The main risk factor for asthma in childhood is considered a genetic predisposition to allergies, together with the early exposure to aeroallergens and sensitization of the respiratory tract to them. While exposure to allergens can actually exacerbate, most acute asthma attacks in children, especially young children, are associated with a respiratory viral infection. The relationship between a respiratory viral infection and exacerbations of asthma is extremely interesting and important, since it is often difficult to diagnose asthma in young children and interpret the role of acute respiratory viral infections in the development of asthma and its exacerbations
Immunological studies have shown that in the respiratory tract there are two subpopulations of helper lymphocytes Th1 and Th2. The Th1 subtype secretes certain cytokines, including interferon-gamma and interleukin-10, which are important in protecting against bacterial and viral infections. The Th2 subtype is regarded as “pro-atopic,” since it secrets cytokines such as IL-4 and IL-5, which promote mast cell proliferation, IgE production, differentiation, and the attraction and survival of eosinophils. The production of cytokines by these two subtypes of lymphocytes is mutually controlled: interferon-gamma and IL-10 inhibit Th2 differentiation, and IL-4 inhibit Th1 differentiation. Thus, a decrease in the frequency of acute respiratory viral infections in childhood can hypothetically contribute to the Th2 response to aeroallergens.
Viruses that cause obstruction in children depend on age. So in children under two years of age, obstruction is provoked (while asthma may not be) mainly respiratory syncytial virus and parainfluenza virus.
In children of the first year of life who do not suffer from asthma, obstruction at an early age as a result of a viral infection is associated with the action of inflammation on the small airways, which have anatomical features. They have a lower maximum expiratory flow rate, even when they are healthy, compared with children who have never had obstruction, and this difference persists in later life, although bronchial hyperreactivity is not observed.
When children get older and have asthma, the virus profile changes significantly, dominating the rhinovirus infection. With the introduction of highly sensitive and highly specific methods of polymerase chain reaction for the determination of viruses, it has been shown that more than 80% of asthma exacerbations in children are combined with SARS, and rhinovirus is found in more than 60% of the viruses detected. Influenza and parainfluenza can also cause obstruction in children with asthma, but to a lesser extent. In addition, there is a seasonality of SARS causing obstruction. In children with asthma, exacerbations are not uncommon in September, after summer vacations, and in early spring, as well as in November and early winter, when an influenza epidemic develops.
Epidemiological studies of children suffering from lower respiratory tract infection with obstructive syndrome in the first 2 years of life have shown that obstructive syndrome in young children does not increase the risk of developing asthma in subsequent years. Even most children from families with an atopic history do not have obstruction after 3 years. However, in children and adults who already have asthma, the most common cause of exacerbation is viral respiratory infections. Numerous changes in the airways during acute respiratory viral infections can exacerbate existing airway inflammation and hyperreactivity. Examination of patients entering the emergency room with exacerbation of asthma during acute respiratory viral infections indicates that their sputum contains a high proportion of polymorphonuclear leukocytes and a high concentration of neutrophilic elastase, albumin, mucin, mast cell tryptase and IL-8 and IL-6. An increase in polymorphonuclear leukocytes is especially pronounced in those patients in whom symptoms of a respiratory viral infection precede exacerbation of asthma. All this made it possible to establish that the exacerbation mechanism involves a normal inflammatory response to a viral infection.
In practice, it is not always possible to determine which virus caused an exacerbation of asthma and accordingly study its effect on the course of the disease. In experimental studies, it has been shown that viruses (especially intensively rhinovirus) increase bronchial reactivity, a key sign of asthma. Bronchial hyperreactivity after rhinovirus infection can be up to 15 days long; rhinovirus infection increases the risk of developing late allergic reactions and the severity of components such as increased mast cell secretion, increased inflow of eosinophils into the bronchial mucosa, and the sensitivity of beta-adrenergic receptors decreases. Viruses can enhance cholinergic activity, increasing the response of the respiratory tract to vagal stimulation, nonspecific triggers.
To date, there is a point of view that children in whom rhinovirus causes obstruction have asthma, and the virus causes the manifestation of the disease, worsens its course. The following criteria help diagnose asthma in this group of children: repeated obstruction over a period of more than three times during the year, protracted obstruction, good response to bronchodilator therapy, heredity often aggravated by allergic diseases, and early allergic manifestations in a child.
A biopsy of the nasal mucosa during acute respiratory viral infections shows slight signs of damage to the epithelium or inflammation, even when inflammatory cells are abundantly present in nasal secretions, but the experiment shows impaired ciliary cell function. Since the epithelium is not significantly disturbed, attention is shifted to the role of inflammatory mediators that cause the clinical and physiological consequences of viral respiratory infection in the lower respiratory tract. A possible role is played by intercellular adhesive molecules (ICAM 1), which are located on the surface of nasal epithelial cells and are the receptor for the main group of rhinoviruses and the IL-11 cytokine, which activates B cells through a T-cell-dependent mechanism.
Despite the pronounced combination of rhinovirus infection with exacerbations of asthma in epidemiological studies, experimental virological studies suggest that the rhinovirus infection itself is not sufficient to provoke an exacerbation. Only some viruses or serotypes can cause an asthmatic attack in a sensitive host. It is possible that an enhanced inflammatory response to a viral infection provokes cytokines present in the airways. The same cytokines that cause inflammation caused by contact with specific allergens in individuals with allergies can even direct the mucosal immune response to respiratory viruses from the usual Th1 to Th2 defense response, and instead of the response to viral peptide stimulation in the usual way with interferon production the gamma and cytolytic effect of infected epithelial cells, Th2 cytokines are produced and the most important of them is IL-4, which attracts cells involved in allergic inflammation, as well as IL-8, tumornecro tizing factor and others. Cytokines also interact with other cells, such as macrophages, and these cells secrete their cytokine profile. Thus, the regulation of existing inflammation is disrupted and a cascade of mutually reinforcing effects occurs.
Another mediator that is produced by the epithelium is involved in the development of asthma – nitric oxide (NO). Nitric oxide can have an antiviral effect and is part of the response to viral infections of the upper respiratory tract. It is also a mediator that enhances bronchial blood flow, eosinophilic infiltration, damage to the respiratory epithelium, and can inhibit the proliferation of Th1 T cells, shifting the profile of T cell cytokines towards the Th2 phenotype. Kinins, which are peptide hormones formed in tissues and fluids, are involved in the pathogenesis of asthma in connection with the bronchoconstrictor and pro-inflammatory effects. Experimental rhinovirus infection significantly increases the level of kinins, as well as the overall level of IgE in serum. An increase in the level of virus- and allergen-specific IgE may reflect a dysregulation of IgE production.
Understanding the mechanisms by which a respiratory viral infection leads to inflammation suggests possible directions for therapeutic effects. Since allergic inflammation alters the immune response to a viral infection, preventive anti-inflammatory therapy can help restore the usual defense mechanism against infections. A decrease in the intensity of allergic inflammation in the airways will also reduce the likelihood of severe asthma attacks associated with a virus infection. In addition, the intensity of responses to viruses is related to the intensity of existing airway obstruction in children with asthma, i.e. in more severe asthma, when the secretion of pro-inflammatory cytokines is most pronounced, the response to a viral infection will be more pronounced. An important factor is the number of eosinophils in the airways.
Thus, the main way is to reduce the processes of inflammation in the airways. In accordance with the Russian National Program “Bronchial Asthma in Children. Treatment strategy and prevention ”in children with mild to moderate asthma, the basic anti-inflammatory drugs are sodium cromoglycate (intal) and sodium nedocromil (tiled). Long-term use of these drugs for at least two months leads to a decrease in the number of eosinophils both in the mucosa of the respiratory tract and in blood serum, a decrease in the secretion of cytokines, and a decrease in bronchial hyperreactivity. Accordingly, the clinical manifestations of bronchial asthma, the need for bronchodilators are reduced, the incidence of obstructive syndrome during the onset of respiratory viral infections is reduced.
Inhibition of cytokine production can be achieved with drugs such as corticosteroids. Inhaled corticosteroids (beclomethasone, flunisolide, budesonza, fluticasone propionate) are the first choice for basic treatment of severe asthma, and are also used in children with non-steroidal anti-inflammatory drugs. The use of inhaled corticosteroids in children with asthma with the first onset of cold symptoms reduces the frequency of hospitalizations for asthma by 90%. The use of nasal sprays of non-steroidal drugs (lomuzole, cromoglin) and corticosteroid (flixonase, beconase) in children with a combination of bronchial asthma and allergic rhinitis reduces allergic inflammation from the upper respiratory tract, reduces the response to viral infections.
Another way is to increase the nonspecific resistance of the organism of children, which can be achieved both by using immunostimulating therapy and non-drug methods. In numerous studies, the effectiveness of the immunostimulant of the microbial origin of ribomunyl has been proved, combining the properties of specific and non-specific immunostimulants, which is associated with the presence in its composition of ribosomes of the most common pathogens of respiratory tract infections (diplococcus pneumonia, streptococcus, Klebsiella pneumonia). Ribomunyl stimulates polynuclear cells and macrophages, promotes the production of IL-1 and IL-6, increases the production of specific antibodies, the activity of natural killers. A good effect on the incidence of acute respiratory viral infections in children with bronchial asthma is the method of interval hypoxic training using inhalation of a gas mixture with a low oxygen content. Conducting such repeated courses with an interval of 3-4 months 2.5-3 times reduces the frequency of acute respiratory viral infections and, accordingly, exacerbation of bronchial asthma, normalizes vegetative tone, stimulates adrenal function. As a rule, drug and non-drug methods are used in combination, complementing each other. The doctor should assess the environmental factors, eliminate or reduce the effects of house dust, tobacco, possible provoking allergic factors, carry out sanitation of the nasopharynx in the presence of chronic foci of infection, use hardening, dosed physical activity. Further study of virus-induced exacerbations of asthma, an understanding of the mechanisms underlying them, will allow us to develop new ways of therapeutic interventions.