Refractory asthma is asthma whose symptoms are difficult to control after treatment with large doses of glucocorticoids and short-acting β2 agonists, as recommended by conventional treatment (e.g., recognized global asthma control protocols). The pathogenesis is more complex than that of common asthma and has not been fully elucidated. The incidence of refractory asthma is generally reported to be in the range of 5% – 10%. This paper summarizes the new advances in the diagnosis and treatment of refractory asthma.
1.Definition and diagnosis of refractory asthma
The definition and diagnostic criteria of refractory asthma have not yet been fully unified, and the British Thoracic Society and the European Respiratory Society use the clinical response to hormone therapy as the main indicator to diagnose refractory asthma. These cases are referred to as refractory asthma. That is, refractoryasthma or recalcitrantasthma (RA) or difficulttocontro1asthma (DTCA). The American Thoracic Society (ATS) defines RA as a patient with asthma who has good compliance with treatment, has excluded wheezing caused by other diseases or has been treated for factors that cause asthma exacerbations, and still has the following characteristics
(1) Main characteristics.
(i) To achieve a mild to moderate level of asthma control.
(ii) The need for continuous application or near continuous application (more than half of the time in 1 year) of oral hormone therapy.
(3) The need to apply high-dose inhaled hormone therapy.
(2) Secondary characteristics.
(i) In addition to daily application of hormone therapy, long-acting β2 agonists (LABA), theophylline or leukotriene modulators need to be applied.
(ii) The need for almost daily inhalation of short-acting agonists (SABA) to relieve symptoms.
(iii) Exertional expiratory volume in one second (FEV1) 20%; >1 emergency room visit per year.
④ the need for treatment with oral hormones >3 times per year.
⑤ oral or inhaled hormone reduction ≤ 25% can cause worsening of asthma.
⑥Have had a near-death asthma attack.
The Global Initiative for Asthma (GINA) in 2006 considered RA for asthma that did not reach a manageable level of asthma after step 4 treatment (relieving medications such as short-acting beta2 agonists, 2 or more control medications such as inhaled hormones, anti-leukotrienes, etc.) and to exclude wheezing caused by non-bronchial asthma that including abnormal vocal cord function, occlusive fine bronchitis and COPD to be diagnosed. Diseases with certain asthma features such as allergic bronchopulmonary aspergillosis and allergic granulomatous vasculitis often affect the treatment of asthma, while specific types of asthma such as hormone-resistant asthma, anti-β2 receptor autoantibodies or β2 receptor downregulation asthma can also be important factors in the difficulty of asthma control. Therefore, when evaluating whether such patients are RA, the above-mentioned diseases should be excluded first.
2.Differential diagnosis of refractory asthma
Although wheezing is the main symptom of bronchial asthma, all patients with wheezing symptoms should not be treated as asthma patients. On the one hand, there are many diseases that manifest as airflow obstructive wheezing rather than asthma, and a study found that 12% of patients with refractory asthma seen in multiple treatment centers were not refractory asthmatics; some concomitant diseases and triggers often affect the treatment of asthma, while inappropriate treatment and specific types of asthma can also be important factors that make asthma difficult to control. Patients whose symptoms do not improve significantly despite regular and aggressive anti-asthma therapy should be distinguished from those with “asthma-like” symptoms caused by the following diseases.
2.1 Cardiogenic asthma
When this atypical cardiogenic asthma is suspected, the diagnosis should be further clarified by ECG, ambulatory ECG, 2D echocardiography and other auxiliary examinations in a timely manner, and low-dose digitalis or fast-acting diuretics may be given as appropriate. Cardiogenic asthma should be excluded first for RA in elderly patients.
2.2 Chronic obstructive pulmonary disease
(COPD) combined with tension pneumothorax is difficult to relieve the asthma symptoms in these patients despite the administration of various wheezing medications (including high-dose glucocorticoids and β2 agonists). The diagnosis can be made by raising the awareness of the disease, making a careful and detailed physical examination, and taking a timely chest X-ray. Intubation of the pleural cavity on the affected side and closed drainage can rapidly relieve the clinical symptoms. If the type and dose of asthma medication is increased, the condition is often delayed.
2.3 Airway or mediastinal tumor
The main points of differentiation between this disease and bronchial asthma are
(1) Patients mostly have no previous history of recurrent wheezing, with progressive worsening of asthma symptoms and no obvious remission period.
(2) It is more common in middle-aged and elderly patients.
(3) Mostly inspiratory dyspnea with obvious trigeminal signs and croup is mostly limited.
(4) It is often accompanied by irritating cough, wasting, chest pain, and persistent blood in the sputum.
(5) Asthma medication is often ineffective.
The possibility of endotracheal tumor should be considered if the following conditions occur.
(1) the appearance of wheezing without obvious causes.
(2) wheezing symptoms are related to body position.
③Sometimes accompanied by swallowing discomfort.
(iv) windchest-like breath sounds in the neck.
⑤ No obvious effect of antispasmodic drugs.
Timely chest x-ray can clarify the diagnosis.
2.4 Allergic bronchopulmonary aspergillosis
Allergic bronchopulmonary aspergillosis (allergicbronchopulmonaryaspergillosis, ABPA) was first reported by Hinson in 1952, the disease is caused by Aspergillus fumigatus in atopic organisms in a respiratory metaplasia. Asthma symptoms are the common clinical symptoms of ABPA patients, 1% – 2% of patients with bronchial asthma symptoms are ABPA patients, most of them have a long history of asthma.
(1) Positive IgG precipitating antibody to Aspergillus antigen in blood.
(2) Transient, wandering infiltrative shadow in the lungs.
(3) proximal bronchial dilatation.
(4) History of brown sputum embolism.
(5) repeated sputum culture or microscopic examination of Aspergillus fumigatus.
(6) Aspergillus antigen for skin test shows delayed metaplasia.
2.5 Granulomatous lung disease
Granulomatous lung diseases (GLD) are a group of granulomatous diseases involving the lungs, which may present with asthma-like symptoms and need to be differentiated from bronchial asthma.GLD include
(1) Nodular polyarteritis.
(2) Churg-Strauss syndrome: referred to as CSS, also known as allergic granulomatosis.
(3) allergic granulomatous vasculitis: a relatively rare form of systemic vasculitis, mainly invading small arteries and veins, often fine arteries, and can involve a variety of organs, characterized by pulmonary infiltrates and a marked increase in peripheral vascular eosinophils, with asthmatic symptoms in about 98% – 100% of patients.
(4) Bronchial centripetal granulomatosis, etc.
2.6 Recurrent polychondritis
This disease is caused by softening of the tracheal stent and abnormal widening of the posterior wall of the trachea, and the airway cannot maintain its original normal shape. The patient’s intrathoracic pressure rises during expiration and coughing, causing narrowing or occlusion of the airway, which is clinically manifested as expiratory wheezing. It is sometimes misdiagnosed as bronchial asthma, which can be differentiated by high-resolution CT.
2.7 Affective laryngeal wheeze
In affective laryngeal wheezing (emotionallaryngealwheezing), the onset of clinical wheezing symptoms in patients are all related to psychiatric factors without the pathophysiological features of bronchial asthma: such as increased alveolar air-arterial partial pressure of oxygen difference (A-aDO), hyperinflation sign on chest X-ray, abnormal small airway function, and increased airway reactivity. All of these patients have the loudest stridor in the neck.
2.8 Vocal fold dysfunction
VCD is an incomplete vocal fold closure (especially during inspiration) due to laryngeal airway obstruction caused by constriction within the upper 2/3 of the vocal folds is often misdiagnosed as bronchial asthma. In the United States, 25% to 30% of “severe asthma” at the National Jewish Hospital is finally diagnosed as vocal cord insufficiency. The flatness of the inspiratory branches in the flow volume loop is characteristic of this disease, and fiberoptic laryngoscopy is also helpful in the diagnosis of this disease.
Therefore, when dealing with so-called “RA”, clinicians should first clarify whether the patient is suffering from bronchial asthma, rather than just increasing the type and dose of asthma medication. For “asthma” symptoms that are confirmed to be caused by the above non-bronchial asthma, they should be treated separately according to the specific conditions.
3.Epidemiology and pathogenesis of refractory asthma
Due to different research methods, the prevalence of refractory asthma varies widely among countries and regions. ENFUMOSA reported that most patients with refractory asthma have a male to female ratio of 1:4, while WenzelSE et al. reported that there is no significant difference with gender.
At present, the pathogenesis and pathological changes of refractory asthma have not been fully elucidated, and the author believes that the pathogenesis of refractory asthma is an intricate network of many interrelated factors. There are still many doubts to be confirmed.
4.Treatment of asthma
4.1 β2 agonists
β2 agonists mainly act on the β2 receptors of the smooth muscle of the airways, activating adenylate cyclase and relaxing bronchial smooth muscle, so they are the first choice for controlling asthma attacks. β2 agonists are divided into two types: short-acting (action maintained for 4–6h) and long-acting (action maintained for 12h). Salbutamol, fenoterol, levosalbutamol, terbutaline, etc. Salbutamol aerosol inhalation, adults, 0.2 mg per inhalation, if necessary or 3 times daily. Long-acting agents include formoterol, salmeterol, etc. Formoterol tablets, adults, 40ug orally, twice daily. Short-acting β2 agonists are used to relieve asthma symptoms, but long-term overuse may cause a partial loss of their efficacy, i.e., the development of so-called drug resistance. Therefore, long-term use of β2 agonists alone and in excessive amounts should be avoided.
4.2 Hormone therapy
Glucocorticoids have the effects of inhibiting the migration and activation of inflammatory cells, inhibiting the production of cytokines, and inhibiting the release of inflammatory mediators. The main control treatment for asthma is inhaled glucocorticoids (InhaledCorticosteroids, ICS). ICS is the most effective drug for asthma control, with the advantages of strong local anti-inflammatory effect, direct drug action, small dose, high systemic safety and fewer adverse reactions. When the recommended maximum dose of inhalation, the treatment effect is not good, you can increase the amount of inhaled glucocorticoids. If the effect of aerosol or dry powder inhalation of glucocorticosteroids is not good, it can be replaced by air pump nebulized inhalation. Short-term oral glucocorticosteroids or intravenous medication can be used if necessary, but it is important to note that long-term high-dose inhalation or oral glucocorticosteroids have certain side effects. Although inhalation of larger doses than recommended by current guidelines is also a reasonable option, however, unfortunately, FardonTC et al. found that when the amount of inhaled budesonide was significantly increased, the increase in efficacy was not as pronounced as the increase in side effects. In contrast, DahlR et al. found that ciclesonide was less bioavailable at higher doses, which would suggest that it also has fewer systemic side effects at higher doses.
4.3 Leukotriene antagonists
Leukotriene modulators include cysteine leukotriene receptor antagonists and leukotriene synthesis inhibitors with mild bronchodilator, symptom relief, improved lung function, reduced airway inflammation, and reduced deterioration, mainly montelukast. Recent studies have found that leukotriene modulators are promising adjuvant therapies for the treatment of asthma, as hormones can neither inhibit leukotriene biosynthesis nor its biological activity. At present, it is mainly used for refractory asthma, allergic rhinitis asthma, aspirin asthma, montelukast usage, oral 10J, once a night. dahle et al. study results especially for aspirin asthma that has been treated with hormone can well improve lung function and quality of life.
5. New advances in the treatment of refractory asthma
5.1 Anti-IgE monoclonal antibodies
In 2006, GINA advocated low-dose oral glucocorticoids or anti-IgE therapy for cases that have not achieved asthma control after combined application of high-dose inhaled hormones and various other therapeutic asthma drugs. Anti-IgE monoclonal antibodies have the ability to inhibit the binding of IgE to receptors on mast cells and basophils, and show good efficacy in allergic asthma with increased serum IgE levels in vivo. It can reduce the serum free IgE level by 95%.
WalkerS et al. found in a retrospective study that the use of Sorrel in asthmatic patients with stable inhaled hormones reduced the number and duration of exacerbations and reduced hospitalizations by 96%. Although sorrel has been shown to be an effective drug for asthma in clinical trials, more clinical evidence is needed in refractory asthma. It has not been used clinically in China, but it has been used clinically abroad, and its clinical application is limited by its high price.
5.2 Glucocorticoid-based combination therapy
GINA 2006 emphasizes that LABA should not be used alone in the treatment of asthma unless combined with appropriate doses of ICS. the combination of ICS and LABA has synergistic anti-inflammatory and wheezing effects. The combination of ICS and LABA has synergistic anti-inflammatory and antiasthmatic effects, resulting in efficacy equivalent to (or better than) that achieved with doubled doses of ICS alone, increased patient compliance, and reduced adverse effects associated with larger doses of ICS. It is particularly suitable for the long-term treatment of patients with moderate to severe persistent asthma, but should be used in combination with LABA and ICS under the guidance of a physician. In recent years, it is not a matter of increasing the amount of inhaled glucocorticoids in patients with severe persistent asthma, but rather advocating combination therapy to avoid adverse reactions in patients due to excessive amounts of glucocorticoids. Combination therapy: is the combination of glucocorticoids and inhaled long-acting β2 agonists, such as fluticasone/salmeterol, budesonide/formoterol; ICS plus theophylline can relieve asthma symptoms in mild to moderate patients, improve lung function and reduce airway hyperresponsiveness, and its efficacy is equivalent to 2 times the dose of ICS; when mild to moderate asthma patients inhaled low-dose ICS cannot control symptoms, it can also be added with slow-release theophylline; ICS and the leukotriene receptor modifier zallust or montelukast, compared with low-dose ICS alone, low-dose ICS + montelukast can significantly improve lung function and reduce daytime asthma symptoms and the number of nighttime awakenings.
5.3 BronchialThermoplasty (BT)
Bronchial thermoplasty is a new technique of high-temperature ablation of airway smooth muscle by an interventional method that reduces the abnormal contraction of smooth muscle, thus relieving the spasticity of smooth muscle during an asthma attack and thus achieving a therapeutic goal. This treatment is aimed at asthma patients who have been treated with multiple medications with little success. The theory was first investigated in animals in 2000 by Asthmatx, Stanford University, the University of California, McMaster University, and seven other institutions. 2006 saw the start of clinical trials with BT, with a consortium of 29 medical institutions worldwide, including 17 US hospitals. In recent years, clinical trials conducted by these different institutions have yielded the same results, i.e., patients with refractory asthma have experienced significant improvement in asthma symptoms, a reduction in the number of attacks, a reduction in the amount of hormones used during attacks, and thus some control of their asthma and a significant improvement in quality of life after using BT. In the animal and human studies that have been conducted, no serious adverse effects have been found to be caused by BT, but as an invasive treatment, it is important to ensure safety during the operation. Due to the short duration of the research clinical trials, the long-term efficacy, adverse effects and impact on the quality of life of BT remain to be tested.
5.4 Biofeedback therapy
Biofeedback therapy, also known as biological teach-back therapy, or phyto-neural learning method, is a new psychotherapeutic technique/method developed on the basis of behavioral therapy. Among the various methods of biofeedback, heart rate variability biofeedback is currently one of the promising ones. Although his physiological mechanisms are currently unknown, several randomized controlled trials have found that biofeedback that increases HRV improves lung function and reduces asthma symptoms and medication use. Although some patients in this study were severe asthmatics, serious consequences did not occur and it could be one of the complementary treatments for refractory asthma.
5.5 Use of immunomodulators
SpahnJD et al. showed that long-term asthma patients treated with oral hormones by long-term intravenous immunoglobulin administration significantly reduced hormone use and hospitalization of patients, with the possible mechanism being synergistic inhibition of lymphocyte activation by dexamethasone and increased hormone receptor activity after 3–6 months of use, for hormone-resistant asthma and non-hormone-resistant asthma with the same effect. Intravenous application of immunoglobulin, 0.5–1.0 g/(kg-dose), once a month for 5 months. Although this treatment has minimal side effects and is well tolerated by the patient, the high cost and inconvenience of continuous intravenous administration make this approach very limited in refractory asthma.
The use of immunosuppressive agents, such as methotrexate, gold salts, and cyclosporine A, has been shown to have hormone replacement effects in hormone-dependent asthma by Kabra et al. However, these drugs are effective in only about 60% of patients and do not improve lung function, with large toxic side effects. While Frew pointed out that the use of gold salts can reduce the use of hormones in large doses, but accompanied by serious side effects, cyclosporine A trials have shown that it can improve lung function and reduce the number of exacerbations, moderate reduction in the use of hormones. Methotrexate 5 – 25mg/week for 4 – 6 weeks, need to use more than 24 weeks, adverse reactions, in addition to nausea, vomiting, mucosal ulcers, liver function is easily impaired, the bone marrow is easily suppressed, and easy to secondary fungal infection.
5.6 Stem cell transplantation
Stem cells are cells with self-renewal and differentiation potential, capable of producing highly differentiated functional cells, and stem cells can differentiate into various different types of cells and organs. Weiss et al. found that bone marrow-derived mesenchymal stem cells reduced airway hyperresponsiveness and a large number of eosinophils in bronchial lavage fluid in mice after having OVA stimulation. ), a type of pluripotent stem cell, and found that this cell protected the mice from severe allergic and asthmatic symptoms, noting that this protective effect is likely due to the ability of this cell to normalize the typical two-stage inflammatory response in humans, which often becomes unbalanced in the presence of severe asthma.
In conclusion, the treatment of refractory asthma is still difficult, and we treat it clinically by dividing it into emergency measures during acute exacerbations and treatment during remission. Emergency measures in acute attacks: First of all, we should still treat acute attacks of severe asthma as usual (see related topics for details), inhaling sufficient amount of β2 receptor stimulants, with salbutamol stock solution being the best once in 20 min, three times in a row or even continuous nebulization, if there is no abnormal β2 receptor problem, the symptoms should improve. If there is a history of lethal asthma, early tracheal intubation, endotracheal administration, and alveolar flushing after tracheal intubation are considered. When current results with β2 agonists are poor, it is important to standardize the correct use of aminophylline in addition to concurrent systemic glucocorticoid stimulation. In remission treatment, the first is the combination of glucocorticoid and inhaled long-acting β2 agonist; or you can also add slow-release theophylline and leukotriene receptor antagonist; or take glucocorticoid and leukotriene receptor antagonist, immunomodulator, bronchial thermoplasty and many other new methods and techniques selectively used in combination according to the conditions.