RU2542377C1 - Method of treating pertussis in children under age of three years - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: conventional integrated therapy involving anti-tussive medications and drugs restoring the bronchopulmonary patency accompanies administering an oral complex immunoglobulin preparation 1 dose of protein 300mg once or twice a day for 5-7 days.

EFFECT: method enables fastening recovery with reducing a rate of complications and improving the clinical outcome.

4 tbl, 1 ex

Description

The invention relates to medicine, in particular to the treatment of pertussis infection in children.

In childhood infectious diseases, pertussis occupies an important place. Susceptibility to pertussis is high: in the pre-vaccination period, the contagiousness index is 70.0-80.0%. Currently, the same susceptibility to this infection persists in children under the age of 1 year who have not received preventive vaccinations, and newborns. The high susceptibility to pertussis of newborns is due to the fact that transplantally tolerated antibodies from the mother do not protect against the baby's disease. Of the greatest importance in the pathogenesis of pertussis is pertussis toxin, which causes a disorder of central respiration regulation, which leads to hypoxia, disorders of the cardiovascular system, encephalopathy, the development of lymphocytosis, the appearance of diarrhea syndrome, changes in the physicochemical composition of the blood, and an increase in the body's sensitivity to histamine and other biologically active substances (1, 2, 3). In the formation of severe and complicated forms of the disease, mixed infections, i.e. combination of pertussis with respiratory viral, mycoplasma and cytomegalovirus infections.

Complex treatment of pertussis involves the fight against respiratory failure and the elimination of the effects caused by hypoxia (oxygen therapy, antioxidants, including phenobarbital), the use of antitussive (non-narcotic antitussive drugs - synecode) and mucolytic (potassium iodide, lazolvan, etc.). According to indications, antibacterial and glucocorticoid therapy is carried out.

Recently, in the treatment of moderate and severe forms of the disease, various immunotherapeutic agents have been used that increase the nonspecific resistance of the body, such as interferon (viferon), interferon inducers (cycloferon, amixin), monoclonal antibodies, immunoglobulin preparations.

A known method for the treatment of pertussis in children, including drug pathogenetic and etiotropic therapy, in which realdirone containing interferon alpha is additionally rectally administered for 5 days, twice a day with an interval of 12 hours, 500,000 ME for children from 3 to 7 years (4 ) The disadvantages of this method of treatment are the difficulty of introducing the drug in microclysters into the rectal ampoule after a cleansing enema or defecation, poor tolerance of the drug by children. In addition, realdiron, being an antiviral drug, does not affect the treatment of pertussis infection and is often used for the combined course of pertussis infection.

A known method of treatment and prevention of pertussis in humans and animals using inhaled solutions of monoclonal antibodies of predominantly IgA class to membrane glycoconjugates of mammalian respiratory tract epithelial cells. (5) The disadvantage of this method of treatment and prophylaxis of whooping cough is the difficulty of obtaining the drug.

The closest to the claimed method of treating pertussis in children is the method described in the literature for the treatment of pertussis with pertussis immunoglobulin (PCIG) with a single intramuscular injection of 2 doses for three days (3). The drug was effective in the early stages of the disease. The method of obtaining this drug involved the selection of individual donor blood serums containing specific antibodies to pertussis exotoxin (6). Despite its good effectiveness, the use of PPIG in the treatment of pertussis is not currently carried out due to its absence in medical practice.

The present invention is to develop a method for the treatment of pertussis in children under the age of three years, which allows to accelerate the recovery of patients with whooping cough, reduce the incidence of complications and improve the outcome of the disease.

The objective of the invention is achieved by using the oral form of a complex immunoglobulin preparation (CIP) at a dose of 300 mg protein, 1-2 times a day for 5-7 days, along with the use of conventional complex therapy for the treatment of pertussis.

The complex immunoglobulin preparation of domestic production is well known in medical practice as a means for the prevention and treatment of bacterial and viral diseases. A method for its preparation is presented in the following patent description (7).

Immunobiological preparations occupy one of the important places in the treatment of various infectious diseases. At the same time, among the therapeutic agents used for whooping cough, currently there are still no specific anti-pertussis immunoglobulins. In this regard, a study was undertaken of the effectiveness of the complex immunoglobulin preparation (CIP) in the treatment of pertussis in children. The main area of application of the oral form of CIP is limited to the treatment of intestinal infections, although the drug, being prepared from a pool of donated blood, contains a wide range of antibodies, and not only to intestinal pathogens. So, in all series of CIPs, antibodies to pathogens of controlled infections, in particular, to the pathogenicity factors of the pertussis microbe, exotoxin and hemagglutinin, are contained. This allowed theoretically to suggest that the use of instrumentation in patients with pertussis can have a specific antitoxic effect, as well as affect the concomitant infectious pathology and prevent the violation of intestinal microflora.

It is known that the first line of defense of the mucous membranes (respiratory tract, digestive tract, urogenital tract, etc.) from pathogens is provided by unencapsulated lymphoid tissue, including group lymphatic follicles (Peyer's plaques, tonsils, appendix, etc.) and diffuse cells of the immune system in the epithelium of the mucous membrane (intraepithelial T-lymphocytes), in the lamina propria (Lamina propria), as well as in the submucosal layer (8, 9, 10, 11, 12, 13, 15, 18).

In the gastrointestinal tract (GIT), the number and size of lymphoid accumulations increase in the distal direction. They are especially numerous in the terminal ileum, where they are called Peyer's plaques. The local immune system in the stomach is less developed than in the intestine; therefore, antigens not only enter it, but are also actively absorbed into the blood through its mucous membrane (8).

It has already been established that foreign molecules and agents normally normally enter the body through the mucous membranes. Their transport is carried out by specialized epithelial cells - M-cells. M cells are present in the follicular epithelium, which lines the inner surface of the mucous membrane above the locations of the lymphoid follicles or Peyer's patches. They do not belong directly to the cells of the immune system. M cells lack a layer of mucus covering the other epithelial cells of the mucous membranes. The main purpose of M cells is the active transport of antigenic material (including microbial bodies) from the body cavity to the lymphatic structures without their processing (8, 9, 10, 11, 13, 14, 15, 18, 21).

Directly under the layer of M-cells in the gastrointestinal mucosa there are many B-lymphocytes and antigen-presenting cells, in particular dendritic cells. Dendritic cells absorb antigenic material and present it to T-lymphocytes. After interacting with the antigen, lymphocytes from the T- and B-dependent zones migrate to the mesenteric lymph nodes, and then to the effector zones of the mucous membranes (intestinal villi) and eventually end up in Lamina propria and in the surface epithelium (9, 10, 11, 12, 13, 14, 15, 18).

T-lymphocytes of lymphatic follicles and Peyer's gastrointestinal plaques (unlike the immune system of the whole organism) are not all thymus-dependent, a significant part of them become mature regardless of the thymus. Mucosal T lymphocytes differ markedly from systemic T lymphocytes in their ability to recognize antigens, activation conditions, and their inherent functions (8, 10, 15, 18).

In addition, crested cells are scattered throughout the intestine, on the surface of which there are long microvilli protruding into the intestinal lumen. Various functions are attributed to these cells, including specialized sensory reception and selective absorption (8).

It is also known that antibodies, also called immunoglobulins (Ig), are a soluble form of antigen-binding B-cell receptors. While one part of the antibody molecule (Fab fragment) is designed to bind to the antigen, the other part (Fc fragment) interacts with immunocompetent cells - macrophages, neutrophils, follicular dendritic cells, platelets, T and B cells, activated eosinophils. In fact, antibodies act as intermediary molecules that involve various elements of the immune system in the recognition of pathogenic microbes and their metabolic products (9, 10, 11, 12, 13, 14, 15, 16, 18, 21).

The recognition of pathogens and cells bound by antibodies is carried out using Fc receptors located on the surface of immunocompetent cells. For example, T-helpers carry receptors for the IgM Fc fragment on their surface (B lymphocytes also have receptors for the IgM Fc fragment). These receptors recognize the tail regions (Fc fragment) of immunoglobulin molecules, after which the corresponding immunocompetent cells are activated (8, 9, 10, 11, 15, 16, 18, 21, 24). In humans, the properties of T-suppressors are attributed to T-lymphocytes with Fc receptors for IgG, and the properties of T-helpers are attributed to T-lymphocytes with Fc receptors for IgM (21).

T-helpers are divided into 2 main classes - Th1 and Th2. Both are activated approximately equivalently by M. immunoglobulin. Th1 lymphocytes protect against intracellular pathogens, secrete gamma interferon and pro-inflammatory cytokines. The first inhibits the proliferation of Th2 lymphocytes, activates macrophages after sensitizing the lymphocyte with an antigen, and also switches the synthesis of immunoglobulins in the B lymphocyte from the original IgM to IgG2 and IgG3. Th2 lymphocytes are responsible for protection against extracellular pathogens, which include the causative agent of whooping cough, and produce anti-inflammatory cytokines. Both subpopulations of T-helpers act on B-lymphocytes, but each in its own way. Th2 lymphocytes have a more pronounced helper activity, they are the main activators of B-lymphocytes. The functional load of Th2 lymphocytes is the support of humoral immunity (8, 9, 10, 11, 15, 16, 18, 19, 20, 21, 22, 23).

It is also known that α-interferon switches T-helpers from the synthesis of the Th2-set of cytokines to Th1 (9, 21). In general, the entire system of interferons inhibits the formation of antibodies, lymphocyte proliferation, the complement binding reaction (30), directing the immune system to protect against intracellular pathogens, thereby reducing the body's defense against extracellular pathogens, in particular against pertussis.

It was found that passively introduced together with the antigen IgM antibodies specifically enhance the immune response to this antigen, whereas IgG antibodies inhibit it. F (ab) and F (ab) ′ ₂ fragments of antibodies and the immune complexes containing them, as well as IgG antibodies of other specificity, do not have an inhibitory effect. The inhibitory effect of free IgG antibodies and their complexes with antigen on antibody production depends on the presence of an Fc region in their molecules, as well as on the specificity of their active center, which should correspond to the specificity of suppressed antibodies (9, 10).

Given that the pertussis toxin causes the development of a secondary T-immunodeficiency state (19, 20, 24), and alveolar macrophages are either weak stimulators of T-lymphocytes or have a suppressive effect on the antigen-induced proliferative response of T-lymphocytes (8), then the need the presence of IgM in immunoglobulin preparations during the treatment of pertussis becomes extremely desirable.

Instrumentation contains a complete set of immunoglobulins (IgM, IgG and IgA), which determines the entire wide spectrum of its immunological activity, in particular, against the causative agent of pertussis.

It is important to note that the products of the catabolytic destruction of immunoglobulins have high biological activity. F (ab) ′ ₂ fragments of homologous IgG1 are capable of non-specifically enhancing immunogenesis. Cleavage products of the Fc fragment of immunoglobulins of various classes enhance the migration and viability of polymorphonuclear leukocytes, the presentation of antigen by A-cells (macrophages), favor the activation of T-helper cells, and increase the immune response to thymus-dependent antigens (17).

It was also established that F (ab) ′ ₂ fragments of heterologous immune immunoglobulin preparations (for example, from cattle blood) retain their antigen-binding activity in the lumen of the human gastrointestinal tract (25, 26, 27, 28). Clinical trials of a cow's anti-shigellosis immune immunoglobulin by oral administration have shown its high immunological activity against various gram-negative microorganisms of the human intestinal group (29).

There is evidence that a complex immunoglobulin preparation (CIP), administered orally in the treatment of children with intestinal infection and dysbiosis, has a pronounced immunomodulating effect - it activates immunocompetent cells of the digestive tract mucosa, enhances phagocytosis, complement synthesis, secretion of anti-inflammatory cytokines 30 (11).

To summarize, it can be argued that with oral consumption of KPIs, a multiple effect on the human immune system occurs both due to the whole complex of immunoglobulins and their individual fragments formed by digestion by digestive enzymes. Despite the fact that the mucous membrane of the upper respiratory tract is the entrance gate for pertussis infection, it is impossible to exclude the possibility of pathogenicity factors of the pertussis microbe entering the gastrointestinal tract due to the natural ingestion of the secretion of the nasopharynx. Thus, the interaction of antibodies and their fragments contained in the instrumentation with pertussis antigens, presumably, can occur both on the gastrointestinal mucosa and in the blood.

A study of the clinical efficacy of a complex immunoglobulin preparation was conducted during clinical observation.

The aim of the study was to evaluate the effectiveness of the use of instrumentation in young children with pertussis.

The criteria for inclusion in the study were:

- children with pertussis under the age of 3 years who have not received vaccinations against whooping cough;

- the absence of antibacterial, glucocorticoid and immunotropic drugs in therapy.

Studies were conducted in 2 groups of children. Group I (main) consisted of 40 children, for whom CIP was included in the complex treatment of whooping cough. Group II (n = 34, comparison group) included pertussis patients who received complex therapy without CIP. Both the 1st and 2nd groups were divided into 2 subgroups. In children 1.1 subgroups (n = 26, 65%) whooping cough proceeded as a monoinfection, in 1.2. the pertussis subgroup was accompanied by acute respiratory viral infections (n = 9, 22.5%) or mycoplasma respiratory infection (n = 5, 12.5%). A similar ratio was noted in the subgroups of the comparison group (2.1 and 2.2). Pertussis as monoinfection occurred in 20 children (58.8%), in combination with acute respiratory viral infections - in 6 (17.7%), and with respiratory mycoplasma infection - in 8 (23.5%).

The examined groups of children were comparable in age composition (table 1).

Table 1 The distribution of patients by age. Age groups The main group n = 40 Comparison Group n = 34 Abs. number % Abs. number % 0-3 months eighteen 45.0 13 38,2 4-6 months 7 17.5 6 17.6 7-12 months 8 20,0 9 26.5 1-3 years 7 17.5 6 17.6

In the main group, pertussis was confirmed by the bacteriological method in 2 (5.0%) children, by PCR in 14 (35.0%), by ELISA in 24 (60.0%) children. In the comparison group, the proportion of children whose diagnosis of pertussis was verified by isolation of the pathogen was 8.8% (3 children), detection of the pertussis microbe genome by PCR - 64.7% (22 children), ELISA - 26.5% (9 children).

The main group and the comparison group were representative of each other not only by the age of the patients, but also by the severity of the disease, the frequency of detection of unfavorable premorbid background, and the duration of the disease (table 2). Thus, the ratio of clinical forms in the main group was as follows: severe pertussis was diagnosed in 2 (5.0%) children, moderate in 36 (90.0%), mild in 2 (5.0%), and in the group comparisons - in 1 (2.9%), 30 (88.2%) and 3 (8.8%), respectively.

In most patients, both in the main and in the comparison group, an unfavorable premorbid background was revealed. As aggravating factors, various CNS lesions, prematurity, morpho-functional immaturity, anemia, and thymomegaly were most often diagnosed.

An analysis of the vaccination history showed that in both groups of children examined there were no fully vaccinated children. Incomplete vaccination had 8 patients who are classified as non-immune.

All patients with whooping cough, in the complex therapy of which used CIP, were hospitalized in a hospital during a spasmodic cough. Depending on the duration of the disease, the drug was prescribed on the 2nd week from the onset of the disease to 8 (20.0%) patients, on the 3rd - 25 (62.5%), on the 4th - 7 (17.5%) sick.

table 2 Comparative characteristics of patients. Compared Indicators The main group n = 40 Comparison Group n = 34 Abs. number % Abs. number % Clinical forms heavy 2 5,0 one 2.9 medium heavy 36 90.0 thirty 88.2 light 2 5,0 3 8.8 The timing of initiation of therapy 2nd week 8 20,0 6 17.6 3rd week 25 62.5 24 70.5 4th week 7 17.5 four 11.7 Weighted premorbid background 9 22.5 7 20.6

Instrumentation was administered orally at 1 dose (1 vial) 1-2 times a day for 5-7 days. Treatment began from the first day of hospital stay, regardless of the severity of the pertussis infection. CIP treatment was carried out against the background of complex therapy (antitussive drugs - synecode, phenobarbital, mucolytic drugs - and drugs that restore bronchopulmonary patency). In the comparison group, children were prescribed complex therapy in the same volume.

A comparative assessment of the effectiveness of instrumentation was carried out on the basis of the following criteria:

- a change in the nature of the cough with a decrease in the number and duration of seizures;

- the disappearance of cyanosis of the face during coughing attacks;

- reduction of the phenomena of hypoxia;

- improvement of well-being, appetite and normalization of sleep.

Comparison of treatment results in groups of children who received and did not receive CIP showed the effectiveness of this drug in the main indicated comparison parameters. The therapeutic effect of instrumentation was determined primarily by a reduction in the number of spasmodic attacks; the cough became more productive, the cyanosis of the face (lips, nasolabial triangle) disappeared with coughing, and vomiting was less frequent. A clinical analysis of the dynamics of the nature of cough in the main group showed that a decrease in the number of seizures by 4-5 days of the use of CIP was observed in most children (n = 27, 67.5%). In a comparative assessment of the effectiveness of the use of CIP in children, depending on the timing of the appointment, it was found that after the use of CIP, a 2.4-fold decrease in the frequency of coughing attacks was observed if it was used at the 2nd week of illness and 2.1 times at the 3rd week (table 3). The appointment of the drug at a later stage of the disease with whooping cough did not give a pronounced therapeutic effect.

Table 4 presents a comparative analysis of the duration of the main symptoms of whooping cough. If in the main group coughing attacks with a frequency of more than 25 times a day persisted for 2.7 ± 0.2 days, then in the comparison group - 4.3 ± 0.2 days (p <0.001), and attacks with a frequency of 15- 25 times a day - 8.4 ± 0.3 and 10.2 ± 0.4 days, respectively (p <0.01).

Table 3 The nature of coughing in children on the background of taking CIP, depending on the timing of the appointment. Disease periods, number of patients The frequency of coughing attacks Significance of differences, p before taking instrumentation M ± m after taking instrumentation, M ± m 2nd week, n = 8 20.6 ± 3.8 8.6 ± 2.8 p <0.05 3rd week, n = 25 20.5 ± 5.4 9.7 ± 1.2 p <0.05 4th week, n = 7 11.0 ± 3.8 9.0 ± 2.9 p> 0.05

A significant result of the use of instrumentation was the reduction in the average length of hospital stay of pertussis patients. So, if in children receiving instrumentation it was 7.6 ± 0.4 k / day, then in the comparison group it was 9.7 ± 0.7 k / day (p <0.05). Reducing the length of hospital stay reduced the risk of layering of acute respiratory viral infections. As mentioned above, from the main group and from the comparison group, patients were identified in whom pertussis proceeded in combination with acute respiratory and mycoplasma infections. Bronchopulmonary complications (bronchitis) developed only in the case of mixed infection with acute respiratory viral infections - in 4 patients in each group. In general, the more favorable course of concomitant respiratory infections in children receiving CIP was noteworthy.

It is well known that a significant number of patients with whooping cough have dyspeptic disorders (regurgitation, flatulence, changes in the nature of stool). As our studies have shown, in the group of children receiving instrumentation, such phenomena were not observed. In the comparison group, 6 (17.6%) patients aged 0-3 months had diarrhea syndrome.

Table 4 The duration of the main clinical symptoms of pertussis in children of the examined groups. Clinical symptoms The duration of symptoms in days (M ± m) Significance of differences, p The main group n = 40 Comparison group
n = 34 Disturbance of health 4.3 ± 0.2 7.8 ± 1.3 p <0.01 Facial cyanosis with cough 4.0 ± 1.8 7.8 ± 0.4 p <0.05 Seizure frequency > 25 times 2.7 ± 0.2 4.3 ± 0.2 p <0.001 15-25 times 8.4 ± 0.3 10.2 ± 0.4 p <0.01 Vomiting 2.5 ± 0.9 4,5 ± 0,5 p <0.05 Decreased appetite 4.3 ± 0.2 6.1 ± 0.9 p <0.05 Average hospital stay 7.6 ± 0.4 9.7 ± 0.7 p <0.05

In a number of cases (in 3 children), at the beginning of the period of spasmodic cough, a pronounced effect was observed with the use of the drug.

Example. one

A clinical example is the case history of child K., aged 1 month, with a diagnosis of whooping cough, moderate form. When collecting an anamnesis of life, it was found that the child from the 1st pregnancy, which proceeded with the threat of interruption, is of 1 birth. Delivery at the 40th week, the baby was born with a body weight of 3660 g, a length of 52 cm, cried out right away. He was breastfeeding, gained enough weight. Previously not sick. From the medical history of the disease, it is known that the child fell ill on 11/13/12, when a rare cough appeared without an increase in temperature and catarrhal phenomena. Since November 17, 12, the cough has acquired a paroxysmal character with hyperemia of the face. From 11/18/12, Flemoxin-solutab was prescribed, lazolvan, but the cough intensified. By 11/23/12, the attacks were prolonged, with a reddening of the face and cyanosis of the nasolabial triangle. An ambulance was hospitalized in the hospital No. 1.

Upon admission to the hospital, the condition is regarded as moderate. The child is lethargic, appetite is reduced. Coughing up to 20 times a day, paroxysmal, with reddening of the face, short-term cyanosis of the lips. The coughing attacks are long. Objectively: the skin is clean. There is puerile breathing in the lungs. Heart tones are rhythmic, clear. The abdomen is soft, painless. The liver and spleen are not enlarged. Stool and diuresis are normal. The prescribed treatment: 1 dose 2 times a day, medicine with aminophylline and potassium iodide, phenobarbital, oxygen therapy.

Against the background of the therapy, the child’s condition improved: coughing attacks by the 3rd day of treatment became shorter, from the 4th day their frequency did not exceed 9 times a day. Along with this, the child’s well-being improved: there was an appetite, the baby became more active. On the 6th day from the moment of admission to the hospital, the child was discharged home.

Examination data: analysis for pertussis by PCR from 11.24.12 - the B.pertussis gene was isolated, the results of the study by ELISA from 11.23.12 - no IgM, IgG 6 U / ml, IgA 0, from 11.28.12 - no IgM, IgG 19 U / ml, IgA 7 U / ml. General blood test from 11.24.12 - lake. 40 × 10 ⁹ / l, hemogl. 116 g / l, ESR 4, p / 3, s / I 22, lymph. 71, monoc. four; from 11/28/12 - a lake. 27.3 × 10 ⁹ / l ′, hemogl. 116 g / l, ESR 7, p / 1, s / I 22, lymph. 67, monoc. 8; urine analysis without pathology.

A distinct clinical effect of the proposed method of treatment was detected in 87.5% of sick children.

In 5 (12.5%) pertussis patients, there was no significant regression of clinical symptoms during treatment with complex immunoglobulin preparation, which was associated with a later start of treatment (4th week from the onset of the disease).

In the main group, leukocytosis in dynamics against the background of the use of instrumentation was studied in 15 children. The studies were conducted mainly at 2-3 weeks from the onset of pertussis disease. Differences in the number of leukocytes before and after the use of instrumentation were not found.

The inclusion of instrumentation in the complex of pertussis therapy had a positive effect on the production of specific antibodies. The results of a serological study of blood serum samples of 25 children in dynamics showed that, against the background of the use of this drug, an increase in titers of class G antibodies was observed in 18 (72.0%) children after 7 days. Seroconversion of class A and M immunoglobulins detected in 5 (20.0%) and 2 (8.0%) patients, respectively, was most likely due to the natural increase in antibodies of these isotypes during the infection process.

During the study, much attention was paid to identifying adverse events from the therapy. Daily clinical observation and laboratory studies in the dynamics of the disease did not reveal a negative effect of instrumentation on the body of children with whooping cough. When examining patients for the total amount of IgE in the blood before and after treatment with a complex immunoglobulin preparation, only 1 child revealed elevated IgE numbers. In this case, there was a layering of influenza and adenovirus infection during pertussis.

Thus, the achieved technical result of the claimed method of the invention consists in a fundamentally new use of the drug CIP and confirms that oral administration of CIP containing antibodies to pertussis toxin and filamentous hemagglutinin can have a positive effect on the course of whooping cough in young children, which are characterized by a change in the nature of cough with a reduction in the number and duration of seizures, the disappearance of facial cyanosis during coughing attacks, a decrease in the phenomena of hypoxia, mproving health, appetite and sleep normalization, lack of dyspeptic disorders, more favorable course of concomitant respiratory infections and, as a consequence, reduction of terms of hospitalization.

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Claims (1)

 A method for the treatment of pertussis in children under three years of age, including the use of conventional complex therapy in the form of antitussive drugs and drugs that restore bronchopulmonary pertussis pertussis, characterized in that sick children are additionally prescribed an oral complex immunoglobulin drug in a single dose containing 300 mg of protein, 1-2 times a day for 5-7 days.