smooth muscle spasm, shedding of ciliated epithelium, exposure of the basement membrane, goblet cell hyperplasia, and increased bronchial secretions. These pathological changes are collectively referred to as chronic desquamative eosinophilic bronchitis. The aforementioned changes can vary depending on the severity of airway inflammation. If asthma recurs repeatedly over a long period, it may progress to an irreversible airway narrowing stage, characterized mainly by hypertrophy of the bronchial smooth muscle layer, airway remodeling due to subepithelial fibrosis, and loss of support from surrounding lung tissue.

In the early stages of the disease, due to the reversibility of the pathology, organic changes are rarely found anatomically. As the disease progresses, pathological changes become more pronounced. Macroscopically, lung hyperinflation and emphysema are prominent, with the lungs appearing soft, loose, and elastic. The bronchi and bronchioles contain viscous sputum and mucus plugs. The bronchial walls thicken, and the congested and swollen mucosa forms folds. Localized atelectasis may be observed in areas with mucus plugs.

bubble_chart Clinical Manifestations

Typical bronchial asthma is often preceded by prodromal symptoms such as sneezing, runny nose, cough, and chest tightness. If not managed in time, it may worsen due to increased bronchial obstruction, leading to an asthma attack. In severe cases, patients may be forced into a sitting position or exhibit orthopnea, with dry cough or expectoration of large amounts of white frothy sputum, and even cyanosis. However, symptoms usually resolve on their own or after treatment with anti-asthmatic medications. Some patients may experience another attack hours after relief, or even develop status asthmaticus.

Additionally, there are clinically atypical manifestations of asthma, such as cough-variant asthma. Patients may experience unexplained cough lasting more than two months, often occurring at night or in the early morning, and worsening with exercise or cold air. Airway hyperresponsiveness is detected, and treatment with antibiotics, antitussives, or expectorants is ineffective. Bronchodilators or corticosteroids are effective, but other causes of cough must be ruled out.

bubble_chart Diagnosis

(I) Diagnostic Criteria

1. Recurrent episodes of wheezing, dyspnea, chest tightness, or cough, often related to exposure to allergens, viral infections, exercise, or certain irritants.

2. During episodes, scattered or diffuse wheezing sounds, predominantly during expiration, can be heard in both lungs.

3. The above symptoms can be relieved with treatment or resolve spontaneously.

4. Other diseases that may cause wheezing or dyspnea must be excluded.

5. For atypical cases (e.g., without obvious wheezing or signs), at least one of the following tests must be positive: ① If baseline FEV₁ (or PEF) is <80% of the normal value, FEV₁ (or PEF) increases by ≥15% after inhaling β₂ agonists. ② PEF variability (measured with a peak flow meter, once in the morning and once at night) ≥20%. ③ Positive bronchial provocation test (or exercise provocation test).

(II) Classification Based on the characteristics of medical history, symptoms, signs, and laboratory test results, asthma is clinically divided into extrinsic asthma and intrinsic asthma (Table 1).

Table 1 Differences Between Extrinsic and Intrinsic Asthma

		Extrinsic	Intrinsic
Medical History	Family and personal allergy history	Common	Rare
	Age of Onset	Childhood or adolescence	More common after middle age
	Seasonality	Marked seasonality, frequent in spring and autumn	Can occur year-round
	Prodromal Symptoms	Nasal and eye itching, sneezing, clear nasal discharge	Cough is more common
	Onset	Rapid	Gradual
	Frequency of Attacks	Intermittent	More frequent
	Status Asthmaticus	Rare	Common
	Aspirin-Induced Asthma	Rare	More common
	Efficacy of Sodium Cromoglycate and Ketotifen	Better	Poorer
Physical Examination	General Condition	Better	Poorer
	Nasopharynx	Pale mucous membranes, edema	Dark mucous membranes, congestion
	Wheezing Sounds	Absent during remission	Often present
	lung qi swelling sign	Often absent	More common
	nasal polyp	Often absent	More common
Laboratory tests	Allergen skin test	Positive	Negative
	Serum total IgE	Increased in more than half	Mostly normal
	Eosinophils	Increased	Normal or slightly increased
	Sputum	Contains many eosinophils	Contains many neutrophils

（III）Severity grade III classification (Table 2).

Table 2 Severity grade III classification

Asthma severity grade III	Clinical manifestations before treatment	Lung function	Treatment required to control symptoms
Grade I	• Intermittent, brief attacks, 1-2 times per week	• EFV1(or PEF) 80% of predicted value	• Only intermittent inhalation (or oral)
	• Nocturnal attacks ≤2 times per month	• PEF variability ≤20%	β-agonists or theophylline
	• No symptoms between attacks	• After bronchodilator use, EFV1(or PEF) within normal range
Grade II	• Asthma attacks >2 times per week	• EFV1(or PEF) 60-80% of predicted value	• Frequent need for bronchodilators
	• Nocturnal asthma attacks >2 times per month	• PEF variability between 20-30%	• Daily inhaled corticosteroids required
	• Almost every attack requires inhaled β2agonists	• After treatment, EFV1(or PEF) can recover
Grade III	• Frequent asthma attacks	• EFV1(or PEF) <60% of predicted value	• Daily bronchodilators required
	• Activity limitation	﹒PEF variation rate >30%	. Requires daily inhalation of high-dose corticosteroids
	. Recent life-threatening severe attack	. Despite aggressive treatment, FEV1 (or PEF) remains below normal	. Frequent systemic use of glucocorticoids

bubble_chart Treatment Measures

In recent years, with in-depth research into the disease causes and pathogenesis of bronchial asthma, it has been recognized that asthma is a chronic airway inflammation characterized by airway hyperresponsiveness. Consequently, new concepts have emerged in the prevention and treatment of asthma, suggesting that relying solely on bronchodilators for treatment is insufficient. For moderate to severe (grade III) asthma, regular use of bronchodilators (such as β₂ agonists) may even be harmful. Since β₂ agonists lack anti-inflammatory effects, symptomatic treatment alone may mask the progression of inflammation and exacerbate airway hyperresponsiveness. Therefore, anti-inflammatory medications must be used in combination. To evaluate treatment efficacy, assess disease severity, and determine treatment and management plans, it is essential to maintain patient diaries, adhere to home lung function (PEF) measurements, and monitor changes in airway reactivity. With consistent and rational systematic prevention and treatment, most asthma patients can achieve effective disease control, enabling them to lead normal lives, study, and work. Recurrent episodes are often caused by inadequate prevention and treatment, which can lead to irreversible lung function damage. Thus, in asthma management, it is crucial to prioritize patient education, control environmental triggers, monitor disease progression, and implement systematic and rational treatment.

(1) Patient Education: Foster ongoing collaboration among healthcare providers, patients, and their families to ensure patients have a correct understanding of the disease, build confidence, and actively cooperate with doctors. Patients should maintain diaries, monitor lung function at home, attend regular follow-ups, and stay informed about the latest diagnostic, preventive, and therapeutic methods for asthma.

(2) Controlling Environmental Triggers: Identify, manage, and avoid exposure to various allergens, occupational sensitizers, and other nonspecific irritants.

(3) Pharmacotherapy: Develop separate medication plans for long-term asthma management and acute attack stages. The primary goals of treatment are to suppress airway inflammation, reduce airway hyperresponsiveness, control symptoms, prevent asthma attacks, maintain normal lung function, and ensure normal activity levels, with a PEF diurnal variability of less than 20%. Drug therapy should be individualized and adjusted as needed, following a stepwise approach based on disease severity. The ultimate aim is to minimize or eliminate the need for bronchodilators such as β₂ agonists, methylxanthines, and anticholinergics. In terms of administration routes, inhalation therapy is superior to systemic injections or oral medications, as it delivers higher drug concentrations to the airways with lower doses and minimal systemic side effects. Current inhalation methods include metered-dose inhalers (MDIs), dry powder inhalers, and nebulized solutions. Nebulization is often used for acute severe asthma patients, as well as children under five and those with particularly severe attacks. For patients who struggle with MDIs, spacer devices can improve bronchodilator delivery, enhance clinical efficacy, and reduce potential adverse effects. Dry powder inhalers, when used with appropriate devices, are highly effective, simple to use, and easy to master.

1. Glucocorticoids Glucocorticoids are currently the most effective anti-inflammatory drugs for treating asthma, although their exact mechanism of action in asthma treatment is not fully understood. Their primary effects include: inhibiting the metabolism of arachidonic acid, reducing the synthesis of leukotrienes and prostaglandins; promoting vasoconstriction of small blood vessels, increasing endothelial tightness, and reducing vascular leakage; inhibiting the directional movement of inflammatory cells; activating and enhancing the responsiveness of β-receptors in airway smooth muscle; preventing cytokine production; inhibiting histidine decarboxylase, thereby reducing histamine formation; increasing the number of PGE receptors; inhibiting the synthesis of acidic mucopolysaccharides in bronchial glands; and reducing the release of plasminogen activators as well as the secretion of elastase and collagenase. Glucocorticoids can be administered systemically or via inhalation. In the early stages of acute severe asthma attacks, oral glucocorticoids can prevent worsening of the attack; in cases of status asthmaticus, high-dose glucocorticoids are required for short-term systemic administration. Long-term low-dose or short-term high-dose inhaled glucocorticoids are safe and effective for the long-term treatment of asthma. Long-term high-dose inhaled glucocorticoids are useful for treating chronic severe asthma, as they reduce the need for long-term oral glucocorticoids and significantly minimize systemic side effects. Studies suggest that inhaling more than 1 mg of beclomethasone dipropionate (BDP) or an equivalent hormone per day may lead to systemic adverse reactions. Local side effects of inhaled glucocorticoids include oropharyngeal candidiasis, dysphonia, and occasional upper respiratory tract irritation cough. However, using a spacer with an MDI or switching to a dry powder inhaler can prevent or mitigate these side effects. Rinsing the mouth after inhalation can prevent oral candidiasis. Currently available MDIs and dry powder inhalers contain glucocorticoids such as beclomethasone dipropionate (BDP) and budesonide. The usual adult dose ranges from 400 to 800 µg/d.

2. Sodium cromoglicate is a non-hormonal, inhaled anti-inflammatory drug used to treat asthma. Its exact mechanism of action is not fully understood, but it is known to inhibit IgE-mediated release from some human mast cells in a dose-dependent manner. It has cell-selective and mediator-selective inhibitory effects on inflammatory cells such as alveolar macrophages, eosinophils, neutrophils, and monocytes. It also reduces the excitability of respiratory terminal receptors or inhibits the afferent limb of the vagal reflex arc, providing preventive effects for both IAR and LAR. Inhaling sodium cromoglicate can reduce or eliminate the need for glucocorticoids in patients. To prevent seasonal asthma attacks, preventive treatment should be initiated before the high-risk season, with 20mg inhaled 3–4 times daily. Discontinuation should not be too early; if no improvement is observed after 4–6 weeks of treatment, the medication can be stopped.

3. β₂-agonists relax bronchial smooth muscles, enhance mucociliary clearance, reduce vascular permeability, and modulate mediator release from mast cells and basophils. These drugs are highly effective for treating IAR but ineffective for LAR. Short-acting inhaled β₂-agonists are the first-line treatment for acute asthma attacks and for preventing exercise-induced asthma. The newer long-acting inhaled β₂-agonists, formoterol and salmeterol, can inhibit antigen-induced early- and late-phase reactions as well as histamine-induced airway hyperresponsiveness, but they do not reduce inflammatory cell responses in blood and sputum. Long-term, regular use of β-agonists can lead to β₂ receptor desensitization and downregulation, increasing the frequency of asthma attacks. Therefore, it is now recommended not to use β₂-agonists long-term or regularly. For patients requiring long-term use, combination therapy with glucocorticoids, nedocromil sodium, or ipratropium bromide is advised to prevent β₂ receptor desensitization and downregulation. Slow-release and controlled-release oral formulations of β₂-agonists significantly prolong the duration of action and maintain effective blood concentrations, making them suitable for patients with nocturnal asthma.

4. Xanthine derivatives: The bronchodilatory effect of aminophylline has been confirmed by over half a century of clinical practice, and understanding of its mechanism continues to evolve. Traditionally, theophylline was thought to act by inhibiting phosphodiesterase (PDE), reducing cAMP hydrolysis. However, it has been shown that the concentration of theophylline required to inhibit PDE in vitro far exceeds effective plasma theophylline levels, making this mechanism insufficient to fully explain its effects. Studies indicate that theophylline stabilizes and inhibits mast cells, basophils, neutrophils, and macrophages; antagonizes adenosine-induced bronchospasm; stimulates the adrenal medulla and extra-adrenal chromaffin cells to release catecholamines; and enhances the contractile response of fatigued or healthy diaphragms to low-frequency stimulation. Increasing evidence suggests that theophylline not only dilates bronchi but also has anti-inflammatory and immunomodulatory effects. It has been found that significant anti-asthma effects can occur even when plasma theophylline levels are below those required for bronchodilation. Therefore, the recommended therapeutic plasma concentration for asthma is 5–10 mg/L, rather than 10–20 mg/L, significantly reducing side effects. Some researchers suggest that oral theophylline should be initiated early in asthma treatment, combined with low-dose inhaled glucocorticoids, as a fundamental therapeutic regimen. Currently, slow-release or controlled-release theophylline formulations are available domestically, requiring only 1–2 daily doses to maintain stable plasma concentrations of 5–10 mg/L.

5. Anticholinergic drugs　Inhaled anticholinergic drugs (ipratropium bromide) can block the postganglionic vagal pathways, reduce vagal tone in the airways, and dilate the bronchi. They can also block reflex bronchoconstriction caused by inhaled irritants. Although the onset of action is slow with inhaled therapy, the effect is relatively long-lasting, and no medicinal property of tolerance has been observed with long-term administration. When combined with inhaled β₂ agonists, the clinical efficacy can be enhanced. The usual dosage is 20–80 µg per inhalation, 3–4 times daily.

(4) Stepwise management of asthma (see Table 3).

Table 3 Long-term management of asthma: stepwise approach to asthma therapy

Outcome: Controlled asthma • Minimal (ideally none) chronic symptoms, including nocturnal symptoms • Minimal (infrequent) exacerbations • No emergency visits • Minimal need for as-needed β 2 -agonist • No limitations on daily activities, including exercise; PEF diurnal variation <20% • (Near) normal PEF values • Minimal (or no) medication side effects

Outcome: Best possible outcomes • Minimal symptoms • Minimal use of as-needed β 2 -agonist • Minimal activity limitations • Minimal PEF diurnal variation • Optimal PEF values • Minimal medication side effects

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Treatment + • As-needed inhaled short-acting β 2 -agonist, no more than 3 times/week • Inhaled short-acting β 2 -agonist or cromolyn before exercise or allergen exposure	Treatment + • Daily anti-inflammatory medication △ Start with inhaled corticosteroids 200–500 µg or cromolyn or nedocromil (children may start with cromolyn) △ Increase inhaled steroids to 400–750 µg if needed (or, especially for nocturnal symptoms, step up to level 3 and add long-acting bronchodilators) • As-needed inhaled short-acting β 2 -agonist, no more than 3–4 times/day	Treatment + • Inhaled corticosteroids 800–1000 µg/day (>1000 µg should be used under specialist supervision) and • Sustained-release theophylline, oral β 2 -agonist, or inhaled long-acting β 2 -agonist; for nocturnal symptoms, consider adding anticholinergics and • As-needed inhaled short-acting β 2 -agonist, no more than 3–4 times/day	Treatment + ﹒Inhaled corticosteroids 800–1000 µg/d (>1000 µg should be used under expert supervision) ﹒Sustained-release theophylline and/or oral β2 agonists, or inhaled long-acting β2 agonists, especially for those with nocturnal symptoms, with or without: ﹒Inhaled short-acting β2 agonists once daily, or consider inhaled anticholinergics and ﹒Oral corticosteroids (taken every other day or once daily) and ﹒As-needed inhaled short-acting β2 agonists, not exceeding 3–4 times/d	Step Down ﹒When control is achieved and maintained at any step, cautious step-down therapy may be considered to determine the minimal medication required to maintain asthma control. ﹒Educate patients on symptoms of exacerbation and corresponding control measures
Clinical manifestations before treatment* ﹒Intermittent, brief symptoms <2 times/week ﹒Nocturnal asthma symptoms <2 times/month ﹒No symptoms between attacks ﹒PEF or FEV1>80% predicted value, variability <20%	Clinical manifestations before treatment* ﹒Attacks >2 times/week ﹒Attacks affect activity or sleep ﹒Nocturnal asthma symptoms >2 times/month ﹒Almost daily chronic symptoms requiring short-acting β2agonists ﹒PEF or FEV160-80% of predicted value, variability between 20-30%		Clinical symptoms before treatment* ﹒Frequent attacks ﹒Persistent symptoms ﹒Frequent nocturnal attacks ﹒Physical activity limitation ﹒PEF or FEV1 <60% predicted value, variability >30%
Grade 1: grade I	Grade 2: grade II	Grade 3: grade II-grade III	Grade 4: grade III

(5) Management of status asthmaticus　Status asthmaticus refers to acute severe asthma attacks that persist for more than 24 hours despite treatment with general antiasthmatic drugs, including intravenous aminophylline.

1. Fluid replacement　Administer isotonic intravenous fluids according to dehydration and cardiac status, 2000-3000ml/day, to correct dehydration and dilute sputum.

2. Corticosteroids　An important treatment measure to control and relieve severe asthma attacks. Commonly used methylprednisolone 40-120mg IV each time, repeatable after 6-8h.

3. Salbutamol (Ventolin) nebulization, IV or IM injection

(1) Nebulization: 1ml of 0.5% (W/V, 5mg/ml) salbutamol solution, diluted with appropriate normal saline for nebulization. May repeat every 2-6h as needed.

(2) Subcutaneous or IM salbutamol: 500µg/dose (8µg/kg body weight), repeatable every 4-6h.

(3) IV salbutamol 250µg/dose (4µg/kg body weight), inject slowly (over about 10min), repeat as necessary.

4. Ipratropium bromide solution nebulization

5. Aminophylline IV infusion and injection　Measure or estimate plasma theophylline concentration. If <5mg/L, give loading dose (5mg/kg body weight) diluted in 20-40ml 5% glucose solution, inject slowly over >15min. If plasma theophylline is 10-15mg/L, give maintenance infusion at 0.7mg/kg/h, monitor plasma levels and adjust dosage accordingly.

6. Oxygen Therapy　Generally, the inhaled oxygen concentration is 25-40%, and attention should be paid to dampness transformation. If the patient has significant hypoxemia and PaCO₂ <4.66 kPa (35 mmHg), oxygen can be administered via a mask. When the inhaled oxygen concentration exceeds 50%, the inhaled oxygen concentration and the duration of high-concentration oxygen therapy should be strictly controlled to maintain PaO₂ >6.65 kPa (50 mmHg), while preventing oxygen toxicity.

7. Correcting acidosis Due to hypoxia, insufficient fluid replacement, etc., metabolic acidosis may occur. Intravenous infusion of 5% sodium bicarbonate is commonly used, with the dosage calculated as follows:

Required milliliters of 5% sodium bicarbonate = [Normal BE (mmol/L) - Measured BE (mmol/L)] × Body weight (kg) × 0.4

In the formula, the normal BE is generally calculated as -3mmol/L.

8. Maintain electrolyte balance If salbutamol is administered, some patients may develop hypokalemia, and potassium supplementation should be considered as needed.

9. Correcting carbon dioxide retention The presence of carbon dioxide retention indicates a critical condition, suggesting respiratory muscle fatigue. Attention should also be paid to complications such as atelectasis, pneumothorax, or mediastinal emphysema. If pneumothorax occurs, immediate air extraction and water-seal bottle drainage are required. Nasotracheal intubation, tracheostomy, and mechanical ventilation may be necessary when indicated.

bubble_chart Differentiation

Bronchial asthma should be differentiated from wheezing bronchitis, cardiac asthma caused by left heart failure, dyspnea due to airway obstruction caused by large airway tumors, pulmonary eosinophilic infiltration, and wheezing caused by bronchiolitis in children.