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Bronchial asthma in children

Severe bronchial asthma (BA) of childhood is a serious medical and social problem. This is determined by a number of circumstances, among which one can single out the most important.

1. The steady increase in asthma mortality. In the UK, mortality over the past 20 years has increased by 7 times, in Europe, North America - by 2–3 times, in Russia (St. Petersburg) in the years 80–90 - by 2 times. The results of research on asthma indicate an increase in the frequency of fatal outcomes, including in children, in recent decades. The risk group for adverse BA outcomes consists mainly of patients with a severe form of the disease.

The highest mortality rate from asthma is observed in the group of adolescents. For example, from 1990 to 1992 in the UK, the mortality from asthma at the age of 10–14 years was 3 times higher than that of 5–9 years old, and in the age group 15–19 years old - 6 times higher than that of 5–9 years old. According to the observations of D.S. Korostovtsev and I.V. Makarova, in St. Petersburg in 1976-1998. Fatal asthma also prevailed in adolescents.

2. The complexity of diagnosis (differential diagnosis) and monitoring of clinical symptoms of the disease, especially in young children. The criteria for diagnosing asthma in children are based on the presence of clinical manifestations of bronchial obstruction, evidence of reversibility of airway obstruction in the study of respiratory function and determining signs of bronchial hyperreactivity. It is characteristic that up to 70% of patients with severe asthma develop illness before the age of 3 years, when the diagnosis of the disease is difficult, since clinical symptoms are atypical, and instrumental studies of lung function are difficult. The cumbersome list of pathological conditions and diseases involving the syndrome of bronchial obstruction, coughing and wheezing in young children complicates diagnosis and delays the start of therapy.

Most researchers pay attention to the rapidly progressive increase in the negative dynamics of the disease due to persistent inflammation in severe BA. Perhaps this is due to the late diagnosis of asthma in children due to the above reasons.

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3. The underestimation of the problems of asthma by the parents of the child and the patient. According to the results of an epidemiological study of asthma in Russia, only 7% of parents considered asthma in their child to be severe (as opposed to 13.5% detected during the examination of severe forms), only 4.5% of them considered asthma uncontrolled (AIRCEE in RUSSIA, Final Report). Doctors who do not always fully use the assessment of lung function in patients and who do not control the skills of using inhalers and a peak flow meter also contribute to this problem. So, in just 47% of children, lung function evaluation was performed at least once a year, only in 45% of children the peak expiratory flow rate (PSV) was periodically evaluated at the reception. This may be the reason for underestimating the severity of asthma, reducing compliance. Patients are regularly observed by doctors, have no action plan, they are not assigned follow-up visits (AIRCEE in RUSSIA, Final Report).

Thus, in Russia there is still a significant gap between the understanding of the main provisions of the National Program “Bronchial Asthma in Children. Tactics of treatment and prevention ”and real clinical practice. This circumstance significantly impedes the implementation of preventive programs related to severe BA.

4. Difficulties in the use of drug therapy in children. An example of problematic use of drugs for asthma can be the refusal of adolescents from inhalation therapy, associated with the peculiarities of the formation of psycho-emotional status at this age, a significant influence of others on the behavior of a teenager, his reluctance to look sick in the eyes of peers.

Problems of steroid phobia, fear associated with the use of high doses of X or SCS, are also associated with the treatment of severe forms of asthma in children.

5. Lack of research on severe asthma in young children. Most ideas about the pathogenesis of asthma are based on studies confirmed by morphological and pathological-anatomical methods carried out in a group of adolescents, while projects in infants and young children for objective reasons are only partial. At the same time, studies in the latter have significantly advanced the understanding of severe asthma in adult patients due to the evaluation of the mechanisms of genetic and clinical polymorphism. The absence of such studies of childhood asthma does not contribute to a clear understanding of patient management.

6. Social aspects of the disease. The significant daily impact of severe asthma on quality of life, as well as the disproportionately high costs of treating severe asthma in a small number of patients compared to the cost of treating patients with other forms of the disease determine the importance of the problem of severe asthma for society as a whole.

Key provisions

  • Severe asthma in children is the most severe clinical form of the disease, which is characterized by the presence of constant day and night symptoms, frequent exacerbations, leading to a decrease in pulmonary function parameters and exercise tolerance, a high level of bronchial hyperreactivity.
  • Predictor of severe asthma is a high atopy index associated with gene polymorphism of interleukin-4 (IL-4).
  • Severe asthma in children is heterogenous in clinical characteristics.
  • There is persistent, intermittent, life-threatening or fatal (asthmatic status) course, complicated by emphysema, pneumothorax, pulmonary heart.
  • In some patients, due to rapidly progressive inflammation, therapeutically resistant forms develop due to a decrease in sensitivity to average doses of ICS and remodeling.
  • A severe form of asthma due to the high risk of a fatal outcome is an indication for use in treatment, along with X-rays and SCS, short courses, less often - long ones.
  • Continuously relapsing nature of the disease leads to a significant impact on the quality of life.

Factors predisposing to the development of severe asthma

A high atopy index is the only known predictor of severe asthma today, which is confirmed by a number of studies. Thus, in various works there are indications of the association of severe BA in children with the following factors:

  • Candidate genes associated with severe atopic BA:
  • 583-T polymorphism of the IL-4 gene,
  • polymorphism C-590T and G + 717C of the IL-4 gene,
  • HLA-DRB1 genotype;
  • High level of IgE (510 IU / ml in severe and 198 IU / ml in moderate asthma);
  • high level of IL-4 (189 pkg / ml in severe and 47 pg / ml in moderate BA);
  • Bronchial asthma in the mother;
  • Concomitant atopic dermatitis.

Detection of a high level of IgE in a child with asthma, supported by a hereditary history of the mother, refers to the high risk factors for the rapidly progressing development of inflammation, an uncontrolled increase in the severity of asthma.

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Thus, modern studies indicate a predisposition to severe asthma, which is determined by the genotype of atopy (IL-4 levels, IgE, atopic diseases in relatives).

Other factors predisposing to the uncontrolled course of asthma in children are: sinusitis, various diseases of the upper respiratory tract, dysfunction of the vocal cords, contact with the allergen, emotional and psychological factors, excessive use of b2-agonists, smoking (passive and active), low compliance , socio-economic, ethnic factors (African-American children).

The difficulty lies in the fact that many of them influence both the occurrence of the disease and its uncontrollability. For example, smoking is a factor predisposing to the development of asthma and significantly influencing the course of the disease.

Up to 15% of cases of severe asthma can be associated with continued contact with the allergen, although this fact is rarely recognized in everyday practice. A significant number of cases of atopic asthma remain without a cause-significant allergen identified. More recently, it was believed that any treatment will not be sufficiently effective if there is no control over contact with the allergen. Recent studies show that even the most effective environmental control often does not lead to the desired improvement in the clinical picture. Despite this, in the case of severe asthma, it is necessary to recognize the importance of carefully controlling all possible triggers, including allergens. House dust mites, cat allergens, cockroaches and Alternaria can not only provoke asthma exacerbation, but also be directly involved in the pathogenetic mechanisms of the disease. In addition, Alternaria is one of the major allergens, sensitivity to which is associated with very severe and fatal asthma.

Gastroesophageal reflux is often detected in patients with BA. And as reported, it occurs in 60% of children with moderate to severe asthma. Currently, no clear mechanisms are known for the relationship between reflux disease and the worsening course of asthma, however, there has been an improvement in the course of asthma with effective treatment with H2-histamine blockers.

Sinusitis / rhinitis and asthma are often associated problems, and significant improvements in asthma control can be achieved with their effective treatment. Viral and bacterial infections of the paranasal sinuses are considered as possible factors of exacerbation of asthma, but their clear significance in the development of severe asthma has not been determined.

Psychological factors, such as social deprivation, often ignored by clinicians, are associated with poor asthma control. In patients aged 6–18 years, high levels of panic and fear are associated with a high risk of hospitalization. The conflict between the parents and the doctor about the treatment of the child, poor self-care in the hospital, the conflict between the patient and the hospital staff, the neglect of depression symptoms by the doctor are associated with a real increase in the risk of death. Problems in the family, the loss of a close friend or family member increases the risk of exacerbation, resulting in death. Sometimes asthma is used as a means of lifestyle manipulation. The ability of higher cortical centers to influence the synthesis of pro-inflammatory cytokines is being actively studied, which may make it possible to understand the relationship of psychological problems and poor asthma control in a number of patients.

Another factor in the development of severe asthma may be excessive use of b2-agonists. Data from recent studies confirm that the use of more than two cartridges of b2-agonists per month is associated with a high risk of death.

There are publications that indicate that in some patients, the uncontrollability of asthma may be due to an increased metabolism of leukotrienes. In these situations, episodes of life-threatening asthma attacks can develop against the background of a normally controlled course of the disease.

Various air pollutants, endotoxins, viral infections of the respiratory tract can also increase the risk of uncontrolled BA. There is some evidence of the involvement of chlamydial infection in the development of severe forms of AD.

The patient’s low compliance, disagreement and unwillingness to follow the doctor’s instructions are largely associated with asthma’s uncontrollability. When inhalation therapy with corticosteroids compliance is low, moreover, low compliance is generally characteristic of inhalation therapy. According to prof. Costello, the main cause of severe asthma is the patient's disagreement / inability to follow the treatment, and this should always be borne in mind. Compliance is very difficult to assess, and, as a rule, it is overestimated in clinical trials and in practice. The reasons for low compliance are heterogeneous and include a complex therapeutic regimen, psychosocial factors. Compliance can be significantly improved by giving the patient clear, written advice, using simple therapeutic regimens and educational programs.

Risk factors for severe asthma in children

  • Atopy genotype.
  • Critical age periods (infant, adolescent).
  • Concomitant diseases: sinusitis, gastroesophageal reflux, DGS, neuropsychiatric diseases, psychological problems.
  • Contact with high concentrations of allergens (polyvalent sensitization, hypersensitivity to Alternaria).
  • Infection of the respiratory tract (viruses), chlamydia (discussed).
  • Low compliance.
  • Inadequate doses of corticosteroids.
  • Intolerance to nonsteroidal anti-inflammatory drugs.
  • Socio-economic problems.
  • Quantitative and functional disorders of the receptor glucocorticosteroids.

Mechanisms for the development of severe BA

Inflammation

Despite the common pathogenesis of immune inflammation in asthma, severe asthma is characterized by a more active cellular response and increased production of critical cytokines, even with corticosteroid therapy, as well as a change in the ratio of cellular composition in the mucosal infiltrate.

However, differences in biological markers of inflammation are determined in different patients. This concerns, for example, the predominance of IL-4 cytokine surveillance in some or IL-5 in other patients. While most patients with severe asthma determine a high level of total and allergen-specific IgE, confirmed by positive skin test results, it is difficult to confirm the allergic component of asthma in some patients. This situation is true for the cellularity of inflammation: in most clinical cases, the study of bronchoalveolar lavage (BAL), endobronchial biopsy or induced sputum shows elevated levels of eosinophils, although an increase in neutrophil count is sometimes detected, including, very importantly, in fatal asthma. The value of neutrophilia in asthma is still not completely clear. Since glucocorticosteroids can stimulate neutrophil survival, it is possible that the observed increase in neutrophil count is the effect of corticosteroid therapy.

Characteristics of immune inflammation in asthma:

  1. infiltration of the bronchial mucosa with activated CD4 + lymphocytes;
  2. an increase in the number of eosinophils in induced sputum, BAL, bronchial wall biopsy specimens;
  3. increasing the number of cells expressing IL-4 and IL-5;
  4. increased production of IgE;
  5. an increase in the number of neutrophils in the mucous membrane of the bronchi and BAL with fatal BA.

Morphology

The structural reorganization of the bronchial tree (hypertrophy and hyperplasia of smooth muscle cells and subepithelial fibrosis), according to many authors, makes a great contribution to the clinical manifestations of asthma severity. It is believed that the remodeling of the respiratory tract is an important component of the pathogenesis of severe BA. At the same time, subepithelial fibrosis caused by the deposition of collagen I, III, V type and fibronectin correlates with the severity of the disease. At the same time, hypertrophy and hyperplasia of smooth myocytes are the main structural changes related to bronchial hyperreactivity and bronchial obstruction. Increased mucus production, as one of the main causes of bronchial obstruction in severe (especially fatal) asthma, is determined by hypertrophy and hyperplasia of the glands and increased secretion. The main source of factors responsible for the stimulation of smooth muscle proliferation and collagen synthesis (transforming growth factor - TGF-beta, IL-11 and platelet sprout factor) are eosinophils. Thus, eosinophils can be the main link between inflammation and remodeling in asthma.

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It is interesting to note that when examining patients with asthma, it was not possible to detect differences in the thickness of the basement membrane among patients with moderate and severe BA, but a significantly greater membrane thickness was recorded in patients with a high content of eosinophils in the bronchial mucosa. In this group, the number of cells positive for TGF-beta was also increased. These results are of clinical significance, since these patients have a higher risk of developing seizures that are close to fatal, while these morphological features did not affect the severity of response to bronchodilators.

Therapeutic response

Impaired response to therapy is important in the mechanisms of development of some clinical variants of severe BA in children. This applies primarily to a decrease in sensitivity to corticosteroids. The basis for the decrease in sensitivity in most cases lies in various mechanisms of dysfunction and / or affinity of corticosteroid receptors, as well as disturbances of interaction with transcriptional proteins caused by inadequate treatment or progression of inflammation. These include:

  • violation of the binding of the steroid receptor with DNA;
  • decrease in the affinity of steroid receptors, caused by IL-2, IL-4, IL-5 and TNF;
  • a decrease in the number of available receptors due to competition with proinflammatory factors (protein activator 1);
  • reduction of the number of available receptors due to competition with cAMP-binding protein, the amount of which increases under the action of b2-agonists.

Another mechanism of a defective response to therapy is a reduction in the reversibility of broncho-obstruction in response to b2-agonists, which is caused by dysfunction of b2-adrenoreceptors, whose regulation is under genetic control, as well as remodeling of the bronchial wall.

Age dynamics of inflammation

The development of BA is determined by the complex interaction of hereditary and environmental factors. In young children, eosinophilic infiltration of the bronchial mucosa is noted even before the appearance of IgE antibodies to tick antigens. Thus, the first mechanism responsible for asthmatic inflammation is IL-5-dependent eosinophilic infiltration of the respiratory tract mucosa. Over time, over the age of 2 years, the leading role in the pathogenesis of severe BA proceeds to IL-4-dependent mechanisms, resulting in the formation of IgE hyperproduction. A number of studies indicate an earlier start of IL-4 production and the appearance of a high level of IgE to aeroallergens in children with severe asthma already at the age of 1 year. Thus, the launch of IL-4 products is a key factor in the rapid progression of inflammation in children with severe asthma.

The cytokine imbalance mediates the structural reorganization of the bronchial tree, in parallel with this, the reversibility of bronchial obstruction decreases and the sensitivity to corticosteroids decreases. The combination of these components and determines the severity of clinical manifestations in asthma.

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Thus, the results of recent studies indicate that one pathological mechanism cannot explain all cases of severe asthma. Most children with severe asthma fall into the “classic asthmatic / allergic inflammation group” with a bad or good response to corticosteroid therapy. At least one of the other groups consists of patients with a pathologically distinct disease, in which corticosteroids completely reduce inflammation, but do not affect the clinical severity of the disease.

Diagnosis and classification

The verification of asthma is based on the assessment of clinical and functional symptoms, as well as the identification of increased sensitivity of the respiratory tract, mucous membranes and skin to allergens and triggers. However, such a physiological definition of asthma, based on registration of bronchial hyperresponsiveness and restriction of expiratory airflow, is not specific. Thus, bronchial obstruction in asthma is reversible, and bronchial hyperreactivity in a large part of asthma patients has never been objectively confirmed. Nevertheless, the definition of severe asthma is based on similar measurements (not always positive in the diagnostic sense) and it is diagnosed in patients with daily daily and frequent night symptoms, severe degree of bronchial obstruction and a high level of bronchial reactivity. Unfortunately, these inaccurate definitions leave room for many pathological conditions that can cause similar physiological and clinical manifestations. In this regard, among patients with severe asthma, clinical variants, physiological changes (except FEV1), and pathological findings vary widely. This requires an understanding of the “clinical phenotype of severe asthma” problem, and also determines the expansion of the patient's examination program with the aim of differential diagnosis, identifying and eliminating factors that reduce asthma control.

Diagnosis in young children

  1. The main task in the diagnosis of severe asthma in young children (up to 3 years) is the timeliness of identifying asthma itself. Since severe asthma can begin at an early age, when symptoms are atypical and the lung function is assessed, allergy testing is difficult, it is very important to recognize the diagnosis and prescribe anti-inflammatory therapy.
  2. To improve the diagnosis of asthma in early childhood, it is important to use various diagnostic algorithms, as well as the implementation of differential diagnosis programs.
  3. When assessing the symptoms of severe asthma in children, it should be borne in mind that the disease can manifest itself only by wheezing or coughing.

Differential diagnosis in children with asthma

  • Bronchiolitis obliterans
  • Dysfunction of the vocal cords
  • Bronchomalacia
  • Bronchial foreign body
  • Cystic fibrosis
  • Aspiration syndrome (especially in infants)
  • Anomalies of the upper respiratory tract
  • Immunoglobulin deficiency
  • Primary ciliary dyskinesia.

Diagnosis in older children

  • The severity of asthma is often underestimated by the patient and his parents, which leads to progressive inflammation due to inadequate therapy. For a real diagnosis of the current severity, monitoring of clinical and functional parameters and regular medical observation is necessary (at least 2 times a year).

  • Examination programs for patients with severe asthma should be designed in such a way as to facilitate the targeted identification of factors responsible for the uncontrolled course of asthma.

  • Important factors of severe asthma in the group of older children are low compliance and psycho-emotional problems of adolescence. To assess the real severity of asthma in this case, psychologists may be required.

Diagnosis of severe BA

Grade severity:

  • monitoring of symptoms and use of b2-agonists,
  • spirometry and gas diffusion,
  • BHR (methacholine / histamine),
  • PSV variability,
  • the quality of life.

Evaluation of pharmacological response:

  1. test with bronchodilator,
  2. response to prednisone (sensitivity to the COP),
  3. control of compliance and inhalation techniques.

Radiological examination methods:

  • chest X-ray,
  • barium esophagus research,
  • X-ray of the paranasal sinuses,
  • CT scan of the lungs and paranasal sinuses (high-resolution methods).

Blood test:

  • PC analysis with a formula that includes the assessment of eosinophils,
  • immunoglobulins A, M, G, E,
  • allergen-specific IgE.

Other studies:

  • inflammatory biomarkers (exhaled NO, eosinophils in induced sputum),
  • sweat electrolytes,
  • daily monitoring of the pH of the esophagus,
  • examination of the nasopharyngeal zone,
  • assessment of ciliary insufficiency,
  • skin allergy tests
  • fibrobronchoscopy with biopsy and BAL,
  • psychological testing.

Expansion of the examination program for severe asthma in children is dictated by the incomplete reversibility of the broncho-obstructive syndrome in some patients, reduced sensitivity to therapy, the presence of atypical clinical symptoms and an insufficient level of disease control, which is cause for doubt and may cause undiagnosed asthma. Reliability of diagnosis is a key aspect of the control of severe asthma.

Phenotypes of severe asthma

Severe BA in different age groups

The course of severe asthma has clinical features in various age groups (infant asthma, early school, adolescent). The basis of age heterogeneity is the evolution of immune inflammation and morphological changes in the bronchi from acute and chronic inflammation in young children to remodeling in schoolchildren. A significant contribution to the "pediatric" severe asthma is made by the anatomical and physiological features of the child's development, including the structural evolution of the respiratory tract, sensitivity to hypoxia, the development of psycho-emotional status, etc.

In early childhood asthma can occur in the form of typical attacks of expiratory choking, coughing attacks or persistent wheezing. Exacerbations are possible due to viral infection, may be accompanied by fever and intoxication. Asthma manifestations are often preceded by atopic dermatitis. When examining a child, along with aeroallergens, the nutritional nature of sensitization is revealed.

At this age, the choice of dose and the route of delivery of short-acting b2-agonists is problematic. As an illustration, here are the results of two studies:

  1. In children under 5 years of age who were treated in the emergency room for an acute asthma attack, plasma plasma salbutamol concentration was significantly lower both on admission and after nebulizer therapy compared with children over 5 years of age. Despite the appointment of relatively higher doses of salbutamol in the group of children under 5 years of age, the overall absorption of the drug in this group was lower.
  2. Studies conducted on small children (mean age 2.1 years) in the emergency room for an acute asthma attack demonstrated the same effectiveness of nebulizer therapy and DAI + spacer (improvement of lung function). The group of children who received DAI + Spacer therapy spent less time in the emergency room; moreover, children in this group had less frequent vomiting and changes in heart rate.

This suggests that young children may need higher doses of salbutamol to achieve optimal treatment results, but on the other hand, high-dose salbutamol therapy in a group of young children may have side effects. Salbutamol dose selection is a problem in pediatric practice. However, research in the framework of medicine evidence on this issue is not enough.

Infant asthma is more common in boys. The male effect affects the severity of asthma in some patients. This is due to the fact that boys' lungs are late in structural development in early childhood compared with the lungs of girls. Male sex is associated with large lung volumes, but with proportionally narrow bronchi. Androgens stimulate the production of epithelium inhibitory factor by fibroblasts, with which they associate a greater frequency of respiratory infections in boys. Severe asthma in boys leads to persistent narrowing of the anatomically narrow bronchi. The frequency of respiratory infections is associated with severe exacerbations and the risk of life-threatening conditions in boys, narrow airways are a risk factor for BA in a group of infants. Despite this, cases of fatal outcome in the infant age group are not frequent and their number has decreased in recent years. Probably, in this age group, sensitivity to therapy is preserved due to the acute course of inflammation and the absence of signs of bronchial remodeling (research on this issue is not enough).

Childhood asthma (3–10 years) is not associated with the risk of fatal outcomes of severe asthma, but research has found much evidence of the progression of inflammation in this age group and signs of remodeling out of touch with the duration and severity of asthma.

In the group of older children (10 - 18 years), the most relevant in the clinic is to increase the frequency of asthmatic status, this age is the peak of infant mortality from asthma. The role of trigger factors is increasing (weather situation, emotional stress, exercise, smoking, pollutants), which indicates an increasing bronchial hyperreactivity. Severe asthma significantly affects the quality of life. In this age group, severe asthma in some children occurs with complications.

An important role in the choice of approaches to the management of patients in the older age group is played by a decrease in sensitivity to steroids, largely due to pro-active inflammation and inadequate basic therapy at the previous stage of treatment. In this regard, in some patients, forms of the disease that are resistant to treatment can be found, which requires modification of treatment approaches.

Refusal of treatment in the group of adolescents, associated with problems related to the attitude of their surrounding people and the underestimation of asthma problems by adolescents themselves, seriously complicates the prognosis of asthma in children. It is noteworthy that instability, emotional lability, and egocentrism dominate among personality traits in the group of children with severe BA. The fear of suffocation forms anxiety, a feeling of rejection, reinforced by the experiences of their difference from peers.

Severe asthma and pharmacological response

As already noted, in some patients with severe asthma adequately, according to the recommendations, the therapy performed does not lead to the desired improvements. Attempts to enhance the pharmacotherapy regimen also do not bring results. This situation is probably known to any doctor treating patients with asthma, and presents constant difficulties in clinical practice. Patients with severe asthma who do not respond to adequate therapy often differ significantly from each other, have different symptoms, functional indicators, a history of the disease and prognosis, but nevertheless all of them belong to the group of “therapeutically resistant” patients.

Severe / Therapeutically Resistant Asthma

Definition

  • Severe / therapeutically resistant asthma is a condition that is not sufficiently controlled (chronic symptoms, episodic exacerbations, persistent and varying airway obstruction, constant need for short-acting b2-agonists), despite the use of adequate doses of corticosteroids.
  • Adequate doses of IKS in relation to complex asthma are:
  • 800 µg of beclomethasone dipropionate or 400 fluticasone propionate.

Place of severe / therapeutically resistant asthma in pediatrics

  1. Prevalence of 1: 1000 population.
  2. Primary age: patients older than 10 years.
  3. Concept: lack of control of the disease with adequate therapy.
  4. Risk factors: the effect of triggers, lack of compliance, associated diseases, etc., corticosteroid resistance.

Diagnostics of therapeutically resistant asthma is carried out on the basis of the following data: if during the last year of observation and the last 6 months of adequate treatment (average doses of ICS) in a patient with severe BA, control cannot be achieved, it should be assigned to the group of therapeutically resistant patients. Such patients should be further examined to identify the causes of the uncontrolled course of the disease, make sure that there is no error in the diagnosis and the child has asthma, to assess compliance and to change the approaches to basic therapy.

Corticosteroid resistance is the only currently known mechanism for therapeutically resistant asthma. Other mechanisms are proposed and discussed. Primary corticosteroid resistance is a rare situation with asthma. Even secondary resistance, which is the end result of progressive inflammation and parallel to the remodeling that goes along with it, is not typical of pediatric practice. Nevertheless, not all patients with severe asthma achieve effective control using a moderate dose of IRS. A small proportion of patients need high doses of IRS, a smaller part - in SCS (as a rule, long courses of SCS after asthmatic status and persistent severe asthma). This is evidence of a partial decrease in sensitivity to corticosteroids in some patients with severe asthma, which is currently regarded as a stage in the formation of corticosteroid resistance.

If a child with severe BA has secondary corticosteroid resistance, it is important to understand that it is reversible in the case of treatment with high doses of corticosteroids.

Clinical phenotypes of therapeutically resistant asthma

  • Fatal and close to fatal asthma. Clinical characteristic: fatal and close to fatal episodes of asthma, accompanied by hypercapnia and requiring EVL. Patients in this group may experience repeated life-threatening seizures, despite adequate X-ray therapy or repeated courses of systemic steroids.
  • Intermittent severe asthma, characterized by sudden acute attacks developing within a few minutes or hours without an objective cause and against the background of almost normal bronchial function or well-controlled asthma. Patients in this group may also experience a wide range of bronchial obstruction, with significant fluctuations in PSV during the day. This group includes patients with night and morning asthma. This clinical option is often called fragile “brittle” asthma.
  • Chronic asthma with persistent bronchial obstruction, with episodes of sudden deterioration or without them, requiring systemic treatment of CS, which nevertheless leads to an incomplete response. It is often referred to as a corticosteroid.

Thus, the group of patients with severe BA is pathogenetically and clinically heterogeneous. This determines their difference in response to therapy, mainly on IRS.

The heterogeneity of severe asthma in children

Depending on age:

  1. infant asthma,
  2. teenage asthma.

Due to the anatomical and physiological features in young children:

  • the narrowness of the bronchi in boys,
  • less elasticity of the lung tissue,
  • nonspecific bronchial hyperreactivity.

Depending on the morphological changes:

  • different severity of the restructuring of the bronchial tree,
  • BA with eosinophilic and BA with neutrophilic infiltration,
  • BA with hyperproduction of IgE and BA with a low level of IgE.

In relation to therapy:

  1. sensitive,
  2. resistant.

According to clinical manifestations:

  • intermittent severe asthma,
  • persistent severe asthma,
  • Fatal and close to fatal asthma.

Maintaining children with severe asthma

Severe BA is heterogeneous. This is obvious to doctors who treat people with asthma every day. Since the clinical phenotypes of severe asthma are not yet clearly defined, an understanding of the treatment of these patients is difficult. However, there are general provisions that need to be fulfilled are postulated in many working papers relating to severe and refractory asthma.

One of them includes 4 components for successful treatment:

  1. Regular assessment of severity by clinical and functional monitoring.
  2. Control factors contributing to the symptoms and severity of the disease.
  3. Pharmacological therapy.
  4. Education of the child, parents and people involved in asthma: a long-term treatment plan and a management plan in exacerbation

1. Regular assessment of severity and monitoring

Children with severe asthma should be monitored by a doctor every month. To this end, the doctor must appoint repeated visits, it is better to record the dates and times of visits in the medical records of the patient. Since the severity of asthma can vary, regular monitoring of patients with any severity of asthma will contribute to the timely diagnosis of deterioration in disease control and the revision of therapy.

2. Control of factors contributing to the symptoms and severity of BA

The patient must have a checklist or clear entries in the outpatient card or self-control diary regarding elimination regimens, the dangers of smoking, the dangers of certain drugs, environmental impacts, and individually significant triggers. The child should, as far as possible, be maximally examined regarding diseases and pathological conditions associated with the deterioration of asthma control. The patient should be vaccinated against childhood infections and the most common respiratory infections.

3. Pharmacological therapy (key points)

Basic therapy

  • Severe BA is best controlled by daily use of corticosteroids.
  • Doses of corticosteroids should be sufficient to effectively suppress inflammation and quickly achieve control of the disease.
  • In case of severe moderate exacerbation or therapeutically resistant asthma, the appointment of SCS should be considered.
  • A stepwise approach to drug therapy is recommended:
    • it is advisable to start therapy with a higher level (step down tactics)
    • treatment revision and step reduction in severe BA should be done every 3 to 6 months, for therapeutically resistant BA, every 6 to 9 months as control is achieved
    • constant monitoring of clinical and functional symptoms is necessary to evaluate the effectiveness of treatment and establish the possibility of a stepwise decrease in therapy.
  • The choice of delivery systems is an important problem in severe BA due to the need to use high doses of drugs. The use of DAIs without spacers or nebulizers is not recommended in both emergency and planned therapy for severe asthma.
  • Verification of therapeutically resistant asthma is necessary in the group of older children to modify the basic therapy to prevent a fatal outcome of severe asthma.

The goals of therapy:

  • prevention of exacerbations
  • prevention of chronic symptoms,
  • maintaining normal lung function,
  • maintaining a normal level of physical activity,
  • optimization of therapy with minimization of side effects,
  • satisfaction of expectations from therapy in the child and his parents,
  • prevention of mortality, disability and complications

Criteria for the effectiveness of therapy / achievement control

  1. Daily symptoms - minimal (0 - 1).
  2. Night symptoms - absent.
  3. Asthma exacerbations are absent.
  4. The need for short-acting bronchodilators - less than 2 doses per day.
  5. Appeals for emergency care / hospitalization are absent.
  6. Daily lability of the bronchi - less than 20%.
  7. PSV (daily average) - more than 80%.
  8. Side effects from the therapy are absent.

In the basic therapy of severe asthma use:

Medium / high doses anti-inflammatory drugs X

Additives:

  • long-acting inhaled b2-agonists,
  • prolonged theophylline forms,
  • anti-leukotriene preparations.

In most children with severe asthma, it is possible to control the course with the help of medium doses of X. Medium doses of IRS can be used as a baseline therapy, as they have demonstrated a good efficacy / safety ratio.

For the additive effect (enhancement of the anti-inflammatory effect of medium doses of IRS and prolonged control of symptoms), prolonged b2-agonists or prolonged theophyllines should be introduced into the basic therapy of severe BA in children.

Modern basic therapy of moderate and severe forms of BA is based on a combination of IRS and B2-agonists with prolonged action. This is due to the preferred clinical pharmacology of the B2-agonists of prolonged action in comparison with theophylline, as well as with the emergence of the combination of serateti and symbicort on the pharmaceutical market. Modern combined drugs for the treatment of moderate and severe asthma in children allow to solve a number of problems in the management of patients with severe asthma due to:

  • higher anti-inflammatory effect when using medium doses of IRS;
  • achieving compliance by simplifying the treatment regimen, higher clinical efficacy, high-quality delivery system, optimal cost / effectiveness ratio;
  • a significant improvement in the quality of life.

Indications for the administration of SCS in children with severe asthma

SCS in the treatment of childhood asthma, especially in long-term therapy, is used infrequently. However, short courses of SCS should be appointed in a timely manner to prevent the fatal course of the disease:

  • aggressive initial therapy to achieve rapid control of asthma or when the control of severe asthma worsens and symptoms increase (a short course of 3–10 days);
  • long-term therapy for severe persistent asthma with the ineffectiveness of other drugs (high doses of ICS and long-acting bronchodilators);
  • in case of severe exacerbation caused by respiratory infection (a short course of 3–10 days);
  • with severe exacerbations of intermittent BA, most often triggered by a respiratory infection (short course of 3–10 days);
  • preventive treatment of exacerbations (immediate administration with worsening of control) in case of fatal asthma.

Regular medical observation in severe asthma, a systematic assessment of the effectiveness of therapy according to the criteria of “well-controlled asthma” allow us to diagnose therapeutically resistant asthma in a timely manner. Isolation of patients who are resistant to therapy, and the revision of the tactics of their treatment are the basis for the prevention of adverse dynamics of asthma and its fatal outcomes.

Treatment of patients with therapeutically resistant asthma

  • Persistent severe asthma: the minimum effective dose of SCS and the maximum dose of X. Repeated attempts should be made to reduce the dose of SCS to the minimum effective (FEV1> 80%)
  • Intermittent severe BA (brittle): high doses of X-ray and b2-agonists of the prolonged action or seretid (on fluticasone 250 mcg 2 times a day).
  • Fatal asthma: high doses of IRS and prolonged action bronchodilators. Early appointment of SCS during exacerbation.

4. Education

In severe asthma, patient formation can most often be initiated by ambulance doctors, intensive care units, hospitals and intensive care units. It is important to use these health care providers to inform patients about where they can get the necessary information about their illness (asthma schools, asthma days, patient associations, Asthma and Allergies). Education in this group of patients should be targeted, it should focus on risk factors contributing to severe asthma, and on preventing fatal outcome (use of high doses of IC in necessary situations - SCS, early taking of SCS during exacerbation, treatment of complications, etc.).

Important for a child with severe asthma are regular medical observation and the joint development of a long-term treatment plan and a plan of action in an emergency. If the child had a history of asthmatic statuses or life-threatening seizures, then parents should know to which emergency room their child is attached, the patient himself should have this information.

Conclusion Doctors often consider it a success if patients with severe asthma succeed in reducing the severity of symptoms, rather than in complete control of the disease, as stated in the national program “Bronchial Asthma in Children. Treatment strategy and prevention. Meanwhile, severe asthma in the vast majority of children, unlike adult patients, has an optimistic prognosis, provided that it is correctly administered and adequate basic therapy. The physician must correctly determine the treatment goals for his patients. This approach will allow for better control of asthma and increase the expectations of patients and their parents from the treatment.

  • The patient should be attributed to the group of severe asthma, if there is at least one sign corresponding to the severe form of the disease.
  • The severity of asthma may change over time.
  • Changes in the treatment of asthma in the last 10 years indicate that not only clinical and functional parameters, but also the amount of therapy received, which leads to control of the disease, should be taken into account when diagnosing severity (R. Liard, 2000). If the clinical and functional parameters for asthma fit the criteria for moderate, but asthma is resistant to therapy and requires high doses of ICS, the patient should be classified as severe asthma.

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