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МИНИСТЕРСТВО ЗДРАВООХРАНЕНИЯ УКРАИНЫ
Харьковский государственный медицинский университет
Clinics, diagnostics, treatment
METHODICAL ELABORATIONS FOR FOREIGN STUDENTS
БРОНХИАЛЬНАЯ АСТМА У ДЕТЕЙ.
Клиника, диагностика, лечение.
МЕТОДИЧЕСКИЕ РЕКОМЕНДАЦИИ ДЛЯ СТУДЕНТОВ
Утверждено
Ученым советом ХГМУ
Протокол № ___ от ____________
Харьков ХГМУ 2007
Бронхиальная астма у детей. Клиника, диагностика, лечение: Метод. Указ. Для студентов / Сост. Ю.В. Одинец, А.Ф. Ручко, И.Н. Поддубная, Н.П. Алексеева.- Харьков: ХГМУ, 2007.- 11 с.
Составители: Ю.В. Одинец
А.Ф. Ручко
И.Н. Поддубная
Н.П. Алексеева
Bronchial asthma in children. Clinics, diagnostics, treatment: Methodical elaboration for students / Authors: Yu.V. Odinets, A.F. Ruchko, I.N. Poddoubnaya, N.P. Alekseeva.- Kharkov: KhSMU, 2007. – 11 p.
Учебное издание
БРОНХИАЛЬНАЯ АСТМА У ДЕТЕЙ.
КЛИНИКА, ДИАГНОСТИКА, ЛЕЧЕНИЕ.
Методические указания для студентов.
Составители: Одинец Юрий Васильевич
Ручко Анатолий Федорович
Поддубная Ирина Николаевна
Алексеева Наталья Павловна
Ответственный за выпуск Ю.В. Одинец
Редактор _____
Компьютерная верстка ___
План 2005 г., поз.
Подп. к печ. ______________. Формат А5. Бумага типогр. Ризография.
Усл. Печ. Л. Уч.-изд. Л. Тираж 300 экз. Зак. № Бесплатно.
ХГМУ, 61022, Харьков, проспект Ленина, 4
Редакционно-издательский отдел
Clinics, diagnostics, treatment
METHODICAL ELABORATIONS FOR FOREIGN STUDENTS
Authors: prof.Yu.V.Odinets
prof. Ruchko A.F.
top lecturer I.N.Poddoubnaya
ass.N.P.Alekseeva
Progressive increase of number of patients with nonspecific lungs diseases, especially with respiratory allergoses, in pathogenesis of which allergy plays main role, and affection of respiratory organs are on the first plan in clinical picture, is seen from the second half of XX century. Respiratory allergoses – it’s a collective concept. It unites allergic affection of upper respiratory tract (small forms of respiratory allergoses: allergic rhinitis, pharyngitis, tracheitis), bronchial asthma (BA), exogenous allergic alveolitis, allergic pneumonia, eosinophilic pulmonary infiltrate.
Bronchial asthma is the widespread disease all over the world. Epidemiological investigations of last years are evidence of bronchial asthma presence in 4 to 8% of population, in children population this figure increases up to 5-10%. There are more than 100 millions of patients with bronchial asthma in the world. Hereditary predisposition in children with BA varies between 30 to 80% and more, that testifies to unfavorable prognosis as for BA morbidity in future.
Problems of BA diagnostics and treatment obtained international significance. In 1992 by initiative of Institution of Heart, Lungs and Blood (USA) work team of 18 expert from 11 countries prepared “Report on International Consensus of Asthma Diagnostics and Treatment” in which scientific achievements in disease’s investigation are presented, and practical approaches of its diagnostics and treatment are determined. According to definition given in report, bronchial asthma – is genetically determined inflammatory disease of respiratory ways, which is characterized with:
reversible obstruction of bronchi (variability of obstruction)
presence of allergic process in mucous membrane of bronchi
hyperreactivity of bronchi – increased sensitivity of bronchial tree to various environmental factors.
There are 2 elements having important practical meaning for BA treatment in this definition:
Henceforth strategy of therapy tactics was essentially supplemented in “Report of International Work Group at Risk and Safety of Anti-Asthmatic Therapy” in 1994. Work group of experts in 1998 elaborated national program of BA diagnostics and treatment in Kiev.
Thus, BA remains actual, widely studied problem at present.
Etiology of bronchial asthma.
Sensibilization of an organism to various allergens plays prominent role in BA etiology. Increased sensitivity to allergens is often genetically determined. Inclination to IgE hyper production is transmitted as autosomal-recessive sign. A child has more chances to fall ill (40-60%) if both parents suffer from BA; if maternal heredity is charged – disease appears in 50%, if paternal – in 25% of cases. Polygenic type of heredity is assumed. It has been noticed that boys fall ill 2,4 times more often than girls. Exudative-catarrhal diathesis, child’s exema, allergic reactions to food products and remedies, Quinke’s edema and nettle-rash are seen in patients with BA trustworthy more often.
At present genes, which control IgE and cytokines production (they are localized on 14th chromosome – 14q11.2, 14q23, 14q32.1) and development of bronchial hyperreactivity (genes identified and localized on 5th chromosome – 5q23.31, as well as genes responsible for interleukins 3,4,5,9,12,13 synthesis, glucocorticoid and b2-adrenoreceptors) are mapped. Each from genetic predisposing factors increases probability of BA development, and their combination leads to high risk of disease’s appearance at minimal assistance of environmental factors. Risk factors taking part in BA development in children are presented in the table 1.
Different allergens, invading an organism predominantly by inhalation way, are causative factors, which leads to BA attack development. Domestic allergens (especially domestic dust) play paramount role among non-specific allergens. This is compound as for composition and structure antigen, which contains non-organic components (lime, cement etc.) and organic particles, mainly products of domestic human activity: fibers of woolen and plant tissues, desquamated epithelial cells, human and animal’s hair. To a considerable extent allergenicity of domestic dust is due to presence of great quantities of micromites Dermatophagoides pteronissimus - from 500 up to 2270 in 1g. They dwell mainly in bedclothes, soft furniture, carpets, human and animal’s hair, and appear in the air during cleaning. Desquamated epithelium and secretion of sebaceous glands are nutrient medium for these mites. Mite itself is allergenic as well as its excrements and dead mites.
Pollen allergens constitute the second group, as a cause of BA. Grass pollen is the most often cause. In Ukraine there are pollen of timothy-grass, in south regions – ambrosia, absinth, orach. Tree pollen provokes BA rarely: birch, maple, and nut-tree. Flower pollen provokes sensibilization even more rarely.
Epidermal allergens is the next group. At present epidermal allergens of domestic animals (dogs, cats, guinea-pigs, rabbits, parrots – in diminishing frequency) are the most often causes of allergic diseases’ development.
Role of food and drugs allergens in BA development is considered to be possible.
Sensibilization to non-bacterial antigens doesn’t exclude sensibilization to infectious ones – to microbial in particular (chlamidias) and often to fungal ones. From enormous quantity of natural fungi (about 100 000 kinds) allergic characteristics are detected in 300-350 kinds. The most widespread spore formative mold fungi, which predominate in atmosphere air (Cladosporium, Alternaria) and in the air of premises (Aspergillum, Penicillium) are of greatest importance in BA etiology. Apart from it, other fungi (Mucor, Fusarium etc.), having more local circulation, can be the cause of sensibilization also. All of them discharge tremendous quantity of spores in the air, size of which are from 0,5 to 12 microns, due to it they invade respiratory ways with inspired air deeply.
Table 1
Risk factors of bronchial asthma in children
|
Factors predisposing to BA development: |
Factors aggravating action of causative ones: |
|
|
|
Causative (sensibilizing) factors: |
Factors provoking BA exaggeration – triggers: |
|
|
There is certain sequence of sensibilization’s development.
Food allergens are the leading sensibilization’s factors for infants of first months of life, first of all there are cow’s milk and formula on its base, afterwards – yolk and protein of the eggs, and semolina. So called asthma of milk precipitates exists in small children, it combines often with inborn hyperreactivity of airways. Gradually sensibilization to food allergens diminishes. Increased sensitivity to inhalation, domestic and pollen allergens appears to 3-5 years. Monovalent allergy becomes polyvalent one.
Invading of an organism with allergen, predominantly through inhalation, is the necessary condition of BA appearance. However majority of antigens consistently presented in inhaled air can’t exert harmful influence because they collide with natural resistance – system of local protection. Mucous membrane with its mucociliar apparatus (ciliate epithelium and discharge of mucous membrane glands, produced by serous and goblet epithelium cells) are the elements of local protection.
Alien particles, which were not excreted, undergo the action of various humoral substances. There are substances with antimicrobial action: lysozyme, lactoferrin, proteins’ inhibitors (a1-antitrypsin, a2-macroglobulin, antithrombin III), proteases and complement system. Antibodies – secretory fraction of IgA – take part in local protection against inhalation antigens simultaneously with them. Summary effect of all above-mentioned mechanisms of local protection provides excretion, neutralization, destruction and digestion of most part of alloys presented in inhaled air. Defects of any link of broncho-pulmonary apparatus local protection mechanism, beginning with disorders of cilia’s mobility and finishing with immunologic inborn or acquired disorders, create the prerequisites for antigens invading from airway’s empty space inside the organism.
Factors negatively influencing upon various protective links condition, so called triggers, are the following - supercooling, dust loading and gas-laden atmosphere, smoking, and broncho-pulmonary infections.
In children recurrent respiratory infections precede appearance of BA attacks in 75-90% of cases. Respiratory viruses affecting airways epithelium provoke disorders of bronchial mucous membrane’s protective function, that alleviates allergens invasion through disordered epithelium and promotes bronchial hyperreactivity formation.
Clinics of bronchial asthma.
BA exacerbation appears as a result of triggers action – ARI, allergens, physical and psychoemotional load, changes of meteorological situation, ecological impacts, intolerable products, vaccines and sera.
Attack of expiratory suffocation is typical. Attack appears more often at night or at 4-6 a.m. that is connected with circade rhythm of bronchial hyperreactivity. Patient’s breathing becomes noisy, participation of abdominal press muscles, scalene muscles, sternocleidomastoid muscle in respiratory act is seen. Supra- and subclavicular spaces, intercostal intervals fall in. A patients feels fear; as a rule he tries to fix shoulder girdle, he sits leaning with his hands against knees; shoulders are raised and moved ahead, the head is pulled in shoulders, chest id elevated and enlarged at the expense of front-back size. Great majority of children has frequent anguished dry cough, increased BP and tachycardia.
Objectively at the moment of attack box-band shade of percussive pulmonary sound, low borders of lungs, narrowing of relative heart dullness borders, plenty of dry diffuse “musical” whistling wheezes at expiration and less of them at inspiration are revealed. In some patients not dry whistling wheezes but moist rales predominate, which can be auscultated both at expiration, and at inspiration. In such case we are speaking about so called “humid asthma”. At the moment of attack temperature is normal, but short-term fever may be seen in infants without infectious process. Duration of attack may vary from 30-40 minutes to several hours and even days (status asthmatic). Gradually facilitation takes place: patients begin to expectorate transparent foamy and than dense sputum, breathing becomes not so difficult, the face looks of normal color, but its edema may be preserved for a while. Epithelium cells, eosinofiles, macrophages and crystals of Sharko-Leiden may be revealed under microscope.
More 4 groups of symptoms are the diagnostic criteria of BA:
symptoms of respiratory discomfort: dry cough, predominantly in the early morning hours or after contact with allergen, its appearance and intensification after physical load, inspiration of strong smells, at meteorological changes;
symptoms of reversible bronchial obstruction: expiratory dyspnea, box-band shade of pulmonary sound at percussion, dry whistling wheezes at expiration, and prolongation of expiration;
extrapulmonary signs of allergy, burdened allergic anamnesis;
eosiniphilia in blood and/or sputum.
Severity of BA course is determined by degree of bronchial obstruction.
Classification of bronchial asthma.
Modern BA classification provides for separation of etiological disease’s factor, degree and character of bronchial obstruction.
Predominantly etiological factor of BA evaluation is reflected in International diseases classification (IDC) of X revision prepared by WHO, Geneva, 1992. Accordingly to IDC-X asthma is divided on:
predominantly allergic (as a rule, connected with established external allergen);
non-allergic (including idiosyncratic, that is connected with unestablished internal factors);
mixed ( in presence of signs of first two forms );
unspecified.
The main moment of any diseases’ classification is its orientation at differentiated patient’s treatment, and severity of disease is such criterion in BA.
In 1998 Problematic commission of children pulmonology in Ukraine adopted BA clinical classification, which provides for following classifications:
By etiologic factor:
atopic
non-atopic
mixed
By severity of the course:
intermittent asthma (1 step)
mild persistent asthma (2 step)
moderate asthma (3 step)
severe asthma (4 step)
By period (phase of course)
exacerbation
instable remission
remission
stable remission (more than 2 years)
Complications:
pulmonary atelectasis
pneumothorax
subcutaneous and mediastinal emphisema
pulmonary heart
pulmonary emphisema
Criteria of BA severity are determined on the base of attacks clinical characteristics, frequency of night attacks, tolerance to physical load, changes of FEV1, PEF and daily bronchial lability (DBL), characteristics and duration of remission periods, mode of attack’s arresting, duration and matter of base anti-inflammatory therapy (table 2).
BA exacerbation may proceed as acute attack or lingering condition of bronchial obstruction. BA attack – it’s acute episode of expiratory dyspnea, difficult and/or whistling breathing and spastic cough at marked decrease of PEF that is exactly noted by patient and his associates.
Period of BA exacerbation – lingering course of attack’s period characterized with prolonged breathing difficulties, which can last days, weeks and months; clinically marked syndrome of bronchial obstruction is present. Acute BA attacks of various severity can be seen in such condition (table 3).
The most severe form of BA is distinguished in separate group – status asthmatics – that is connected obviously with peculiarities of clinical manifestations and medical tactics demanding immediate hospitalization of a patient to intensive care unit.
Non-arresting BA attack with duration more than 6 hours or absence of positive dynamics after 3 adrenaline injections with intervals of 20-30 minutes are criteria of status asthmatics. Status asthmatics is caused by deep block of b2-adrenoreceptors due to:
long term treatment of the disease with frequent exacerbations, that demanded wide use of sympathomimetics;
infectious processes in broncho-pulmonary system;
abrupt decrease of glucocorticoids in hormon-dependent patients.
Table 2
Criteria of BA severity in children
|
Intermittent bronchial asthma (I step) |
Persistence of bronchial asthma |
|||
|
Mild degree of bronchial asthma (II step) |
Moderate degree of bronchial asthma (III step) |
Severe degree of bronchial asthma (IV step) |
||
|
Frequency of attacks |
Several times a year, not more frequent than once a month |
3-4 times a month |
More frequently than once a week but less frequently than once a day |
Every day constantly |
|
Clinical characteristics of attacks |
Episodical, quickly disappearing, mild |
Episodical, quickly disappearing, mild |
Attacks of moderate severity with exact disorders of external respiration function |
Constant presence of symptoms, severe attacks, asthmatic status |
|
Night attacks, activity sleep disorders |
Absent |
Absent or present very rarely, the child episodically awakes |
2-3 times a week, the child awakes |
Almost every night, the child practically doesn’t sleep |
|
Tolerance to physical load |
Not changed |
Not changed |
Decreased |
Essentially decreased |
|
Indices of FEV 1, PEF |
Not less than 80% of norm |
Not less than 80% of norm |
60-80% of norm |
Less than 60% of norm |
|
Changes of bronchial patency during 24 hours |
Not more than 20% |
Not more than 20% |
20-30% |
More than 30% |
|
Characteristics of remission periods |
Normal values of external respiration function between exacerbations |
Symptoms are absent, normal function of external respiration |
Not complete clinical-functional remission |
Not complete clinical-functional remission (respiratory insufficiency) |
|
Characteristics of remission periods |
Normal values of external respiration function between exacerbations |
Symptoms are absent, normal function of external respiration |
Not complete clinical-functional remission |
Not complete clinical-functional remission (respiratory insufficiency) |
|
Duration of remission periods |
Short exacerbations (from several hours up to several days) |
3 months and more |
Less than 3 months |
1-2 months |
|
Physical development |
Is not disturbed |
Is not disturbed |
Is not disturbed |
Possibility of retardation and disproportion of physical development |
Table 3
Criteria for evaluation of attack’s severity
|
Signs |
Light |
Mild |
Severe |
Threat of respiratory standstill (status asthmatics) |
|
Physical activity |
Preserved |
Limited |
Forced position |
Absent |
|
Talking speech |
Preserved |
Limited: separate phrases are pronounced |
Jerky speech |
Absent |
|
Conscience sphere |
Excitement sometimes |
Excitement |
Excitement, fright |
Mental confusion, hypoxic coma |
|
Respiratory rate* |
Hurried breathing |
Expiratory dyspnea is present |
Marked expiratory dyspnea |
Tachypnea or bradypnea |
|
Participation of auxiliary musculature, retraction of jugular fossa |
Feebly marked |
Marked |
Strongly marked |
Paradoxical thoracoabdominal breathing |
|
Whistling breathing |
Registered at the end of expiration as a rule |
Marked |
Strongly marked |
“Mute lung”, absence of respiratory murmurs |
|
Pulse rate* |
Increased |
Increased |
Markedly increased |
Bradycardia |
|
FEV1, PEF in % of norm or of best patient’s indices* |
More than 80% |
60-80% |
Less than 60% of norm |
|
|
PaO2 |
Norm |
More than 60 Hg mm |
Less than 60 Hg mm |
|
|
PaCO2 |
Less than 45 HG mm |
Less than 45 HG mm |
More than 45 HG mm |
* Respiratory rate, pulse rate, FEV1, and PEF is necessary to repeat in dynamics of treatment.
Three stages of status asthmatics are distinguished:
I stage – stage of relative compensation. It is characterized by resistance to sympathomimetics and partially to other broncholitics. It appears more frequently not attack-like, but gradually and lasts for several days. Pallor of skin, acrocyanosis, expiratory dyspnea, swelling of chest, persistent cough and dry whistling wheezes on the background of weakened respiration ate typical. Discrepancy between intensity of respiratory wheezes, which can be heard at a distance and by direct lung’s auscultation, attracts attention. Tachycardia, elevated BP, narrowing of heart’s relative dullness borders due to lung’s emphysema, are registered.
II stage of status asthmatics is characterized by increasing respiratory insufficiency of obstructive type: utmost severity of patient’s condition, pale cyanosis, perioral and acrocyanosis, marked tachycardia, dyspnea, liver’s enlargement, and edema. Practically total absence of wheezes at auscultation (“mute lungs”) or very few dry wheezes on limited region seem to be paradoxical. Cough disappears, pulse is frequent and weak, BP is decreased. Formation of total bronchial obstruction syndrome is typical for this stage of status asthmatic that can lead to hypoxic coma if medical care is delayed. General excitement, sense of fear and asphyxia give place to prostration.
III stage of BA – hypoxemic coma and asphyctic syndrome develop due to decompensated respiratory and metabolic acidosis and marked hypercapnia. Chuchalin A.G. distinguishes 2 types of hypoxemic coma – quickly and slowly appearing ones. Prostration, early loss of reflexes and consciousness on the background of generalized cyanosis, increasing tachycardia and dyspnea, which loses expiratory component, decreasing BP, swelling of cervical veins, and liver’s enlargement are typical for quickly proceeded hypoxemic coma. Wheezes are not auscultated any more, and so called “dead lungs” appear. The same symptoms are typical for slowly proceeded hypoxemic coma also, but its appearance is protracted in time.
Bronchial asthma pathogenesis.
It is underlined in modern definition of BA that it is chronic inflammation of respiratory tract with widespread but variable obstruction. W.Osler (1892) pointed at 3 possible mechanisms of respiratory ways obstruction in asthma: spasm of bronchial smooth muscles, inflammation of airways, and disorders of nervous regulation of bronchial tonus. The supreme significance among these factors has been given to spasm of smooth bronchial muscles.
Such opinion existed not only at the end of XIX century but during 75 years of XX century. At the beginning of 1980 year biopsy examinations of bronchial mucous membrane made by Finnish scientists initiated rapt morphological investigations of bronchi in BA. Histological examinations of bronchial mucous membrane’s biopsy revealed its eosinofilic and lymphocytic infiltration and enlargement of subepithelial basal membrane, i.e. marked inflammatory bronchial epithelium damage at all stages of BA, that changed ideas of disease’s origin.
Inflammatory process forms 4 mechanisms of bronchial obstruction:
acute bronchospasm
subacute edema
chronic formation of mucous plugs
irreversible reorganization of bronchus.
Changes of immune answer play key role in BA pathogenesis. In 70-80y.y. of XX century it was believed that allergic reactions development was connected with decrease of T-lymphocytes – suppressors (CD8) functional activity.
At present it’s proved that organism’s sensibilization, which lays in the basis of IgE hyperproduction, is connected with changes of Th-1 and Th-2 lymphocytes activity ratio with increased activity of the former. Th-2 lymphocytes activation is caused first of all by influence of allergic stimuli; this process may take place both in antenatal and postnatal periods. Respiratory viral disease during pregnancy can be a cause of Th-2 lymphocytes activation with subsequent IgE hyperproduction in a baby.
Hyperproduction of IL-4, IL-6 and IL-13 connected with Th-2 lymphocytes activation in its turn promotes IgE hyperproduction. Process of organism’s sensibilization is finished with fixation of specific relative to certain groups of allergens IgE-antibodies on target cells – mast cells, basophyles in shock organ, in particular in bronchial mucous membranes. Recurring exposition with causal-significant allergen induces initialization of IgE-provoked mechanism (reaction of hypersensitivity of I type by Gell and Coombs classification) with activation of mast cells, their degranulation and excretion of allergy mediators (histamine, SRS-A, neutrophyle chemotaxis factor, eosinophyle chemotaxis factor, prostaglandin F2a, leukotriens LTB4, LTC4, LTD4 and others), which realize development of early phase of allergic reaction in the form of bronchial obstruction syndrome, having features of typical BA attack (at the expense of M-cholinoreceptors activation and intensification of guanilatcyclase, increase of cGMP having powerful bronchoconstrictive action).
In the process of organism’s sensibilization and early phase of allergic reaction there is intensified creation of pro-inflammatory cytokines – IL-3, IL-5, IL-8, IL-16, TNFa and adhesive molecules, contributing to inflow of cells, taking part in allergic inflammation development, to airways mucous membranes (eosinophyles, neutrophyles). Inflammation originated in bronchial mucous membrane and detachment of eosinophile cation protein, cation lysosomal proteins of neutrophils, taking place during inflammation lead to bronchial airway’s epithelium damage, intensification of vascular permeability that promote edema and mucus hyperproduction, and - as a result – intensification of obstruction. The same mediators are able to provoke destruction of mast cells membranes repeatedly that is accompanied by excretion of biologically active substances and thus deferred or late phase of allergic reaction is formed, which is pathogenetic basis of bronchial hyperreactivity syndrome. Bronchial hyperreactivity’s development stipulates appearance of recurrent BA attacks not only at action of specific allergic stimuli but at non-specific ones also (physical load, negative and positive emotions, strong smells, chemical substances).
Allergic inflammation of bronchial tree’s mucous membrane and bronchial hyperreactivity connected with it stipulates recurrent and chronic course of the disease.
In 1968 y. american scientist A.Scintevani advanced hypothesis according to which constitutionally conditioned block of b2-adrenoreceptors (i.e. adenilatcyclase) provokes bronchial hyperreactivity in BA, that was proved in subsequent investigations.
Along with constitutional conditionality of b2-adrenoreceptors block hyperreactivity may be connected with Ca++ accumulation inside the cell. This fact was proved by registration of elevated Ca++ concentration in blood cells in the period of BA exacerbation. Apart, changes of phospholipids metabolism with activation of arachidonic acid’s synthesis, lipid’s peroxide oxidation and phosphodiestherase, which destroys cAMP, point to disorders of bio-membranes characteristics.
Pollutants of foul air may lead to disorders of metabolism and properties of biomembranes and endow into formation of bronchial hyperreactivity in children suffering from BA.
Functional state dysbalance of sympathetic and parasympathetic parts of vegetative nervous system (VNS) play an important role in BA pathogenesis. Predominance of VNS’s parasympathetic part with activation of M-cholinoreceptors under the influence of acetylcholine, that intensifies bronchial obstruction, is typical for many patients with BA.
Diagnostics of bronchial asthma.
Diagnostics of BA is based first of all upon analysis of anamnesis and clinical manifestations with obligatory examination of FVD. It allows to evaluate degree of bronchial obstruction and its dynamics under the influence of treatment, and to determine more exactly both degree of attack’s severity and degree of severity of BA itself.
Total blood analysis is normal in uncomplicated BA. Sometimes negligible eosinophilia is present. ESR is normal as a rule, its elevation testifies to addition of infection.
Sputum’s examination. Macroscopically sputum is sticky, viscous and whitish. Cells of ciliary epithelium, neutrophils, a lot of eosinophils as well as elongated bipyramidal crystals (Sharko-Leiden) released from eosinophils are seen in sputum at exogenic BA. Amount of eosinophils is less, neutrophils predominate if BA is of endogenic origin.
Any changes on X-ray of the chest at interictal period of uncomplicated BA are absent. Increased transparence of lung’s fields and flattening of diaphragm’s cupola appear during attack. Segmental and subsegmental atelectasis may appear due to bronchial obstruction with mucous corks.
Total level of IgE in blood’s plasma is usually elevated in exogenic BA.
Studying of external respiration’s function plays an important role in BA diagnostics. Two methods mainly gained ground in children older than 5 years: spirogram with measurement of forced expiration’s volume in 1 second (FEV1) and determination of expiration peak rate (EPR) by peak-flowmetry. In mild BA FEV1 constitutes 80% and more of proper meaning, in moderate – 60-80% and in severe asthma – less than 60%.
Ratio FEV1/LVC – Tiffno’s test – is an early and sensitive index of bronchial obstruction. Its changes allow to distinct obstructive and restrictive types of respiratory disorders. In norm this index is more than 75%. Lesser figures testify to disorders of bronchial passability: the lower this index is – the more severe the bronchial obstruction is.
At present peakflowmetry, which allows measuring peak expiratory flow (PEF) 2-3 times a day at home, is used for monitoring of patient’s condition. It allows evaluating, except PEF itself, its daily dynamics, i.e. daily bronchial lability as well as circadian rhythm of bronchial passability which is characterized in patients with BA by phenomenon of “morning PEF collapse”.
Formulae for calculation of mean daily bronchial passability (MDBP) and daily bronchial lability (DBL) mentioned below:
(PEF max + PEF min) : 2
MDBP = PEF norm x 100%
PEF max - PEF min x 100%
DBL = PEF norm
Peakflowmetry is carried with use of individual peakflowmeters, with construction of peak flow graph and indication of so called “zones of traffic lights” for every patient in order to treat them adequately. As normal meaning of PEF the mean best index, received in a period of remission or in a period of stable best patient’s condition is used.
One of the main points in BA diagnostics at early stages of disease is the exposure of non-specific bronchial hyperreactivity. Test with physical load is one of the most available one for it. PEF before load is measured, than physical load is given during 6-8 minutes. Immediately after loading and in 5-10 minutes PEF is measured. If PEF decreases more than 15% of initial meaning – test is considered to be positive. Provocative inhalation tests with non-specific agents (histamine, metacholine), cold air, ultrasound spray with distilled water are used also. Provocative tests are used in a period of BA remission.
An index of bronchial obstruction’s reversibility is important diagnostic and prognostic criterion. FEV is measured, afterwards the patient inhales one dose of b2-agonist, and indices of spirometry are repeatedly registered in 15 minutes. The following indices of bronchial obstruction’s reversibility are generally accepted:
marked (25%)
moderate (15-24%)
slight (10—14%)
negative (10%)
Allergologic investigation is made in vivo or in vitro depending upon child’s age, period of illness, and presence of attendant pathology for confirmation of prospective spectrum of sensibilization. Scarificative skin allergic tests are made during a period of remission, allergic specific IgE are measured during exacerbation period.
Determination of nitrogen oxide’s (NO) concentration in expired air is one of the modern non-invasive methods for diagnostics of allergic inflammation in BA. Very shortly living (during several seconds) molecules of this gas are synthesized by vessel’s endothelium, macrophages, neutrophils, mast cells, platelets, and epithelium cells of bronchial mucous membrane. Their concentration increases trustworthy in BA and decreases on the background of treatment with inhale corticosteroids. NO concentration in expired air is decreased in chronic obstructive disease of adults and mucoviscidosis.
Differential diagnosis.
Differential diagnosis of BA is made with conditions for which bronchoobstructive syndrome is typical.
Obstructive bronchitis, acute bronchiolitis: clinical features of acute respiratory infection, intoxication, absence of atopy are typical.
Foreign bodies of respiratory ways: patients mark precise time of condition’s worsening, which is manifested as acute asphyxia with or without cyanosis and following cough. X-ray of the chest and bronchoscopy are necessary.
Stenosing laryngotracheitis – clinical symptoms appear more frequently in the evening or at night on the background of catarrhal manifestations, fever, hoarse voice, inspiratory dyspnea, and typical barking cough.
Cardiac asthma – is seen in patients with inborn heart disease; enlargement of cardiac borders, muffled tones, cardiac murmurs, peripheral edema, liver’s enlargement, bubbling respiration, moist rales, and predominantly inspiratory dyspnea are typical.
Mucoviscidosis – retardation of physical development, absence of atopy, external respiration’s disorders of mixed type, recurrent pneumonia, diarrhea with steatorrhea, and increased content of sodium and chlorides in sweat are present.
Exogenic allergic alveolitis – a disease provoked by inspiration of organic dust with various allergens which is characterized with diffuse affection of alveolar and interstitial lung’s tissue. Disorders of common condition, respiratory insufficiency, expiratory dyspnea, specific fine bubbling “cellophane” rales are typical. At X-ray symptom of “focusing screen” and disorders of external respiratory function are seen.
Treatment of bronchial asthma.
Modern treatment of bronchial asthma in children is pathogenetic and issues of key statement that BA – it is chronic disease, in which bronchial mucous membrane’s inflammation constitutes its pathogenetic base. It is degree of inflammation’s expression that determines severity of symptoms, character of course, prognosis and development of complications.
The main therapy’s tasks are:
struggle with chronic inflammatory process in respiratory ways;
decrease of bronchial sensitivity;
liquidation or relief of disease’s clinical manifestations, diminishing of frequency and severity of exacerbations, normalization or improvement of indices of external respiration function;
prevention of exacerbations and complications, invalidism and morbidity;
prevention of side effects of drug therapy;
abolition or decrease of broncholytics require;
improvement of life’s quality.
Disease control and improvement of life’s quality in modern conditions are achieved due to following abilities:
trigger factors elimination;
pharmacotherapy;
specific hyposensibilization.
Revelation and maximally possible elimination of trigger factors have considerable mean in BA treatment. In cases when organism’s contact with causative allergen is successfully interrupted or at least allergen’s influence is decreased it’s possible to prevent attack, decrease quantity of exacerbations, diminish intensity of drug therapy and stop growth of BA severity.
BA pharmacotherapy includes use of medicaments in order to influence upon inflammatory changes of bronchial mucous membrane and obstruction mechanisms, which are connected with them:
anti-inflammatory drugs;
broncholytics;
mucolytics and expectorants.
BA is the disease of respiratory tract, so inhalation mode of drug’s administration is more preferable in comparison with oral or parenteral ones. Advantages of direct drug’s delivery to respiratory tract are the following: medicament is delivered to target organ in more high concentration, and it’s possible to avoid development of systemic side effects. Dosed aerosol with spacer, as for children less than 5 years old and patients with severe BA - babyhaler, are optimal inhalation devices in most cases.
In Global Initiative for Asthma (GINA 1995, 2002) chromoglicate and nedocromil sodium are recommended as medicaments of first choice for every child suffering with intermittent asthma (step 1). Sodium chromoglicate (intal) is non-steroid anti-inflammatory drug. Its effect is realized by following mechanisms:
the drug inhibits liberation of biologically active substances from cells of allergic inflammation (mastocytes – mast cells, macrophages, eosinophils, monocytes);
it inhibits activity of phosphodiesterase and increases synthesis of cAMP;
it is antagonist in such pathophysiological BA effects as bronchoconstriction, late asthmatic reaction, bronchial hyperreactivity, and inflammation of respiratory tract;
it has preventive effect in prolonged using;
it is the most safe drug for BA treatment, which has not side effects.
Stable improvement of patient’s condition, considerable decrease or cessation of BA attacks are seen in 4-8 weeks of this drug intake. It’s effect is most high in patients with allergic BA.
Nedocromil sodium (Tailed) is also non-steroid anti-inflammatory preparation from the parachinoline class, which being inhaled exceeds 4-10 times intal as for prevention of bronchospastic reactions. Tailed is effective both in allergic, and non-allergic BA.
Corticosteroids have powerful anti-inflammatory action, their effectiveness in BA has no doubts. At present principal effects of steroid action upon cell are proved. Glucocorticosteroids inhibit synthesis of:
some cytokines, and directly or indirectly block action of nitroxidsynthetase – enzyme, which is responsible for production of nitrogen oxide and which plays an important role in development of cells inflammatory damage;
endotheline-1 – one of the most important inflammation’s mediator;
inhibit synthesis and expression on the cellular membrane of certain receptors (for example, NK-receptor, mediating anti-inflammatory effect of P-substance).
Glucocorticoids stimulate synthesis of:
neutral endopeptidase – enzyme, destroying bradikinine, tachikinine and endothelin-1, which promote development of both bronchospasm, and inflammation;
lipocorine-1, which blocks phospholipase, preventing in such a way synthesis not only of leukotriens, but prostoglandines and platelet-activating factor as well;
endonucleases – enzymes, responsible for apoptosis – programmed cells destruction (it reduces life time of eosinophilic granulocytes and mast cells);
stimulate synthesis and expression on cell membrane of adrenoreceptors, which have principal mean for removal of bronchospasm.
Thus, glucocorticoids have powerful anti-inflammatory activity due to block of all molecular inflammatory mechanisms on the basis of function regulation of cellular genome.
Choose of inhalation steroid in BA therapy must be guided by following principle: maximal effectiveness in maximal safety, i.e. high pharmacological activity with minimal side effects connected with systemic bioavailability. Pharmacological activity of glucocorticoids depends upon lipophilia and affinity to steroid’s receptors, i.e. the more high lipophilia and receptor’s affinity the drug has, the more quickly it permeates to target-cell through its lipid membrane, where it influences upon target-genes activity.
Systemic action of topic steroids is determined by a part of a drug or its active metabolites, which fall into systemic blood flow after passage through the liver. It depends upon quantity of preparation absorbed from digestive and respiratory tract (that is determined by steroid’s hydrophily), and upon degree of its inactivation in the liver, that is called “ glucocorticosteroid’s bioavailability”. Fluticason propionate (flixotid) is a preparation of choice among inhaled steroids when tolerance of budesonide or beclamethasone propionate is unsatisfactory, either there is necessity of moderate or high doses prescription. Pharmacokynetic and pharmacodynamic indices of most often inhaled glucocorticosterids used in BA treatment are present in the table 4.
Doses of anti-inflammatory drugs for BA treatment are shown in the table 5.
At present BA anti-inflammatory therapy is expanded due to appearance of leucotrien antagonist - zafirlucast and montelucast. These preparations have moderate protective action blocking receptors to leucotriens and thus preventing activation of target cells. They are used predominantly for treatment of mild and moderate BA.
Table 4
Pharmacokynetic and pharmacodynamic indices of inhaled glucocorticosteroids
|
Index |
Beclamethasone |
Flunisonide |
Budesonide |
Flixotid |
|
|
dipropionate |
monopropionate |
||||
|
Topic effect |
moderate |
high |
low |
high |
high |
|
Lipophily |
high |
high |
low |
low |
high |
|
Speed of dissolving |
3-5 hours |
2 minutes |
6 minutes |
> 8 hours |
|
|
Affinity to receptors |
0,4 |
1,8 |
9,4 |
18 |
|
|
Half life period with receptor |
7,5 hours |
3,5 hours |
5,1 hours |
10,5 hours |
|
|
Half life period in blood plasma |
30-37 minutes |
1,8 hours |
3 hours |
7,8 hours |
|
|
Oral bioavailability |
unknown |
215% |
6-13% |
< 1% |
Table 5.
Doses of anti-inflammatory drugs for BA treatment in children
|
International name |
Trade name |
Drug’s dose |
|
Chromoglicate sodium |
Intal |
Children from2 to 10 years old – up to 8-10 mg/day Children from 10 to 16 years old – up to 20 mg/day |
|
Nedocromil sodium |
Tailed (tailed-mint) |
2 inhaled doses 2-4 times/day |
|
Beclamethasone |
Aldecin, becotid, beclofort, beclocort |
Moderate doses 400-600mg, high doses > 600mg |
|
Budesonide |
Moderate doses 200-400mg, high doses >400mg |
|
|
Flunizolide |
Ingacort |
Moderate doses 500-1000mg, high doses >1000mg |
|
Fluticazone |
Flixotide, flovent |
Moderate doses 200-400mg, high doses > 400mg |
|
Triamcinolone acetonide |
Azmacort |
Moderate doses 800-1000m, high doses > 1000mg |
Preparations eliminating bronchospasm, directly influencing upon non-striated bronchial muscles – broncholytics (b2-agonists, cholinolytics, myolytics) are also used in BA treatment.
At present sympathomimetics of selective action - b-agonists – are the most widespread and acknowledged. Salbutamol is the most selective one from b2-agonists of short action. Salmeterol (serevent) possesses the same place among preparations of prolonged action.
Cholinolytics are used for liquidation of cholinoergic bronchospasm’s components, which are connected with acetylcholine action. Ipratropium bromide (atrovent) has lesser broncholytic action than sympathomimetics. In pediatric practice prescription of ipratropium bromide and combined preparations (cholinolytics + sympathomimetics: combivent, berodual) is especially perspective taking into account anatomo-physiological peculiarities of childhood. Influence of cholinergic innervation is known to be more expressed in large bronchi, and density of muscarin receptors diminishes to the periphery. Viral infection in childhood often appears to be inductor of exacerbation. Meanwhile it is proved that virus activates M2-cholinoreceptors. Due to it predomination of just large bronchi affection in children creates conditions for cholinolitics effectiveness.
Preparations of euphylline have particular place among broncholytics. Theophylline acts directly upon bronchial muscles, inhibits phosphodiestherase, promotes accumulation of cAMP, intensifies synthesis and liberation of cathecholamines from adrenal glands, influences upon intracellular absorption and allocation of calcium, and serves as prostoglandin’s antagonist. Theophylline is of interest due to not only bronchodilatative effect but anti-inflammatory and immunomodulative action. Its immunomodulative action is explained by excretion’s inhibition of lymphokines from Th1 (interleukin-2, alpha-interferon, TNF) and Th2 (interleukin-4, interleukin-5, interleukin-6).
Supportive doses of theophylline for effect’s achievement are twice as much as for liquidation of bronchospasm. Prolonged forms of theophylline are of wide use in moderate and severe BA.
Specific immune therapy is one of the most effective methods in BA treatment. Synthesis activation of blocking antibodies and exhaustion of reagents under influence of small allergen’s doses, injected in increasing concentration, is the basis of therapeutic effect. Injection of even minimal allergen’s doses can provoke diseases’s exacerbation in children with high level of sensibilization and polyvalent allergy. Proceeding from possibility of systemic and local reactions on immune therapy indications for its use are narrowed. Specific immune therapy is used in cases when contact with allergen is inevitable, and medicamental treatment doesn’t control BA. The greatest effect of specific hyposensibilization is achieved in children with hypersensitivity to pollen allergens and mites of domestic dust.
BA treatment must be a long one. Choice of the drug, doses, and duration are individual in every patient and depends, first of all, upon severity of case and degree of symptoms expression in concrete case.
Help system in accordance with BA severity anticipates stepped method of approach to treatment. Drugs choice and method of their use depend upon severity of the disease, which is indicated as corresponding step (table 6).
Table 6.
Stepped method of approach to basis prolonged BA treatment in children
|
Variant of therapy |
Intermittent asthma |
Persistent asthma |
||
|
Step I |
Mild – step II |
Moderate – step III |
Severe – step IV |
|
|
Anti-inflammatory (pathogenetic) therapy |
Chromoglicate sodium 4 times a day or nedocromil sodium 2 times a day |
Inhaled corticosteroids (ICS) in average therapeutic doses (100-400 mcg of budesonide) |
ICS in therapeutic doses (400-800 mcg of budesonide) |
High doses of ICS (more than 800 mcg of budesonide) If asthma symptoms are controlled not completely – add oral corticosteroids |
|
Bronchodilators therapy for persistent prescription (is prescribed simultaneously with anti-inflammatory) |
β2-agonist of prolonged action or theophylline of delayed liberation Prescription of fixed combination in one medicinal form is preferred: Seretid Evohaler 25/50 2 inhalations twice a day, or Seretid Discus 50/100 1 inhalations twice a day |
β2-agonist of prolonged action or theophylline of delayed liberation Prescription of fixed combination in one medicinal form is preferred: Seretid Evohaler 25/125 2 inhalations twice a day, or Seretid Discus 50/250 1 inhalations twice a day |
||
|
Symptomatic therapy |
||||
|
Bronchodilators therapy for quick arrest of attack |
Inhaled b2-agonists of short action or theophilline of short action in a dose of 5-7 mg/kg |
Inhaled b2-agonists of short action not more frequent than 4 times a day or ipratropium bromide or theophilline of short action in a dose of 5-7 mg/kg |
Inhaled b2-agonists of short action not more frequent than 4 times a day or ipratropium bromide or theophilline of short action in a dose of 5-7 mg/kg |
Inhaled b2-agonists of short action not more frequent than 4 times a day or ipratropium bromide or theophilline of short action in a dose of 5-7 mg/kg |
For all steps: after received steady BA control to continue the same treatment program during 3 months then to try gradually withdraw the drugs descending to the previous step etc. If you fail in achievement of BA control during 1 month you must ascend to the higher for severity step.
Literature: