Algorithm for long-term treatment of bronchial asthma in children

At present, there is no single definition of bronchial asthma in children, despite significant advances in understanding the pathomorphology, physiology, immunology, genetics and clinical factors of childhood bronchial asthma. The definitions of asthma vary depending on the purpose for which they were formulated. For a practitioner, determining asthma is valuable only for assessing the prognosis and choice of therapy. Therefore, the International Consensus of Pediatricians recommended that the previous definition of bronchial asthma in children be retained: recurrent attacks of shortness of breath with wheezing in the chest and / or persistent cough under conditions that make asthma likely and after the exclusion of other rare conditions with similar symptoms. With age, especially after 3 years, the diagnosis of bronchial asthma becomes more obvious, and after 6 years, the definition of the National Institute of Heart, Lung and Blood, USA, according to which bronchial asthma is considered primarily as an inflammation of the respiratory tract, the main role in which eosinophils and mast cells play, causing recurrent bouts of coughing and wheezing in the chest, accompanied by hyperreactivity of the bronchial tree and a reversible limitation of its patency.
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The sensitivity and specificity of prognosis assessment methods in young children with signs of asthma has not yet been established. A large number of cohort studies showed that 45-85% of these children in older and adolescents do not suffer from bronchial asthma. Elevated serum IgE levels and positive screening tests, especially a house dust mite test, are predictors of disease persistence at an older age; the only factors determining the prognosis of the severity of asthma are considered to be the presence of eczema in a child and relatives of the first degree of kinship with atopic asthma and / or eczema.
Morbidity and mortality from asthma in children

In childhood, mortality from asthma is low. Over the past 20 years, asthma mortality among children under 4 years of age has decreased significantly, and among children 5-15 years old it is at a stable level. The incidence of so-called preventable deaths among children is lower than in adults. More often, death occurs unexpectedly in persons who have not previously suffered from asthma or who had a relatively mild course of the disease; as a rule, these are children from dysfunctional families or those who poorly follow prescribed therapy.

The increase in the incidence of asthma in children is paradoxically associated with two mutually exclusive factors: inadequate therapy and treatment complications. In the UK, for example, only 15% of patients receive drugs regularly, which makes it possible to consider such therapy as preventive; 85% respectively do not receive adequate prevention. On the other hand, there are frequent cases of unjustified administration of large doses of powerful anti-inflammatory drugs to patients with rare exacerbations of asthma.

The previously published recommendations set unrealistic goals for treating asthma and preventing irreversible obstruction, extrapolating the experience of treating adult patients to children and overestimating the role of peak flow meters, which can give false results and interfere with prescribing, and it’s quite difficult to teach a child to regularly use a peak flow meter.

It is important to emphasize that at the moment there is no way to cure bronchial asthma. Therefore, therapy should be aimed at achieving maximum improvement in the quality of life and lung function with minimal side effects of treatment. For the vast majority of children suffering from bronchial asthma, it is quite possible to normalize the quality and lifestyle, optimize their growth and development. However, in some patients this cannot be achieved; such children may need constant or at least frequent administration of short-acting b2-agonists to combat the symptoms that appear during exercise and during intercurrent viral infection.
Goal of treatment

The goal of treatment should be:

1. Quick resolution of acute symptoms.

2. Application of measures to control environmental factors, if necessary (according to the history and results of allergotest).

3. The use of preventive drugs when the course of asthma justifies their use, taking into account their potential side effects.

4. Optimization of quality of life: eliminating sleep disturbances and preventing asthma of physical effort.

5. Use of inhalers and other devices suitable for drug delivery and appropriate to the age of the patient.

Crucial to achieving these goals is a correct assessment of the severity of the disease, which requires distinguishing between those symptoms that are characteristic of remission of asthma, and those that are caused by its exacerbation.
Clinical types of bronchial asthma

The duration of the course of bronchial asthma in children requires the separation of the disease into three types:

1. Intermittent with rare seizures – characterized by rare asthma attacks – less than 1 time in 4-6 weeks, wheezing wheezing after great physical exertion, lack of symptoms and normal lung function in the interictal period. Preventive therapy in such patients is usually not required.

2. Intermittent with frequent seizures – characterized by more frequent seizures, but less than 1 time per week, wheezing after moderate physical exertion, normal or almost normal lung function in the interictal period. Preventive therapy is usually necessary.

3. Persistent asthma affects approximately 5% of children with asthma; characterized by frequent attacks, wheezing after the slightest physical exertion, in the interictal period, lung function is reduced, and symptoms require the use of b2-agonists more than 3 times a week. Preventive therapy is required.

In a number of studies, it has been shown that daily monitoring of peak expiratory flow rate (PSV) is necessary to assess disease severity and response to therapy in both adults and children. However, the International Consensus Group of Pediatricians believes that 75% of children with rare episodic problems do not benefit from monitoring PSV. Indeed, in some situations incorrect results can be obtained, which can lead to unjustified intensification of therapy or vice versa – to obtain falsely high results of PSV in children who actually have a more severe course of the disease. Evaluation of lung function, however, is of great importance for monitoring recovery after exacerbation and the selection of optimal therapy for patients with severe illness. Attention should also be paid to a thorough clinical assessment of the patient’s condition; it should be carried out at least 2 times a year and be accompanied by spirometry. If FEV1 and the “flow-volume” loops are within the normal range and the need for b2-agonists is less than 3 times a week, there are no sleep disturbances and exercise restrictions, then there is no indication for monitoring PSV.

Provocative tests with methacholine or histamine are of little importance for the diagnosis of bronchial asthma due to their low specificity. A provocative test with exercise and inhalation of dry air, however, is more specific and useful for detecting bronchospasm of physical effort and diagnosing asthma in children in whom the symptoms are limited only by constant coughing.

Bronchoscopy and bronchoalveolar lavage are not part of a routine clinical examination; they should be used only if it is necessary to exclude other conditions similar in the clinical picture to bronchial asthma, such as tracheo-, bronchomalacia, etc. The method of inducing sputum with hypertonic saline can be used to assess the content of inflammatory cells and their products in sputum, but it is usually used in older children.

It is important to emphasize the need for regular anthropometry in all children with asthma; this is especially important for children receiving large doses of corticosteroids inhaled and orally, as well as intranasally or transdermally.

It is known that allergy is an important prerequisite for the development of bronchial asthma. Signs of allergies are observed in 75-90% of asthmatic children over the age of 4-5 years. Cross-sectional long-term studies have revealed a quantitative relationship between exposure to allergen and sensitization, especially in children. A number of studies have also shown that eliminating the allergen leads to a decrease in bronchial hyperreactivity, asthma symptoms and the need for anti-asthma drugs. Measures to eliminate the effects of the allergen should be recommended to all children with asthma, regardless of age. Important are the complete elimination of exposure to tobacco smoke, the rejection of pets. If a child has a sensitization to a house dust mite, reasonable recommendations are to improve ventilation, eliminate high humidity and use anti-allergenic bed covers.

Many asthmatic children also suffer from allergic rhinitis and sinusitis, which are triggers of asthma. Adequate therapy (including antihistamines) of these diseases helps to reduce the symptoms of bronchial asthma and bronchial hyperreactivity. Patients suffering from food allergies in combination with bronchial asthma are at increased risk of developing severe anaphylactic reactions. Such patients should be advised not only to avoid the appropriate types of products, but also to carry adrenaline with them in inhaled or injectable form.

One of the ways to treat bronchial asthma is immunotherapy. The European Academy of Allergology and Clinical Immunology recommends the rare use of hyposensitization in children under 5 years of age. There are also limited indications for this procedure in older children. Hyposensitization is most effective for monovalent allergies; it should be prescribed only if it is proved that a certain allergen is important for the course of asthma in a child. Hyposensitization is contraindicated in poorly controlled asthma, as it can worsen the condition. Currently, the role of this method in the therapeutic algorithm has not been established, however, it is clear that immunotherapy does not replace adequate measures to control environmental factors or pharmacotherapy.
Therapeutic strategies for prevention and early treatment

Prevention and early treatment should be the primary goals of pediatricians treating bronchial asthma. However, it is only economically viable in a high-risk population. Currently, there are no ways to predict the development of severe asthma, in addition, there is no evidence that the prevention of bronchial asthma is indeed possible and early treatment can affect the natural course of the disease. There is evidence that exposure to tobacco smoke in the ante- and postnatal period leads to symptoms and impaired lung function, therefore eliminating this factor is important during pregnancy and the first months of a child’s life , especially in families where relatives have signs of atopy. In the postnatal period, it is also advisable to avoid typical food allergens (cow’s milk, eggs, peanuts), keeping pets and exposure to house dust mites, but in many conditions such recommendations are not feasible.

The early start of pharmacotherapy is currently based on the assumption that a late start in children leads to the development of irreversible bronchial obstruction. However, lengthy studies have shown that the risk of irreversible obstruction in intermittent asthma is very low. There is also no evidence that treatment with inhaled corticosteroids in children with any severity of asthma in any way affects lung function in adulthood. In this regard, there is no need for early administration of inhaled glucocorticosteroids (GCS) for intermittent asthma with rare exacerbations. Patients with persistent asthma should not hesitate to prescribe inhaled GCS regardless of age, since the risk of complications is low.

There is currently no evidence of asthma-preventive antihistamines such as ketotifen, but they may be useful in treating atopic dermatitis or allergic rhinitis. If a child with atopic dermatitis had repeated (more than 2-3 times) episodes of respiratory diseases with wheezing, then the early start of standard anti-asthma prophylaxis is justified.
Therapeutic algorithm

Currently, there is no need to fundamentally change the therapeutic algorithm (see diagram). Despite the emergence of new drugs, none of them has been proven that they will be of leading importance in the treatment of bronchial asthma. Therefore, intermittent asthma with rare seizures can only be treated with periodic inhalations of short-acting b2-agonists. There is no need for regular use of oral b-agonists, although they may be indicated in some circumstances. Nevertheless, the benefit / side effects ratio is largely favored precisely by inhalation therapy.

If the need for taking b-agonists exceeds 3 times a week (not counting inhalations before exercise) or exacerbations occur more often than 1 time in 4-6 weeks, then preventive treatment is indicated. Most participants in the International Consensus agree that preventative treatment should begin with cromolyn sodium. The minimum dose should be 10 mg 3-4 times a day. In some countries, however, there are only metered-dose aerosols containing 1 mg per inhalation. With the use of such dosages, treatment is unlikely to be effective. Therefore, for these countries, it is more appropriate to administer sodium cromoglycate through a nebulizer (20 mg per cup) for young children or using powder inhalers (20 mg per capsule) for older children; if this is not possible, the use of low doses of inhaled GCS is recommended. Before considering alternative drugs, cromolyn sodium should be prescribed for a trial period of 6-8 weeks. When control over asthma symptoms is achieved, sometimes you can reduce the frequency of dosing to 2-3 times a day. It should be emphasized that cromolyn sodium remains the safest of the drugs designed to treat asthma; it practically does not cause side effects, with the exception of a rare cough. This, as well as its effectiveness, make cromolyn sodium the first choice for the prevention of asthma. The exception is children under the age of 1 year, whose preventive effect has not been studied. Some of the participants in the International Consensus believe that low doses of inhaled GCS should be considered prophylactic agents of the first choice, especially in children with a more severe course of the disease or poorly adhering to the treatment regimen.

If symptom control is not achieved when using cromolyn sodium, and the need for b-agonists more than 3 times a week remains, you should switch to inhaled GCS. Whether they are prescribed first in large doses, followed by a gradual decrease to a level that supports symptom control, or from small doses with a gradual increase to achieve the same result, depends on each specific case. In some cases, especially in children with severe asthma, it would be advisable to start therapy with large doses of inhaled GCS and a short 3-5-day course of oral GCS to achieve maximum lung function, followed by cancellation of oral GCS and a decrease in the dose of inhaled. In most cases, this approach is not necessary. The goal should be to achieve the minimum possible dose of inhaled GCS sufficient to maintain adequate control of the disease. It is preferable to use only one drug, as this contributes to adherence to the treatment regimen. There are few situations in which the benefit of the simultaneous administration of cromolyn sodium and inhaled GCS outweighs the possible problems with adherence to therapy and the cost of drugs.

Inhaled corticosteroids are usually effective at relatively low doses. There are no reports of any long-term side effects when taking 200 mcg per day of beclomethasone or budesonide. A well-known complication of oral corticosteroid therapy – posterior subcapsular cataract – does not develop in children when taking moderate doses (on average 750 mcg / day) of inhaled beclomethasone or budesonide. Small systemic effects of GCS can be detected when taking more than 400 mcg per day, and only when the dose of these GCS is exceeded more than 800 mcg per day, is there a pronounced effect on growth, hypothalamic-pituitary-adrenal system and bone density. Systemic side effects can be reduced by using a spacer, which allows you to increase the penetration of the drug into the lungs and reduce its sedimentation on the mucous membrane of the oropharynx and systemic absorption. If it becomes clear that the dose to achieve symptom control does not avoid side effects, a specialist consultation is necessary. Strategies to reduce the dose of inhaled corticosteroids include the use of long-acting inhaled b-agonists, such as salmeterol and formoterol, or prolonged-acting theophylline. Nevertheless, the most common cause of ineffectiveness of inhaled GCS is incorrect and irregular inhalation.

In some cases, high doses of inhaled GCS are required to achieve adequate control. Such patients should be hospitalized in specialized institutions; it is also possible to take oral GCS according to an alternating scheme, the use of methotrexate, cyclosporine, troleandomycin, subcutaneous administration of terbutaline or intravenous infusions of immunoglobulins. However, none of these methods has been studied in large controlled clinical trials of childhood bronchial asthma. Since this situation is extremely rare, it has not been detailed in the main therapeutic recommendations of the International Consensus Group.

Other drugs

Current data do not support the addition of other drugs to the main algorithm. However, in special circumstances, the possibility of prescribing certain second-line drugs and new drugs may be considered.

In a number of clinical studies, it has been shown that with intermittent asthma with rare attacks, ketotifen can support disease control, mainly in young children. It is active when taken orally and is therefore easy to take. However, its effectiveness in asthma is low. Cetirizine has properties that make it especially useful in young children.

Nedocromil sodium was recommended for mild or moderate asthma in adults. A series of studies in children with asthma have demonstrated the effectiveness of this drug compared to placebo. There are no studies on children that would establish the advantage of nedocromil over cromoglicate (although similar comparative studies were conducted in adults), or its place in the algorithm among cromolyn sodium and inhaled corticosteroids. In some studies, its effect was studied when prescribed 2 times a day, in others 3-4 times a day. The advantage of Nedocromil will be proved if it turns out that its 2-fold intake is equivalent to 4-fold intake of cromoglycate.

Currently, long-acting b2-agonists, salmeterol and formoterol, are used in some countries, however, the smallest age limit at which their use is permitted is not defined. They should be used only in cases where the child receives moderate doses of inhaled GCS and, despite this, symptom control is not achieved. Concern remains that the prolonged use of long-acting b-agonists may be accompanied by the same effects as with the frequent use of short-acting b-agonists – worsening of the course of the disease and bronchial hyperreactivity. However, a recent study did not reveal a negative or positive effect of the regular use of b2 agonists in asthma. In another study in adolescents, a decrease in the bronchoprotective effect of salmeterol was found after 28 days of treatment, despite the simultaneous administration of inhaled corticosteroids.

In recent years, they have again returned to theophyllines, since a number of works have demonstrated their anti-inflammatory effect. Theophylline has not only bronchodilating, but also immunomodulatory properties. In the absence of the possibility of widespread use of inhaled drugs, early prophylactic administration of oral theophyllines may be useful for many patients with asthma. Recently, new drugs have been developed, such as phosphodiesterase inhibitors and potassium channel activators with bronchodilating properties; however, their place in the treatment of asthma has not been determined. In clinical practice, antagonists of leukotrienes with anti-inflammatory properties are already used; the results of a study of their use in children are expected with interest.

Optimal use of inhalation devices

For the implementation of effective treatment of bronchial asthma in children, the correct choice of an inhalation device is important. With the advent of modern inhalation devices, it has become possible to lead most children with asthma completely to inhalation therapy. In many countries, however, the lack of suitable inhalation systems forces the continued use of oral medications. However, the rapid onset of action and the low incidence of side effects require inhalation therapy to be preferred, especially for b2-sympathomimetics. In many countries, with exacerbation of asthma, along with b-agonists, nebulized administration of ipratropium bromide is used; nedocromil and cromolyn sodium are effective only when inhaled, and inhaled corticosteroids are clearly preferable to oral forms due to the low incidence of side effects.

If possible, inhalation should be through a spacer, which prevents the sedimentation of the drug on the mucous membrane of the oropharynx and increases the delivery of the drug to the lungs. Spacers are cheap and easy to use; they solve problems associated with improper use of a conventional inhaler. Attaching the face mask to the spacer facilitates its use in very young children, although this reduces the dose of the drug that enters the respiratory tract.

Air compressor nebulizers are bulky and inefficient aerosol systems. With the advent of modern spacers, the need for them has significantly decreased, although nebulizers are still widely used in exacerbating asthma, when large doses of b-agonists are required. A nebulizer is also needed to administer drugs such as sodium cromoglycate in countries where it is available in small doses, or for inhalation of corticosteroids in young children who cannot use the spacer. It should be remembered that ampoules for nebulized administration must be diluted with saline to avoid a progressive increase in osmolality during inhalation, which can be the cause of paradoxical bronchoconstriction.

Powder inhalers should not be used in children under 5 years of age, in a humid atmosphere, and for the administration of GCS, since the particles of the powder deposited on the mucous membranes of the mouth are difficult to rinse when rinsing it, which can cause oral candidiasis.

event_note June 2, 2020

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