Severe asthma is a heterogeneous multi-phenotypic disease, which is rare but costs 30-50% of the total cost of all children with asthma. Recently Prof. Sara Bozzetto et al. published an expert consensus on severe asthma in children in currentopinioninpulmonarymedicine, aiming to explore the differences between conventional drug therapy and novel biological therapies.
In addition Prof. Bozzetto recommends that children with severe asthma should be treated gradually under the guidance of a pediatric asthma specialist. The first step is to exclude other possible diagnoses, the second step is to exclude complications and assess the patient’s compliance with the medication, the third step is to determine the patient’s pattern of inflammatory infiltration, and the fourth step is to observe the patient’s response to treatment.
The lack of adequate awareness of poor prognosis, especially in the pediatric and adolescent populations, is an important factor that can be avoided in both primary and secondary care. In this setting, it is particularly necessary to give the right treatment to patients with severe asthma. Among the subordinate categories of severe asthma, we were able to distinguish 2 main diseases: difficult-to-treat asthma and severe treatment-resistant asthma (STRA) (children with persistent symptoms despite the application of primary treatment).
In 2014, a task force composed of the European Respiratory Society (ERS) and the American Thoracic Society (ATS) developed a guideline protocol, and the task force emphasized the need for a well-established protocol for the diagnosis of severe asthma in children. The guidance protocol developed by the task force emphasizes that patients should be treated by an asthma specialist for 3 months before a diagnosis is established.
According to the ATS/ERS recommendations, in children >6 years of age, severe asthma is defined as daily inhaled high-dose glucocorticoids (ICS) (>800ug per day of budesonide or other drugs that produce the same effect) or a second controller drug (long-acting beta agonist or leukotriene modulator or theophylline) for up to 1 year, or systemic hormone application to prevent progression of asthma to uncontrollable levels treatment, or asthma that is not controlled even with the above treatments.
The definition of high-dose ICS in the diagnosis of severe asthma in children is misleading; there is a significant difference between the ATS/ERS and Global Initiative for Asthma (GINA) definitions of high-dose ICS, which are two times higher in GINA than in ATS/ERS (800ug/day for budesonide and 400ug/day for budesonide).
For the definition of uncontrolled severe asthma, the diagnosis is confirmed by one of the following four conditions: 1. Symptoms are difficult to control: ACQ (Asthma Control Questionnaire) score consistently above 1.5; ACT (Asthma Control Test) less than 20; (or “not well controlled” as defined by the National Asthma Education and Prevention Program or GINA guidelines). “2. Frequent worsening: 2 or more systemic glucocorticoid treatments (>3 days each) in the previous 1 year.)
3. Severe deterioration: hospitalization, ICU admission and mechanical ventilation at least 1 time in the previous 1 year. 4. Inflammatory infiltration of the airways: first second expiratory volume (FEV1) less than 80% of the expected value (defined as less than the lower limit of normal with respect to reduced FEV1 or forceful lung volume (FVC)) after discontinuation of the associated bronchodilator.
The diagnosis of STRA can be considered in children with uncontrolled severe asthma and some innovative drugs should be proposed. Children with severe asthma should undergo continuous evaluation and need to be explicitly considered for such a diagnostic classification.
Step 1: Ruling out a false diagnosis
Many different diseases may have a similar presentation to asthma. Tuberculosis, cystic fibrosis, interstitial lung disease, primary ciliary dyskinesia, bronchopulmonary dysplasia and prematurity, foreign body aspiration, occlusive fine bronchitis, and airway malformations such as tracheobronchial, should be differentially excluded. In older children, the differential diagnosis should be considered with respiratory dysfunction (e.g., vocal cord dysfunction) if there is a presentation similar to asthma.
The use of a number of diagnostic tests can help in the differentiation and pulmonary function tests and acute bronchial reversible diastolic tests should be performed frequently. Bronchial obstruction can be determined using several pulmonary function parameters and corrected reference values. Compared to adults, children with severe asthma have much less impairment of pulmonary function than adults, due to the fact that many children tend to have normal pulmonary function tests during asymptomatic periods.
Pulmonary function tests remain an important component of diagnosis and screening, and objective evaluation of pulmonary function can be used to monitor the efficacy of therapy as well as changes in pulmonary function. Bronchial provocation tests and exercise tests should be used as a routine means of detecting and assessing bronchial hyperresponsiveness when a child is suspected of having severe asthma.
High-resolution computed tomography (HRCT) is useful for differential diagnosis, but is not recommended as a routine test. Bronchoscopy and bronchoalveolar lavage (BAL) can identify the causative agent and the type of airway inflammation can be studied, but again, they are not recommended as routine tests.
Step 2: Examination of comorbidities and medication adherence
Refractory asthma may be associated with comorbidities, adverse psychological and environmental factors, and poor adherence to treatment, and these factors should be carefully considered in the process of confirming asthma diagnosis. Skin allergen testing and specific immunoglobulin E (IgE) testing should be performed at the time of diagnosis. Excessive allergen exposure in the home may be a cause of acute exacerbation of asthma in children, and allergens (especially food allergens) have been shown to correlate with lethal asthma.
2. In addition, special attention should be paid to allergic bronchopulmonary aspergillosis during the differential diagnosis. Viral infections are a major aspect in the deterioration of asthma in children. Most of the asthma deterioration and peak viral infections are synchronized, suggesting a correlation between the two. Rhinoviruses are very common in children in early autumn, a period during which there is no specific treatment or preventive mechanism for controlling viral infections and preventing worsening of asthma caused by respiratory viruses.
In allergy-prone children, we must consider the link between respiratory viruses, exposure and allergens. Asthma worsening due to viral infection and allergen exposure are correlated, and asthma worsening is characterized by the presence of a mixture of eosinophils and neutrophils.
3. Upper airway examination should be included as a routine part of the clinical evaluation, including examination for allergic rhinitis and chronic sinusitis. Allergic rhinitis often coexists with asthma, but there is controversy about the extent to which treatment of allergic rhinitis improves asthma symptoms. in a cross-sectional study, Professor Groot found that corticosteroid treatment of allergic rhinitis significantly improved asthma in children, but this study needs to be validated in a randomized trial.
Chronic sinusitis may be a complication, and this is particularly evident in adults, whose asthma symptoms are also significantly improved when rhinitis is treated. However, it is unknown whether this is evident in children.
Gastroesophageal reflux disease is another common complication. However, there is no evidence that gastroesophageal reflux causes asthma or that treatment of reflux improves asthma, and the relationship between the two conditions is often overemphasized. Gastroesophageal reflux may also be investigated in the diagnosis of severe asthma.
Tobacco smoke is associated with more severe asthma and disease persistence, and it can also reduce the effectiveness of asthma treatment. For children of any age, passive exposure to tobacco smoke is a strong domestic and environmental risk factor that can lead to recurrent coughing or wheezing and asthma symptoms. In adults with asthma, smoking can lead to steroid resistance, and has the same effect in children exposed to secondhand smoke.
Tobacco smoke has particularly harmful effects on children because their airways are smaller in diameter. Therefore, smoking bans should be promoted, and parents should be aware of the adverse health effects of smoking, which can be harmful to themselves as well as to their children.
6. The interrelationship between obesity and asthma is very complex. Obesity can cause steroid resistance, and conversely treatment for asthma may lead to obesity. Weight loss should be encouraged because it can improve asthma symptoms and quality of life, but it is difficult to do.
7. In addition, studies have confirmed that vitamin D deficiency is associated with severe asthma, but there is still a gap in controlled studies on the benefits of vitamin D supplementation.
8. Psychological and emotional problems act as a risk factor for asthma attacks and also for asthma mortality. We have recognized the role of acute and chronic stress in causing asthma to worsen.
9. the most common cause of persistent symptoms is lack of regular treatment. 50% of children with severe asthma have persistent symptoms and poorly controlled asthma symptoms due to inappropriate treatment (poor compliance, inappropriate use of inhalers).
Step 3: Determine the patient’s pattern of airway inflammatory infiltration
The underlying mechanisms and airway pathology of severe asthma are still unknown, and the heterogeneity of severe asthma makes it necessary to identify different underlying patterns of inflammatory infiltration, as this allows for greater individualization of treatment and for determining the potential efficacy of new treatments. The following listed techniques can be used to study inflammatory infiltrates in the airways: induced sputum analysis, exhaled nitric oxide measurement, exhaled breath concentration analysis, BAL bronchoscopy method and bronchial biopsy.
Induced sputum analysis can reveal different types of inflammatory infiltrates – eosinophilic, neutrophilic, mixed (eosinophils and neutrophils), but clinically useful sputum markers for children have not been identified, while at least 20-30% of children are not able to undergo Sputum induction analysis is not available in at least 20-30% of children.
Exhaled nitric oxide fraction (FeNO) is associated with eosinophilic inflammatory infiltrates, and it may decrease after steroid treatment, but some clinical role of FeNO measured in patients with severe asthma is still under investigation.
3. Concentration of exhaled breath can be collected in children and this may reflect the composition of the airway surface fluid. Few biomarkers have been shown to be clinically applicable, and this approach remains challenging.
BAL bronchoscopy and bronchial biopsy may be used for differential diagnosis or to assess patterns of airway structural abnormalities, remodeling, and inflammatory infiltration.
Step 4: Observe the patient’s response to treatment
It is important to be clear that childhood asthma is very different from adult asthma. Children with severe asthma tend to be more atopic and there are no gender differences. One difference from adults is that pediatric STRA patients are more often identified using eosinophils rather than neutrophils in the inflammatory infiltrate of the exhaled airways. This may be due to the different mechanisms driving severe asthma in children and adults, which means that adult asthma treatment regimens cannot be applied uncritically to pediatric patients. This emphasizes the importance of individualized treatment.
For pediatric patients with STRA, there are not many evidence-based treatment options. The data available now are extrapolated from studies of moderate or mild childhood asthma or severe asthma in adults. Standard treatments include high-dose inhaled corticosteroids, long-acting beta agonists, leukotriene receptor antagonists, oral prednisone, single maintenance and remission therapy (SMART), the anti-IgE antibody omalizumab, low-dose oral theophylline, and intramuscular trimethoprim.
First, it is particularly important that these standard treatment regimens are the most complete. new treatment regimens are available for patients with STRA, or for children with refractory asthma with persistent asthma symptoms regardless of successful cure of the comorbidities. Corticosteroids remain the mainstay of treatment for asthma, but STRA includes some conditions in which symptoms are not controlled despite treatment with cortisol.
In children with asthma not controlled by ICS, long-acting beta agonists and leukotriene receptor antagonists should be considered as the next step, while prednisolone therapy may also be tried. If clinically effective, the drug dose should be gradually reduced to the lowest effective dose. Side effects of the drug should be tested along with treatment, but there is currently no evidence to suggest how these side effects work.
Effective methods for assessing systemic hormone response in children are lacking, and there is no consensus on the type of drug, dose, mode of administration (oral versus intramuscular tretinoin), or duration of treatment. Steroid resistance, as defined in adults, does not apply to children, who may have normal lung function despite severe asthma attacks.
In children, the detection of steroid efficacy may depend mainly on the improvement of clinical symptoms in children, as indicated by: asthma control tests; reduced use of bronchodilators for symptom control; improvement in FEV1 with premedication of bronchodilators; and normal induced sputum cell structure or normal FeNO levels. It is now recognized that many factors may contribute to a reduced glucocorticoid response, including obesity and tobacco exposure, and that reducing these factors may help improve the efficacy of treatment.
The SMART approach to treatment is that maintenance therapy uses an inhaler containing budesonide or formoterolv, which has been shown to be effective in rescue therapy in adults. Trials in children may be considered, but the use and efficacy of SMART remains controversial.
Treatment of severe allergic asthma can be achieved with the anti-IgE antibody omalizumab, which is safer. There is no evidence of a minimum serum IgE value corresponding to achieving optimal efficacy. Omalizumab has also recently been reported to have a more significant effect in the treatment of non-allergic asthma. This drug is costly, so it is important to identify some biomarkers that can predict the efficacy response.
There is now a new hot topic of research on theophylline (its immunomodulatory function), namely the low-dose theophylline trial that can be implemented in neutrophilic types of asthma. However, the appropriate timing of this trial is not well understood.
Other experimental therapies include macrolides, cyclosporine, methotrexate, immunoglobulins, antifungal agents, subcutaneous infusion of terbutaline and bronchial thermoplasty, and a number of biologic therapies have been developed (interleukin-13, interleukin-4, interleukin-9).
Macrolides have immunomodulatory properties as well as antimicrobial effects and are safer than other toxic agents. Therefore, it should be reasonable to test the effects of macrolides, especially in children with neutropenic asthma and suspected atypical respiratory infections (diagnosed on the basis obtained from adults). Cyclosporine and other cytotoxins are not recommended at this time.
Itraconazole (and voriconazole if symptoms persist) may predispose patients to fungal susceptibility. Bronchial thermoplasty was approved by the FDA in 2010 for the treatment of severe adult asthma: the results are promising, but its use in children has not been reported so far. Anti-interleukin 5 is effective against eosinophilic inflammation and its may reduce the risk of exacerbation in adults with severe eosinophilic asthma. However, there are no reports in children. For severe catastrophic asthma, epinephrine injections are the emergency treatment option.
Each patient with asthma has unique clinical features, different asthma exacerbation patterns, and a different response to treatment. Severe asthma varies in type, and a commitment to deepening the study of the characteristics of children with severe asthma and improving staging can help us provide an effective individualized treatment plan (ATS/ERS). Acute asthma exacerbation can cause numerous complications and accelerated deterioration of lung function. Future research should make treatment more individualized and should use a biomarker-driven approach to treatment.