Bronchial asthma, also known as asthma, is a heterogeneous disease characterized by chronic airway inflammation and airway hyperresponsiveness. Clinical manifestations include recurrent wheezing, tachypnea, chest tightness, and cough, occurrence and exacerbation at night and early morning, and variable expiratory airflow limitation. The respiratory tract symptoms can change over time and the severity is variable.

Etiology

Asthma is a complex disease with genetic predisposition, and presents familial aggregation. The incidence is directly proportional to kinship. In recent years, the development of genome-wide association studies (GWAS) has brought revolutionary breakthroughs to the research of susceptibility genes for asthma. Currently, GWAS has identified several susceptibility genes for asthma, such as TSLP, ORMDL3, GSDMB, HLA-DQ, and IL-33. Populations with asthma susceptibility genes are greatly affected by environmental factors. In-depth research on gene-environment interaction will help reveal the genetic mechanism of asthma.

Environmental factors include allergenic factors, such as indoor allergens (dust mites, domestic pets, cockroaches), outdoor allergens (pollen, grass powder), occupational allergens (paint, reactive dyes), foods (fishes, shrimps, eggs, milk), drugs (aspirin, antibiotics), and non-allergenic factors, such as air pollution, cigarette smoking, exercise, obesity, anxiety, and psychological stress.

Asthma caused by certain drugs is termed drug-induced asthma (DIA). Common drugs include non-steroidal anti-inflammatory drugs (NSAIDs), antihypertensives, β-receptor blockers, anticholinergics, antibiotics, and certain biologics. Acute asthma can occur few minutes or hours after administration of aspirin in asthma patients. This is an intolerance to NSAIDs represented by aspirin, termed aspirin-induced asthma (AIA). During pregnancy, particularly in the late stage of pregnancy, aspirin can increase the risk of asthma in children during childhood.

Pathogenesis

The pathogenesis of asthma has not been fully elucidated, mainly airway inflammation, airway hyperresponsiveness, and neural regulation.

Airway inflammation

Chronic airway inflammatory response is the result of the joint participation and interaction of various inflammatory cells, airway structural cells, inflammatory mediators, and cytokines. Under the stimulation of allergens, pollutants, or microorganisms, airway epithelial cells release cytokines such as interleukin (IL) including IL-33 and IL-25 and thymic stromal lymphopoietin (TSLP), activating type II helper T cells (Th2) and type II innate lymphoid cells (ILC2). The activated Th2 and ILC2 produce interleukins (IL) such as IL-4, IL-5, and IL-13 to activate B lymphocytes and synthesize specific IgE, which binds to the IgE receptors on the surface of mast cells and basophils. The reentered allergen can cross-link with the IgE bound to the cell surface, activating mast cells and basophils to synthesize and release various active mediators, leading to airway smooth muscle contraction, increased mucus secretion, and inflammatory cell infiltration, thereby resulting in clinical symptoms of asthma, which is a typical allergic reaction process. Cytokines such as IL secreted by activated Th2 and ILC2 can directly activate mast cells, eosinophils, and macrophages, causing their accumulation in the airway. These cells further secrete various inflammatory mediators such as histamine, leukotrienes, prostaglandins, and eosinophil cytokines, forming a complex network of interactions in various inflammatory cells, airway structural cells, and inflammatory mediators, thereby leading to chronic airway inflammation. It is believed that eosinophils not only play a role of terminal effector cells in the pathogenesis of asthma, but also have an immunomodulatory effect. Th17 cells play an important role in the pathogenesis of hormone-resistant asthma and severe asthma mainly infiltrated by neutrophils.

Airway hyperresponsiveness

Airway hyperresponsiveness (AHR) is a state of high sensitivity of the airway to various stimuli such as allergens, physical and chemical factors, exercise, and drugs, which is manifested by too strong or premature contraction of the airway when exposed to these stimuli. AHR is a basic feature of asthma and can be quantified and evaluated by bronchial provocation test. Almost all symptomatic asthma patients have AHR. When the airway is stimulated by allergens or other stimuli, various inflammatory cells release inflammatory mediators and cytokines, causing damage to the airway epithelium and exposure of subepithelial nerve endings, jointly leading to chronic airway inflammation, which is one of the important mechanisms of AHR. Individuals with long-term asymptomatic airway hyperresponsiveness have a significantly increased risk of developing typical asthma symptoms. However, not all individuals with AHR have asthma. For example, mild AHR occurs in individuals with long-term cigarette smoking, exposure to ozone, viral upper respiratory tract infection, or chronic obstructive pulmonary disease.

Neural regulation

Neural factors are one of the important links in the onset of asthma. The bronchi are innervated by complex autonomic nerves，including adrenergic nerves, cholinergic nerves, and non-adrenergic non-cholinergic (NANC) nervous system. In asthma patients, due to hypofunction of β-adrenergic receptors, significantly increased airway responsiveness to inhaled histamine and methacholine suggests an increase in cholinergic nerve tension. The NANC nervous system can release neurotransmitters that relax bronchial smooth muscles, such as vasoactive intestinal peptide and nitric oxide, and mediators that contract bronchial smooth muscles, such as substance P and neurokinin; and their imbalance can cause bronchial smooth muscle contraction. In addition, substance P, calcitonin gene-related peptide, and neurokinin A released from sensory nerve endings lead to vasodilation, increased vascular permeability, and inflammatory exudation, which is neurogenic inflammation. Neurogenic inflammation can cause asthma attacks by releasing sensory neuropeptides through local axon reflexes.

Pathology

Chronic airway inflammation, as a basic feature of asthma, exists in all asthma patients, manifested by the infiltration of mast cells, eosinophils, macrophages, lymphocytes, and neutrophils under the airway epithelium, as well as tissue edema, increased microvascular permeability, bronchial smooth muscle spasm, shedding of ciliated epithelial cells, goblet cell proliferation, and increased airway secretions under the airway mucous embrane. If asthma relapses chronically and frequently, manifestations of airway remodeling such as bronchial smooth muscle hypertrophy and hyperplasia, mucous metaplasia of airway epithelial cells, subepithelial collagen deposition and fibrosis, vascular hyperplasia, and basement membrane thickening can be seen.

Clinical manifestations

Typical symptoms are paroxysmal expiratory dyspnea, with wheezing, with or without tachypnea, chest tightness, and cough. Symptoms may occur within minutes and last for hours to days, and may be relieved spontaneously or after treatment with antiasthmatics. Asthma symptoms can change over time and the severity can vary, and attacks or exacerbations at night and in the early morning are important clinical feature of asthma. Some patients, particularly adolescents, have asthma symptoms during exercise, which is termed exercise-induced asthma.

Atypical asthma includes cough variant asthma, chest tightness variant asthma asthma in pregnancy, and aspirin-induced asthma.

Cough variant asthma (CVA) is an atypical asthma with chronic cough as the only or main clinical manifestation, without obvious wheezing and tachypnea, but with airway hyperresponsiveness. CVA is a common etiology of chronic cough in adults. The main manifestation is irritating dry cough, usually severe. Nocturnal cough is an important feature. Seasonality may be present in some patients. Severe cough may be accompanied by respiratory disturbance, chest tightness, and dyspnea. Allergic rhinitis is often accompanied. Common cold, odors, oil fumes, and cold exposure can easily induce or aggravate cough, but this clinical feature has no diagnostic value.

Chest tightness variant asthma (CTVA) is more common in young and middle-aged individuals, with an insidious onset. Chest tightness can be induced after physical activities. Some patients have more frequent attacks at night, without typical asthma manifestations such as recurrent wheezing and tachypnea, but often with anxiety. There is no wheezing in the lungs on auscultation. Pathophysiological characteristics of typical asthma such as airway hyperresponsiveness and reversible airflow limitation are present, and ICS or ICS+LABA treatment is effective.

Approximately 4% - 8% of pregnant women suffer from asthma, and 1/3 of asthma patients have exacerbation due to pregnancy, mostly in the 24th to 36th week of pregnancy. Weight gain of more than 5 kg in the first trimester of pregnancy is positively correlated with the risk of acute asthma exacerbation, and the risk will increase further with weight gain. Asthma in pregnancy affects not only pregnant women but also fetuses. Uncontrolled asthma can cause eclampsia or pregnancy-induced hypertension in pregnant women, and can also increase perinatal mortality, preterm birth rate, and incidence of low-birth-weight infants.

Nearly 40% of aspirin induced asthma (AIA) patients have chronic rhinitis, nasal polyps, paranasal sinusitis, and dysosmia. Severe asthma occurs 10 - 120 minutes after administration of NSAIDs such as aspirin, with cyanosis, conjunctival congestion, hyperhidrosis, orthopnea, dysphoria, and cough.

Widespread wheezing in both lungs and prolonged expiratory sounds can be heard. However, severe asthma is with weakened or absent wheezing, which is termed silent lung and is a manifestation of critical illness. There are no abnormalities in physical examinations during non-attack periods. Therefore, asthma cannot be ruled out if wheezing is absent.

Laboratory and auxiliary examinations

Sputum eosinophil count

The eosinophil count in the induced sputum of most asthma patients is increased (> 2.5%) and is associated with asthma symptoms. The eosinophil count in induced sputum can be used as one of indicators for evaluating asthma airway inflammation and is also a sensitive indicator for assessing the responsiveness of glucocorticoid treatment.

Pulmonary function test

Ventilation function test

Asthma attack is manifested by obstructive ventilation dysfunction, normal or decreased forced vital capacity (FVC), decreased forced expiratory volume in one second (FEV₁), FEV₁/FVC, and peak expiratory flow (PEF); and increased residual volume and the ratio of residual volume to total lung volume. FEV₁/FVC < 70% or FEV₁ < 80% of the normal expected value is the most important indicator of airflow limitation. These ventilation function indicators can gradually recover in remission. In patients with protracted course and recurrences, their ventilation function can gradually decline.

Bronchial provocation test

Bronchial provocation test (BPT) is used to measure airway responsiveness. Common inhaled provocative agents are methacholine and histamine. Other provocative agents include allergens, adenosine monophosphate, mannitol, and hypertonic saline. Physical provocative factors such as exercise and cold air are also used. The indicators include FEV₁ and PEF. The result is related to the provocative agent used, and is usually indicated by the cumulative dose (PD20 - FEV₁) or concentration (PC20 - FEV₁) of inhaled methacholine or histamine required to reduce FEV₁ by 20%. If FEV₁ decreases ≥ 20%, the result is positive, indicating the presence of airway hyperresponsiveness. BPT is appropriate for the examination in patients without asthma attack but with FEV₁ ＞ 70% of the normal predicted value.

Bronchial dilation test

Bronchial dilation test (BDT) is used to measure the reversible changes of the airway. Common inhaled bronchodilators include salbutamol and terbutaline. When the lung function is retested 20 minutes after inhalation of bronchodilator, compared with those before medication, if FEV₁ increases by > 12% and its absolute value increases by > 200ml, the result is positive, indicating the presence of reversible airway obstruction.

Peak expiratory flow

Peak expiratory flow (PEF) declines during asthma attacks. Due to temporal variability in asthma, monitoring of the daily and weekly variation of PEF is helpful for the diagnosis and assessment of asthma. The average daily diurnal PEF variability (the sum of the daily diurnal PEF variability for 7 consecutive days / 7) > 10%, or the weekly PEF variability { (highest PEF value - lowest PEF value, within 2 weeks)/[ (highest PEF value + lowest PEF value, within 2 weeks) x l/2] x 100% } > 20%, indicates the presence of reversible changes in the airway.

Chest x-ray and CT

During asthma attack, chest x-ray may show increased lucency, suggesting hyperventilation. There are usually no obvious abnormalities in remission. Chest CT can reveal thickening of the bronchial wall and mucus obstruction in some patients.

Specific allergen detection

The elevation of allergen-specific IgE in the peripheral blood in combination with medical history is helpful for etiological diagnosis. Total serum IgE has little diagnostic value for asthma, but the degree of elevation can be used as a basis for the use of anti-IgE antibody treatment and dose adjustment for severe asthma. In vivo allergen tests include skin allergen test and inhaled allergen test.

Arterial blood gas analysis

Hypoxia may occur during severe asthma attacks. Hyperventilation can decrease PaCO₂ and increase pH, presenting respiratory alkalosis. If the condition deteriorates further, both hypoxia and CO₂ retention may occur simultaneously, presenting respiratory acidosis. When PaCO₂ increases, even within the normal range, the occurrence of severe airway obstruction should be alerted.

Fractional exhaled nitric oxide

The measurement of fractional exhaled nitric oxide (FeNO) can be used as an indicator to evaluate airway inflammation and asthma control level, and can also be used to judge the response to inhaled hormone therapy.

Diagnosis

Clinical manifestations of typical asthma include:

Recurrent wheezing and tachypnea, chest tightness, and cough, mostly at night and in the morning, often associated with exposures to allergens, cold air, physical and chemical stimulation, as well as upper respiratory tract infection and exercise
During attacks and in some uncontrolled persistent asthma, scattered or diffuse wheezing heard in both lungs, and prolonged expiratory phase
These symptoms and signs relieved after treatment or spontaneously

Examinations of variable airflow limitation include:

Positive bronchial dilation test
Positive bronchial provocation test
Average daily diurnal PEF variability > 10%, or the weekly PEF variability > 20%

If all clinical manifestations and at least one of examinations are present, and other diseases that can cause wheezing, tachypnea, chest tightness, and cough are excluded, asthma can be diagnosed.

If cough is the only or main symptom, without typical asthma symptoms such as wheezing and tachypnea, at least one of the examinations is present, other diseases that can cause cough are excluded, and asthma treatment is effective, CVA cam be diagnosed.

If chest tightness is the only or main symptom, without typical asthma symptoms such as wheezing and tachypnea, at least one of the examinations is present, and other diseases that cause chest tightness are excluded, CTVA can be diagnosed.

AIA is mostly diagnosed based on the history of acute asthma attacks caused by administration of aspirin and other cyclooxygenase inhibitors

Classification of asthma severity

Asthma can be divided into acute asthma exacerbation, persistent asthma, and clinically controlled asthma.

Acute asthma exacerbation

Acute asthma exacerbation is a sudden onset or exacerbation of symptoms such as wheezing, tachypnea, chest tightness, and cough, accompanied by decreased expiratory flow, and is often caused by exposure to allergens and other irritants or improper treatment. Exacerbation can occur within hours or days, and occasionally may be life-threatening within minutes, so the condition should be correctly assessed and treated promptly.

Acute asthma exacerbation can be divided into mild asthma, moderate asthma, severe asthma, and critical asthma.

Mild asthma presents with tachypnea when walking or going upstairs, with or without anxiety. Scattered wheezing can be heard, and normal pulmonary ventilation function and blood gas test are present.

Moderate asthma is manifested by tachypnea after physical activity, often interrupted speech, anxiety, three concave signs, loud and diffuse wheezing, tachycardia, and paradoxical pulse. PEF is 60% - 80% of the expected value, and SaO₂ is 91%-95% after inhalation of bronchodilators

Severe asthma is characterized by tachypnea at rest, orthopnea, only one word in speech, anxiety, irritability, hyperhidrosis, three concave signs, loud and diffuse wheezing, tachycardia (often>120 times/min), and paradoxical pulse. PEF < 60% of the predicted value, absolute value < 100L/min, or action time < 2 hours; PaO₂ < 60mmHg, PaCO₂ > 45mmHg, SaO₂ ≤ 90%, and normal or reduced pH after inhalation of bronchodilators are present

Critical asthma is manifested by speechlessness, drowsiness, confusion, thoracoabdominal paradoxical movement, weakened or absent wheezing, slowed or irregular pulse rate, severe hypoxemia and hypercapnia, and decreased pH.

Persistent asthma

Patients do not have acute attacks of asthma, but still have wheezing, cough, and chest tightness for long time, with or without decreased pulmonary ventilation function. According to the frequency of asthma attacks during the day and night and the results of lung function test, persistent asthma can be divided into intermittent asthma, mild persistent asthma, moderate persistent asthma, and severe persistent asthma. However, this classification is rarely used in daily work and is mainly used in clinical research. The most widely used method for assessing the severity of persistent asthma is the asthma control level, which includes current clinical control assessment and future risk assessment. According to clinical control level, asthma can be divided into well controlled asthma, partially controlled asthma, and uncontrolled asthma.

** Clinically controlled asthma**

Patients do not have wheezing, tachypnea, chest tightness, and cough for more than 4 weeks. There has been no acute exacerbation in the past year, and the lung function is normal.

Differential diagnosis

Dyspnea caused by left heart failure

Dyspnea caused by left heart failure and severe asthma have similar symptoms. This disease is characterized by hypertension, coronary atherosclerotic heart disease, rheumatic heart disease, sudden tachypnea, orthopnea, paroxysmal cough, often cough with pink foamy sputum, extensive moist crackles and wheezing in both lungs, enlarged left heart border, tachycardia, and gallop rhythm heard at the apex. Chest x-ray can show enlarged heart and pulmonary congestion. If it is still difficult to distinguish, nebulized β₂ receptor agonists or intravenous aminophylline can be used to relieve symptoms and further examination can be conducted. Epinephrine and morphine are contraindicated.

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is more common in middle-aged and older adults, and presents with a history of long-term cigarette smoking or exposure to harmful gases and a history of chronic cough, long time wheezing, and exacerbation. Physical examination reveals significantly reduced breath sound, signs of emphysema, and moist crackles heard in both lungs. In middle-aged and older patients, it is sometimes very difficult to distinguish between COPD and asthma. Bronchodilators and oral or inhaled hormones may be helpful. If patients have manifestations of both asthma and COPD, concurrent asthma and COPD can be diagnosed.

Upper airway obstruction

Airway diseases such as central bronchopulmonary carcinoma, tracheobronchial tuberculosis, and relapsing polychondritis or tracheobronchial foreign bodies lead to bronchial stenosis or concomitant infection, stridor or asthma-like dyspnea may occur, and wheezing may be heard in the lungs. However, based on the medical history, especially the occurrence of inspiratory dyspnea, sputum cytology or bacteriology, chest imaging, and bronchoscopy, a clear diagnosis can often be established.

Allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is often characterized by recurrent asthma attacks, and brown and sticky expectoration or dendritic bronchial casts. Chest CT can show cystic or cylindrical dilatation of proximal bronchi. Aspergillus antigen-specific IgE is positive, and total serum IgE is significantly elevated.

Complications

Severe asthma attacks may be complicated by pneumothorax, mediastinal emphysema, and atelectasis. Long-term recurrent attacks or infections may lead to chronic complications such as chronic obstructive pulmonary disease, bronchiectasis, and cor pulmonale.

Treatment

Medications for asthma treatment can be divided into controller medications and reliever medications, as well as additional medications for severe patients.

Controller medications, also known as anti-inflammatory agents, need to be used daily for a long time, and mainly maintain clinical control of asthma through anti-inflammatory effects, including inhaled corticosteroids (ICS), systemic hormones, leukotriene modifiers, long-acting inhale β₂ agonists (LABA), sustained-release theophylline, suplatast tosilate, and cromolyn sodium.

Reliever medications, also known as bronchodilators, are used on demand when symptoms occur, and improve asthma symptoms by quickly relieving bronchospasm, including rapid-acting inhaled and short-acting oral β₂ receptor agonists, inhaled anticholinergics, short-acting theophylline, and systemic hormones.

Additional medications for severe asthma are mainly biological targeted medications, such as anti-IgE monoclonal antibodies, anti-IL-5 monoclonal antibodies, anti-IL-5 receptor monoclonal antibodies, and anti-IL-4 receptor monoclonal antibodies, as well as macrolides.

Table 1 Medications for asthma treatment

Corticosteroids

Corticosteroids are the most effective drugs for controlling asthma airway inflammation. In persistent asthma patients, there are mainly inhaled and oral administrations, and inhaled administration is preferred.

ICS has a strong local anti-inflammatory effect, acting directly on the respiratory tract. The required dose is small, and there are few systemic adverse reactions. ICS can effectively control airway inflammation, reduce airway hyperresponsiveness, relieve asthma symptoms, improve lung function, improve quality of life, reduce the frequency and severity of asthma attacks, and reduce mortality. ICS + LABA combination preparations and ICS + formoterol combination preparations can significantly improve the treatment effect.

In patients who need to use high-dose ICS to control symptoms or prevent acute attacks, special attention should be paid to ICS-related adverse reactions. Local adverse reactions of ICS in the oropharynx include hoarseness, pharyngeal discomfort, and Candida infection. After inhalation, the oropharynx should be rinsed with clean water. Dry powder inhalers or spacers can reduce the adverse reactions. Systemic adverse reactions are related to factors such as dose, bioavailability, intestinal absorption, first-pass liver metabolism, and half-life of the systemically absorbed medications. Long-term inhalation of ICS within the clinically recommended dose range is safe for asthma patients, but long-term high-dose inhalation of hormones may also cause systemic adverse reactions, such as osteoporosis, adrenocortical axis suppression, and increased risk of pneumonia. The efficacy of inhaled drugs depends on the lung deposition rate, which is affected by many factors such as dosage form, administration devices, and inhalation technique. In general, the lung deposition rate from dry powder inhalers is higher than that from metered dose inhalers, and the deposition rates in bronchioles and alveoli from soft mist inhalers and ultrafine particle inhalers are higher than those from dry powder inhalers and metered dose inhalers.

In severe persistent asthma that cannot be controlled by high-dose ICS+LABA, low-dose oral corticosteroids (OCS) can be added for maintenance treatment. Generally, hormones with a short half-life, such as prednisone, are used, and the recommended dosing regimen is orally once a day or every other day to reduce the inhibitory effect of exogenous hormones on the hypothalamic-pituitary-adrenal axis. The daily maintenance dose of prednisone is preferably ≤ 10 mg. There is currently lack of clinical research evidence on the course of OCS maintenance therapy. Long-term use of OCS can cause osteoporosis, hypertension, diabetes, hypothalamic-pituitary-adrenal axis suppression, obesity, cataracts, glaucoma, thinned skin, and amyosthenia. In asthma patients with tuberculosis, diabetes, fungal infection, osteoporosis, glaucoma, severe depression, or peptic ulcer, systemic hormones should be administered with caution and close follow-up is required.

Β₂ receptor agonists

Β₂ receptor agonists can be short-acting, long-acting, and ultra-long-acting. Long-acting preparations can be divided into fast-acting LABAs such as formoterol, indacaterol, vilanterol and olodaterol; and slow-acting LABAs such as salmeterol. Short-acting inhaled β₂ agonists (SABA) include salbutamol and terbutaline.

Inhaled SABAs include aerosols, dry powders, and nebulized solutions. These medications can quickly relieve bronchospasm, usually take effect within minutes, and the efficacy can last for several hours. They are preferred for relieving acute symptoms of mild to moderate asthma and can also be used to prevent exercise-induced asthma. These medications should be used on demand and should not be used alone or excessively for a long time. Adverse reactions include amyostasia, hypokalemia, and cardiac arrhythmia. It is currently believed that SABA should be in combination with inhaled low-dose ICS.

Oral salbutamol, terbutaline, or procaterol usually takes effect 15 - 30 minutes after administration and the efficacy lasts for 4 - 8 hours. Although these medications are more convenient in use, adverse reactions such as palpitations and amyostasia are more obvious than those of inhaled medications. The antiasthmatic effect of sustained-release and controlled-release formulations can last for 8 - 12 hours. The prodrug of terbutaline, bambuterol, has efficacy lasting for 24 hours, can reduce the frequency of administration, and is appropriate for the treatment of patients with nocturnal asthma symptoms.

Although the antiasthmatic effect of injection is rapid, it is not recommended due to the high incidence of systemic adverse reactions.

The effect of LABA in relaxing bronchial smooth muscles can last for more than 12 hours. The inhaled LABAs in clinical practice mainly include salmeterol and formoterol, as well as ultra-long-acting indacaterol, vilanterol, and olodaterol, which can be administered through devices such as aerosol inhalers and dry powder inhalers. Formoterol takes effect the fastest and can also be used as reliever medication on demand. Long-term use of LABA alone increases the risk of asthma death. Therefore, long-term use of LABA alone is not recommended.

ICS + LABA combination preparations

ICS + LABA combination preparations have synergistic anti-inflammatory and antiasthmatic effects, can achieve an effect equivalent to or better than double-dose ICS, and can increase patient compliance and reduce the adverse reactions of high-dose ICS. It is particularly suitable for long-term treatment in patients with moderate to severe persistent asthma. Low-dose ICS + formoterol combination preparation can be used on demand and for the prevention of exercise-induced asthma. Common ICS+LABA combination preparations include fluticasone propionate-salmeterol dry powder, budesonide-formoterol dry powder, beclomethasone dipropionate-formoterol aerosol, and fluticasone furoate-vilanterol dry powder.

Leukotriene modifiers

Leukotriene modifiers, including leukotriene receptor antagonists (LTRA) and 5-lipoxygenase inhibitors, are long-term controller drugs that can be used alone besides ICS. They can be used as an alternative treatment for mild asthma and a combination medication for moderate to severe asthma. LTRA can relieve asthma symptoms, improve lung function, and reduce asthma exacerbation, but its anti-inflammatory effect is not as good as ICS. Oral LTRA is very convenient, and is suitable for the treatment of patients with allergic rhinitis, aspirin-induced asthma, and exercise-induced asthma. Attention should be paid to the adverse reactions of leukotriene receptor antagonists.

Theophylline

Theophylline has the effects of relaxing bronchial smooth muscles, strengthening the heart, diuresis, and exciting the respiratory center and respiratory muscles. Low concentrations of theophylline have certain anti-inflammatory effects. Low-dose theophylline in combination with hormones in the treatment of asthma has the same effect as high-dose hormone therapy, but its inhibitory effect on the hypothalamic -pituitary-adrenal axis is weaker than that of high-dose hormone therapy. In uncontrolled patients after inhalation of ICS or ICS+LABA, sustained-release theophylline can be added for maintenance treatment. The adverse reactions include nausea, emesis, arrhythmia, hypotension, and polyuria.

Anticholinergics

Inhaled anticholinergics, such as short-acting muscarinic antagonist (SAMA) ipratropium bromide and long-acting muscarinic antagonist (LAMA) tiotropium bromide, have certain bronchial dilation effects, but they are weaker than β₂ receptor agonists and have a slower onset of action. Anticholinergics can be administered through aerosol, dry powder, and nebulized solution. They have a complementary effect when in combination with β₂ receptor agonists. Nebulized inhalation of SAMA ipratropium bromide and SABA salbutamol combination preparations is common for the treatment of acute asthma attacks. In patients in the first trimester of pregnancy, with glaucoma, or with prostatic hypertrophy, these medications should be used with caution. ICS+LABA+LAMA triple combination preparations, such as fluticasone furoate-vilanterol-umeclidinium dry powder and budesonide-formoterol-glycopyrronium bromide aerosol, are very convenient for patients with severe asthma.

Suplatast tosilate

Suplatast tosilate is a selective Th2 cytokine inhibitor that can inhibit the production of IL-4, IL-5, and the synthesis of IgE, reduce eosinophil infiltration, and alleviate airway hyperresponsiveness. It is an oral preparation with good safety and is suitable for the treatment of patients with allergic asthma.

Biotargeted drugs

Biotargeted drugs for the treatment of asthma include anti-IgE monoclonal antibodies, anti-IL-5 monoclonal antibodies, anti-IL-5 receptor monoclonal antibodies, and anti-IL-4 receptor monoclonal antibodies. These drugs are mainly used to treat patients with severe asthma.

Allergen specific immune therapy (AIT)

Subcutaneous injection of extracts of common inhaled allergens can alleviate asthma symptoms and reduce airway hyperresponsiveness. It is suitable for asthma patients with clear allergens and poor control after strict environmental control and medication treatment. AIT has the risk of allergic reactions and should be performed under the guidance of physician. Sublingual administration is more convenient than subcutaneous injection and has a lower incidence of allergic reactions, but its long-term efficacy needs further verification.

Other medications

Second-generation antihistamines (H1 receptor antagonists) include loratadine, astemizole, azelastine, and terfenadine; and other oral antiallergics are tranilast and repirinast. Antihistamines have a weak effect on the treatment of asthma and are mainly used for asthma patients with allergic rhinitis. Long-term use of antihistamines is not recommended.

Treatment of acute asthma exacerbation

The treatment goal is to relieve airway spasm, correct hypoxemia, restore lung function, prevent further deterioration or recurrence, and prevent complications.

Mild asthma is treated by inhaled SABA through MDI once or twice every 20 minutes within the first hour, followed by once or twice every 3 - 4 hours. If the effect is not good, sustained-release theophylline tablets or short-acting anticholinergic aerosol inhalation can be added.

Moderate asthma is treated by continuous inhalation of SABA (usually nebulized) within the first hour. Combination of short-acting anticholinergics, hormone suspensions, and intravenous theophylline can also be used. If the treatment effect is poor and acute attacks occur after controller medication treatment, oral hormones should be given as soon as possible, and oxygen therapy should be used.

Severe and critical asthma is treated by continuous inhalation of SABA, in combination with nebulization of short-acting anticholinergics, hormone suspensions, intravenous theophylline, and oxygen therapy. Intravenous hormones can be switched to oral hormones after the condition is controlled and relieved. Attention should be paid to rehydration, electrolyte balance, and correction of acid-base imbalance. When pH < 7.20 plus metabolic acidosis, appropriate alkali supplementation should be given. After the above treatment, if clinical symptoms and lung function do not improve or even continue to deteriorate, mechanical ventilation treatment should be given. The main indications include respiratory muscle fatigue, PaCO₂ > 45mmHg, and changes in consciousness. In addition, respiratory tract infections should be prevented.

In patients with acute exacerbation, individualized long-term treatment plan should be formulated.

Treatment of persistent asthma

Stepwise treatment is used in persistent asthma.

Step 1 treatment

The treatment is only for patients with occasional, short, daytime symptoms (less than 2 times a month, each lasting for several hours), without nocturnal symptoms, without risk of acute exacerbation, and with normal lung function. Recommended treatment plan is low-dose ICS + formoterol inhalant on demand. Other treatment plans include inhaled low-dose ICS and inhaled SABA as needed. Inhaled anticholinergics such as ipratropium bromide, oral SABA, and short-acting theophylline are not recommended, because these drugs can relieve asthma symptoms, but they take effect slowly, and oral SABA and theophylline have adverse reactions. Rapid-acting LABA, such as formoterol, can relieve asthma symptoms as quickly as SABA. If the symptoms exceed the above level and there are any risk factors for acute exacerbation (such as FEV₁ < 80% predicted value or personal best value) or a history of acute exacerbation in the past year, controller drugs should be used regularly every day.

Step 2 treatment

Low-dose controller plus reliever drugs are used as needed. Recommended treatment plan is low-dose ICS plus relievers used as needed. Low-dose ICS + formoterol used as needed can be preferred, and patients with exercise-induced asthma can also use it before exercise. Other treatment option is LTRA for the initial treatment in patients who are unable or unwilling to receive ICS treatment, cannot tolerate the adverse reactions of ICS, or have allergic rhinitis, cough variant asthma, exercise-induced asthma, or aspirin-induced asthma; but the effect is weaker than that of ICS. Simple seasonal asthma, such as pollen allergy, can be treated using ICS from onset to 4 weeks after the end of pollen season.

Step 3 treatment

Recommended treatment plan is low-dose ICS + LABA combination preparations as maintenance treatment. Low-dose ICS + formoterol as needed or SABA as needed can be administered. Fluticasone furoate-vilanterol can be inhaled once a day. LABA in combination with ICS can more effectively control symptoms, improve lung function, and reduce the risk of acute exacerbation. Other treatment options are medium-dose ICS, or low-dose ICS in combination with LTRA or sustained-release theophylline or suplatast tosilate.

Step 4 treatment

Recommended treatment plan is medium-dose ICS + LABA for maintenance treatment. Other treatment option is high-dose ICS plus inhaled tiotropium bromide. In patients over age 6, high-dose ICS in combination with tiotropium bromide soft mist inhalation can improve lung function and prolong the time to next exacerbation in patients requiring oral hormone treatment. If medium-dose ICS + LABA cannot control the condition, the addition of other controller drugs, such as LTRA, sustained-release theophylline, and suplatast tosilate, should be considered. High-dose ICS + LABA has limited benefits but significantly increases adverse reactions.

Step 5 treatment

Additional medications should be considered. If patients are treated with step 4 therapy, have correct inhalation technique and good compliance, but still have persistent asthma symptoms or acute exacerbation, severe asthma should be treated.

The recommended treatment plan is high-dose ICS + LABA, with additional drugs.

Anticholinergics can further improve lung function and improve asthma control.

Anti-IgE monoclonal antibodies are recommended for severe allergic asthma that is still not controlled by step 4 treatment.

In patients who still have persistent symptoms and frequent acute exacerbation after using high-dose ICS or ICS + LABA, treatment can be adjusted based on induced sputum and peripheral blood eosinophil examination to determine whether asthma is caused by eosinophilia. Anti-IL-5 monoclonal antibodies, anti-IL-5 receptor monoclonal antibodies, or anti-IL-4 receptor monoclonal antibodies can be selected. This treatment regimen can reduce acute asthma exacerbation and reduce the dose of ICS.

Bronchial thermoplasty is a technique for treating asthma by radiofrequency ablation of airway smooth muscle in bronchoscopy, can reduce the number of bronchial smooth muscles in asthma patients, reduce bronchial contractility, and reduce airway hyperresponsiveness.

In patients who still have persistent asthma symptoms after medium-to-high dose ICS+LABA treatment, oral azithromycin can reduce acute asthma exacerbation and improve quality of life. Adverse reactions include diarrhea, prolonged QT interval, and hearing deterioration. Before starting treatment, it is necessary to perform sputum examination to exclude atypical tuberculosis infection.

Oral prednisone ≤ 10 mg/d or other equivalent doses is effective for some severe asthma, but sometimes adverse reactions occur. Osteoporosis prevention is required for patients who are expected to use it for more than 3 months.

Table 2 Stepwise treatment regimen

Step-up and step-down treatment

If asthma cannot be controlled, step-up treatment is required until asthma control is achieved. When asthma is under control and maintains for at least 3 months, and lung function is restored and maintained in a stable state, step-down treatment can be considered.

Immunotherapy

Allergen-specific immunotherapy is a treatment option in asthma where allergies play a major role. Currently, there are two methods consisting of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). In patients with asthma caused by indoor dust mite sensitization and concurrent allergic rhinitis, allergen-specific immunotherapy (AIT) can be added after asthma is well controlled.

Treatment of atypical asthma

The treatment plan for cough variant asthma, chest tightness variant asthma, and asthma during pregnancy are the same as that for typical asthma. Most patients can inhale low-dose ICS in combination with long-acting β₂ receptor agonists, leukotriene modifiers, or sustained-release theophylline. Short-term oral low-dose hormone can be administered if necessary. The course of treatment can be shorter than that of typical asthma.

The most effective way to prevent drug-induced asthma is to avoid the use of such drugs again. In patients with aspirin-induced asthma who need large doses of glucocorticoids to control asthma symptoms, or whose nasal inflammation and polyps are difficult to improve with conventional treatment, or who need to take aspirin for other diseases, desensitization treatment can be performed. Control of nasal diseases and LTRA treatment can help improve the symptoms of aspirin-induced asthma. When there is a clinical need of NSAIDs, it is recommended to use COX-2 inhibitors.

Treatment of severe asthma

Severe asthma refers to asthma requiring high-dose ICS in combination with LABA and/or LTRA/sustained-release theophylline, or systemic hormone therapy for more than 50% of the time in the past year to maintain asthma control, or asthma that cannot be controlled even with the above treatment. Treatment includes exclusion of poor treatment compliance, exclusion of factors inducing exacerbation, exclusion causing uncontrollability; high-dose ICS in combination with or without oral hormones, plus leukotriene modifiers and anti-IgE antibody; other optional treatments including immunosuppressants and bronchial thermoplasty.

Prognosis

After long-term proper treatment, the clinical control rate of asthma can reach 95% in children and 80% in adults. Asthma can be easily controlled in mild patients, but is difficultly controlled in severe patients with significantly increased airway responsiveness, airway remodeling, or other allergic diseases. If not treated promptly and properly, recurrent acute attacks can threaten life, complications may lead to lung dysfunction, and long-term use of high-dose drugs can produce adverse reactions.