Asthma

 Bronchial asthma 

 Asthma is a chronic non-infectious inflammatory disease of the respiratory tract. The key link in asthma is non-infectious inflammation of bronchial tissues  and the response of the body - hypersecretion of protective bronchial secretions (mucus) and bronchospasm - (narrowing of the bronchial lumen, which reduces the entry of allergens or nonspecific irritants into the bronchial tissues). Inflammation is directly caused by specific immunological  or non-specific mechanisms (chemical and physical irritants), and bronchospasm is the most clinically significant symptom of the disease, manifested by recurrent episodes of wheezing, dyspnea, choking attacks, chest tightness/tightness, and choking cough. Bronchial obstruction is partially or completely reversible, spontaneously or under the influence of treatment.

For treatment, symptomatic drugs are used to relieve an attack, and basic therapy drugs that affect the pathogenetic mechanism of the disease. A terrible complication of the disease is status asthmaticus.

Definition 

        According to the GINA 2006 global strategy, bronchial asthma is “a chronic inflammatory disease of the respiratory tract, in which many cells and cellular elements are involved. Chronic inflammation causes bronchial hyperreactivity, which leads to recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing, especially at night and in the early morning. These episodes are usually associated with widespread but variable airway obstruction in the lungs, which is often reversible, either spontaneously or with treatment.

        As defined by WHO experts, bronchial asthma is “a chronic disease, the basis of which is an inflammatory process in the airways involving a variety of cellular elements, including mast cells, eosinophils and T-lymphocytes. In predisposed individuals, this process leads to the development of generalized bronchial obstruction of varying severity, fully or partially reversible spontaneously or under the influence of treatment. The inflammatory process also causes a friendly increase in the response of the respiratory tract in the form of bronchial obstruction to various external and internal stimuli.

 At the end of the 20th century, the formulation of G. B. Fedoseev (1982) was popular in the USSR and Russia, according to which bronchial asthma is “an independent chronic, relapsing disease, the main and obligatory pathogenetic mechanism of which is an altered bronchial reactivity due to specific immunological (sensitization and allergies) or non-specific mechanisms, and the main (mandatory) clinical sign is an asthma attack due to bronchospasm, hypersecretion and swelling of the bronchial mucosa".

  

Epidemiology 

     The incidence of bronchial asthma in the world is from 4 to 10% of the population. In some regions , according to various sources, the prevalence among the adult population ranges from 2.2 to 5-7%, and in the child population this figure is about 10%. The disease can occur at any age; about half of the patients develop bronchial asthma before the age of 10, and in another third - before the age of 40. Among children with bronchial asthma, there are twice as many boys as girls. By the age of 30, the sex ratio levels off.

Studies have noted relatively high incidence rates in New Zealand, Great Britain, and Cuba. This is due to the fact that the concentration of allergens over the islands increases both due to the local flora and due to allergens brought by oceanic air currents. Since the mid-1980s, there has been an increase in the incidence of bronchial asthma. According to an analysis of 34 incidence studies in Europe, in Austria from 1992 to 2002 the incidence among children increased 4 times, in Italy from 1974 to 1998 it increased from 7 to 13%, in many European countries (Great Britain, Finland, Switzerland) - grew until the mid-1990s, but has recently declined somewhat. On the contrary, in Germany from 1992 to 2001 this figure remained at the level of 5%. The increase in the incidence is associated with environmental pollution, an inactive lifestyle, and its decrease in recent years is explained by the success of basic therapy. Thus, the introduction of preventive treatment and patient education in Ireland led to a more than 5-fold decrease in the incidence of severe asthma in schoolchildren from 1992 to 2002. 

Disease development factors 

            There are a number of risk factors that contribute to the onset and development of asthma in certain individuals.

            1. Heredity 

                    Much attention is paid to the genetic factor. Cases of concordance are described, that is, when both identical twins were ill with bronchial asthma. Often in clinical practice there are cases of asthma in children whose mothers are sick with asthma; or cases in several generations of the same family. As a result of clinical and genealogical analysis, it was found that in 1/3 of patients the disease is hereditary. There is a term atopic bronchial asthma- allergic(exogenous)bronchial asthma, which is hereditary. In this case, in the presence of asthma in one of the parents, the probability of asthma in the child is 20-30%, and if both parents are sick, this probability reaches 75%. 

       

                 The PASTURE study, which observed the formation of atopy in newborns in families of farmers and in monozygotic twins, showed that, despite the genetic predisposition, the development of the disease can be prevented by eliminating provoking allergens and by correcting the immune response during pregnancy. Norwegian scientists (Matthias Wjst et al.) found that the place and time of birth do not affect the formation of allergic reactions and bronchial asthma.

  2.  Professional factors 

   The effect of biological and mineral dust, harmful gases and fumes on the occurrence of respiratory diseases was studied in 9144 people at 26 centers in the ECRHS study. Women mainly contacted with biological dust, and men 3-4 times more often than women with mineral dust, harmful gases and fumes. Chronic cough with sputum production more often occurred in people who were in contact with harmful factors; it is in this population that cases of first-time bronchial asthma have been recorded. Over time, nonspecific bronchial hyperreactivity in people with occupational asthma does not disappear, even with a decrease in contact with a harmful professional factor. It has been established that the severity of occupational asthma is mainly determined by the duration of the disease and the severity of symptoms, and does not depend on age, gender, harmful occupational factors, atopy, or smoking.

 3.  Environmental factors 

      Hygiene hypothesis The 9-year epidemiological study ECRHS-II, which included 6588 healthy individuals exposed during the specified period to a number of adverse factors (exhaust fumes, smoke, high humidity, harmful fumes, etc.), showed that 3% of those observed at the end of the study had complaints corresponding to the defeat of the respiratory system. After statistical analysis demographic, epidemiological and clinical data, it was concluded that 3 to 6% of new cases of the disease are provoked by exposure to pollutants. 

     4. Nutrition 

     Studies  on the influence of diet on the course of the disease showed that people who consume plant products, juices rich in vitamins, fiber, antioxidants have a slight tendency to a more favorable course of bronchial asthma, while as the use of animal products rich in fats, proteins and refined easily digestible carbohydrates,associated with a severe course of the disease and frequent exacerbations. 

    6. Detergents 

   A 10-year ECRHS study in 10 EU countries found that floor cleaners and cleaning sprays contain substances that trigger asthma in adults; about 18% of new cases are associated with the use of these agents.

    7.Microorganisms 

           For a long time there was an idea about the existence of asthma of an infectious-allergic nature 

    8.  Overweight 

    According to various studies, in children who suffer from obesity, the risk of developing bronchial asthma increases by 52%.

   9.  Triggers 

        Triggers, that is, factors that cause asthma attacks and exacerbation of the disease, are allergens for exogenous bronchial asthma and NSAIDs for aspirin bronchial asthma, as well as cold, strong odors, physical stress, chemical reagents.

   Pathogenesis 

The key link in bronchial asthma of any genesis is the increased reactivity of the bronchial tree. It is caused by a violation of the autonomic regulation of smooth muscle tone and the action of inflammatory mediators and leads to periodic reversible bronchial obstruction, which is manifested by an increase in airway resistance, hyperextension of the lungs, hypoxemia caused by focal hypoventilation and a mismatch between ventilation and lung perfusion, hyperventilation.

The role of the autonomic nervous system:

      Autonomic nervous system On smooth muscle cells are β1-, β2- and α-adrenergic receptors. β2-adrenergic receptors predominate, in comparison with them, β1-adrenergic receptors are 3 times less. Stimulation of β2-adrenergic receptors reduces bronchial reactivity in patients with bronchial asthma, however, blockade of β-adrenergic receptors in healthy individuals does not cause a noticeable change in bronchial reactivity, stimulation of α-adrenergic receptors has almost no effect on the tone of bronchial smooth muscles. 

      Normally, the tone of bronchial smooth muscles is regulated mainly by parasympathetic fibers of the vagus nerve. The use of drugs that block the conduction of excitation along the parasympathetic fibers leads to the expansion of the bronchi, and the stimulation of these fibers causes bronchospasm. The tone of the smooth muscles of the bronchi also changes under the influence of afferent fibers coming from the bronchial receptors and which are part of the vagus nerve.

The sympathetic nervous system normally plays an insignificant role in the regulation of bronchial muscles, but in bronchial asthma its role increases. Stimulation of unmyelinated fibers (type C afferent fibers located in the wall of the bronchi and alveoli) by inflammatory mediators results in the release of neuropeptides, such as substance P, which cause bronchial constriction, mucosal edema, and increased mucus secretion. 

Biochemical factors 

    Calcium plays an important role in the contraction of bronchial muscles, since the ATP-dependent calcium pump that removes calcium from the cell is involved in maintaining the resting membrane potential of smooth muscle cells. An increase in calcium concentration inside the cell leads to contraction, and a decrease to relaxation of smooth muscle. In addition, an increase in intracellular calcium concentration causes the release of histamine, anaphylactic eosinophil chemotaxis factor and anaphylactic neutrophil chemotaxis factor from mast cells. It is assumed that adrenoreceptors are involved in the regulation of calcium levels in mast cells.

Cyclic nucleotides (cAMP and cGMP) are involved in the regulation of contraction of bronchial smooth muscle cells and degranulation of mast cells. The release of mediators by mast cells under the influence of M-cholinergic stimulants and prostaglandin F2α is mediated by an increase in the level of cGMP. Stimulation of α-adrenergic receptors leads to a decrease in cAMP levels, which also causes degranulation of mast cells. Stimulation of β-adrenergic receptors leads to an increase in the level of cAMP and, as a result, to inhibition of mast cell degranulation. It is believed that the blockade of adenosine receptors also inhibits degranulation. The pathogenesis of exogenous bronchial asthma also involves heparin, thromboxanes, serotonin, oxygen free radicals,kinins, neuropeptides, proteases and cytokines. 

Involvement of inflammatory cells:

 Mast cells. 

    Mast cell activation occurs when allergens interact with IgE fixed on the surface of mast cells in exogenous bronchial asthma. In the case of endogenous asthma, mast cell activation may occur under the influence of osmotic stimuli, such as in exercise asthma. When activated, they release mediators (histamine, cysteinyl leukotrienes, prostaglandin D2) that cause bronchospasm.

In parallel with this, arachidonic acid and platelet activating factor are formed from the phospholipids of the mast cell membrane. From arachidonic acid, in turn, leukotrienes and prostaglandins are formed.

 Eosinophils. 

 The number of eosinophils in the airways is increased. These cells secrete the main proteins that damage the bronchial epithelium and are also involved in the release of growth factors and airway remodeling. 

 

T-lymphocytes. 

    Their number in the respiratory tract is also increased. They release specific cytokines (IL-4, IL-5, IL-9 and IL-13, etc.) that affect the process of eosinophilic inflammation and the production of IgE by B-lymphocytes. Regulatory T cells inhibit Th2 lymphocytes, so an increase in Th2 cell activity may occur with a decrease in the number of regulatory T cells. It is possible to increase the number of inKT cells that secrete Th1 and Th2 cytokines in large quantities. 

    

Dendritic cells capture allergens from the surface of the bronchial mucosa and bring them to the regional lymph nodes, where, interacting with regulatory T cells, they stimulate the differentiation of T lymphocytes into Th2 cells.

 macrophages. 

     The number of macrophages, like eosinophils and T-lymphocytes, is increased in the airways. They can be activated when allergens interact with low-affinity IgE, resulting in the release of inflammatory mediators and cytokines. 

     

Neutrophils. 

   Their number in the respiratory tract and sputum is increased in patients with severe asthma and smoking patients. The role of these cells in pathogenesis has not been elucidated. Perhaps an increase in their number is a consequence of glucocorticosteroid therapy.

   

 Inflammatory mediators 

 

  Histamine and leukotrienes are mediators of the early phase of an immediate allergic reaction. As a result of the action of histamine, an instantaneous and short-term bronchospasm occurs, while leukotrienes cause a delayed and longer bronchospasm. The mediators of the late phase of an allergic reaction of the immediate type include chemotaxis factors and platelet activating factor. The latter cause chemotaxis, activation of 

inflammatory cells in the bronchial mucosa and stimulate the synthesis of leukotrienes in these cells. Bronchospasm caused by them occurs 2-8 hours after the onset of an allergic reaction and can last for several days.

Involvement of structural cells of the respiratory tract:

       The structural cells of the airways also contribute to the development of inflammation. Thus, bronchial epithelial cells, when recognizing their mechanical environment, express various proteins and release cytokines, chemokines, and lipid mediators. Similar inflammatory proteins are produced by smooth muscle cells. Endothelial cells are involved in the migration of inflammatory cells into the respiratory tract. Fibroblasts and myofibroblasts, through the production of collagen, proteoglycans and other connective tissue components, are involved in airway remodeling.

Clinical picture 

    The main symptoms of bronchial asthma are episodes of shortness of breath, wheezing, coughing, and chest congestion. The appearance of symptoms after exposure to the allergen, the seasonal variability of symptoms, and the presence of relatives with bronchial asthma or other atopic diseases are essential. When combined with rhinitis, asthma symptoms may either appear only at certain times of the year, or be present constantly with seasonal aggravations. In some patients, seasonal increases in airborne levels of certain aeroallergens (eg, Alternaria pollen, birch, grass, and ragweed) cause flare-ups.

These symptoms may also develop upon contact with non-specific irritants (smoke, gases, pungent odors) or after physical exertion, may worsen at night and decrease in response to basic therapy. An asthma attack is the most common symptom of asthma. A forced position is characteristic (often sitting, holding hands on the table), the patient's posture is with a raised upper shoulder girdle, the chest becomes cylindrical. The patient takes a short breath and, without a pause, a long painful exhalation, accompanied by distant wheezing. Breathing occurs with the participation of the auxiliary muscles of the chest, shoulder girdle, abdominals.

The intercostal spaces are widened, retracted and located horizontally. On percussion, a box pulmonary sound is determined, a downward displacement of the lower borders of the lungs, an excursion of the lung fields is barely detected. Often, especially with prolonged attacks, there is pain in the lower part of the chest, associated with the intense work of the diaphragm. An attack of suffocation may be preceded by an aura of an attack, manifested by sneezing, coughing, rhinitis, urticaria, the attack itself may be accompanied by a cough with a small amount of vitreous sputum, and sputum may also be separated at the end of the attack. Auscultation revealed weakened breathing, dry scattered rales. Immediately after coughing an increase in the number of wheezing wheezes is heard, both in the inhalation and exhalation phases, especially in the posterior-lower sections, which is associated with the secretion of sputum into the lumen of the bronchi and its passage. As the sputum is discharged, the number of wheezing decreases and breathing from weakened becomes hard [16]. Wheezing may be absent in patients with severe exacerbations due to severe airflow and ventilation limitation. During the period of exacerbation, cyanosis, drowsiness, difficulty in speaking, and tachycardia are also noted. A swollen chest is a consequence of increased lung volumes - it is necessary to ensure the "straightening" of the respiratory tract and the opening of small bronchi. Combination of hyperventilation and bronchial obstruction significantly increases the work of the respiratory muscles. Patients may show no signs of illness between attacks. In the interictal period, patients most often have wheezing during auscultation, confirming the presence of residual bronchial obstruction. Sometimes (and sometimes simultaneously with severe bronchial obstruction), wheezing may be absent or detected only during forced expiration. A special clinical variant is cough variant of asthma, in which the only manifestation of the disease is a cough. This variant is more common in children, with the most severe symptoms usually occurring at night with frequent no symptoms during the day. The importance in diagnosis is the study of the variability of indicators of respiratory function or bronchial hyperreactivity, as well as sputum eosinophilia. The cough variant of asthma should be distinguished from eosinophilic bronchitis, in which cough and sputum eosinophilia are noted, but respiratory function and bronchial reactivity remain normal.

Bronchial asthma of physical effort. 

     In some patients, the only trigger for an attack is physical activity. The attack usually develops 5-10 minutes after the cessation of the load and rarely - during the load. Patients sometimes note a prolonged cough, which resolves on its own within 30-45 minutes. Attacks are more often provoked by running, while inhalation of dry cold air matters. 

Diagnostics 

The diagnosis of asthma is supported by the cessation of an attack after inhaled β2-agonists or the prevention of symptoms due to inhalation of β2-agonists before exercise. The main diagnostic method is the 8-minute run test.

 When making a diagnosis of bronchial asthma, the following key points are taken into account: complaints (cough, shortness of breath, asthma attacks, difficulty in performing physical activity), anamnesis of the disease, clinical manifestations (intermittent speech, orthopnea position); the results of a physical examination (acceleration or deceleration of heart rate, shortness of breath, dry wheezing, aggravated on exhalation); study of the function of external respiration (a decrease in FEV1 values, and an increase in FEV1 after a test with bronchodilators by more than 12% of the initial one, a decrease in FVC, a decrease in PSV and an increase in its daily variability);

the presence of eosinophils in sputum or bronchial secretions, blood eosinophilia, sputum is viscous, difficult to separate, often two-layer, with a large number of eosinophils, Kurschman spirals (weaving of small bronchi), Charcot-Leiden crystals (necrotic neutrophils that previously infiltrated the bronchial wall); allergic status: skin (application, scarification, intradermal) tests, nasal, conjunctival, inhalation tests, radioallergosorbent test, determination of general and specific IgE. Very often, a doctor can make a diagnosis of asthma based on the clinical picture.

If a patient is suspected of having bronchial asthma, the following clinical criteria are evaluated:

 whether the patient has episodes of wheezing, including recurring ones; Does the patient have a cough at night? whether the patient has wheezing and coughing 10-20 minutes after exercise; whether the patient has episodes of coughing, dry wheezing, shortness of breath after meeting with provoking factors (allergens, pollutants); whether the patient notes the transition of the infection to the lower respiratory tract, if SARS lasts more than 10 days; whether the severity of complaints decreases after taking specific anti-asthma drugs.

The presence of one or more of these symptoms allows the doctor to make sure that further examination is necessary to finalize the diagnosis. Clinically, bronchial asthma without exacerbation may not manifest itself or proceed according to the cough variant, when the only sign of the disease is a cough with a small amount of sputum discharge. Often, a cough variant of bronchial asthma is diagnosed as bronchitis without instrumental laboratory research. In such cases, functional respiratory tests with bronchodilators and laboratory tests of blood and sputum come to the fore.

The diagnosis of bronchial asthma, especially in the early stages, with a mild clinic, requires functional tests with bronchodilators, which can detect the presence of clinically unexpressed bronchospasm and determine the degree of reversible bronchial obstruction. In patients with characteristic complaints, with normal indicators of lung function, for a reliable diagnosis, a study of bronchial reactivity is performed, which includes a study of the function of external respiration with pharmacological tests with histamine, methacholine or bronchodilators.

Most patients with atopic asthma have an allergy that can be detected using skin prick tests. They also allow you to detect a provoking factor. In some patients with bronchial asthma, gastroesophageal reflux disease can be found. Other tests (such as a chest x-ray or CT scan) may be needed to rule out other lung diseases. 

BY DR SHER JAHAN