ARIs and "bacterial vaccines" to combat them

Acute respiratory diseases are the most common pathology of childhood: every year children suffer from 2-3 to 10-12 ARIs, which are caused by more than 150 pathogens and their variants. With the beginning of attending preschool institutions, respiratory morbidity increases sharply, so that in the 1st year of attendance, half of the children suffer 6 or more ARIs, forming a group of "frequently ill children". And although in the 2nd-3rd years of attendance the incidence decreases, about 10% of children remain in the group of frequently ill children. As a rule, these are children with an allergic predisposition, which manifests itself mainly in bright manifestations of ARVI. Frequent ARIs lead to large economic losses.

Frequently ill children are not a diagnosis, but only an observation group; it includes under-examined children with specific nosological forms - recurrent bronchitis, including obstructive, mild asthma, chronic tonsillitis and even chronic pneumonia and cystic fibrosis. So, before including a child in a dispensary observation group for frequent illnesses, it is necessary to conduct an examination in order to exclude a specific pathology.

The lack of clear differences in the clinical picture of viral and bacterial ARIs, the impossibility of rapid diagnostics of their etiology, and the fear of missing a bacterial complication lead to excessive prescription of antibiotics to frequently ill children. However, antibiotics for ARIs do not have a preventive effect; they only increase the frequency of bacterial complications.

The arsenal of immunoprophylaxis includes vaccines against a number of pathogens of acute respiratory infections (Hib, pneumococcal, whooping cough, diphtheria, influenza vaccines), but there are no specific vaccines against the main pathogens of acute respiratory viral infections.

In these conditions, it is understandable that a large number of drugs have been created to reduce respiratory diseases. The annotations of these drugs usually emphasize their immunomodulatory effect, usually without a clear explanation. These include thymus preparations (T-activin, Timalin, etc.), herbal remedies (dibazol, eleutherococcus, echinacea), vitamins, microelements, homeopathic remedies (Aflubin, Anaferon), stimulants (pentoxyl, diucifon, polyoxidonium), and many others. Despite intensive advertising, most of these drugs do not have convincing evidence of effectiveness in reducing respiratory diseases despite many years of use. And many of them have clearly negative results. Moreover, the use of immunomodulators without special indications is simply unacceptable. In this regard, drugs from the group of bacterial lysates seem more acceptable, sometimes with the inclusion of more refined components of the microbial cell.

Indications for use

All drugs from the group can be used to prevent recurrent acute respiratory viral infections and related respiratory diseases (rhinitis, sinusitis, pharyngitis, tonsillitis, laryngitis, acute and recurrent bronchitis), including in frequently ill children and children with allergic pathology. Imudon is also indicated for diseases of the oral cavity and pharynx. It is possible to start using the drugs both in a healthy child and during another respiratory disease, continuing the course after recovery.

Characteristics of bacterial lysates

Bacterial lysates have replaced such microbial agents as pyrogenal and prodigiosan, which were used as non-specific immunostimulants. Prodigiosan in the form of nasal drops was quite acceptable as a means of preventing acute respiratory infections in kindergartens, which was shown in a controlled study in Lithuania and Estonia in the 1980s. The effectiveness of bacterial lysates, demonstrated in Europe in the 1980s and 1990s and somewhat later in Russia, was the basis for their recommendation as safe means of non-specific prevention of acute respiratory viral infections in children.

Although lysates are close to vaccines, their mechanism of action is different. By introducing these bacterial preparations, we mean the prevention of viral infections. And when assessing their effectiveness, we do not evaluate the reduction in the frequency of infections caused by the pathogens included in them, but the total respiratory morbidity. Of course, in response to their introduction, antibodies are also produced, for example, to pneumococci or klebsiella, but their role in preventing the corresponding infection is usually not considered.

It has been proven that the basis of the action of these drugs is the stimulation of the immune response of the Th-1 type, more mature, compared to the Th-2 type response with which children are born. The formation of the Th-1 type response in a child occurs mainly under the influence of microbial stimulation, the lack of which in modern children is associated with a high level of hygiene, the relative rarity of bacterial infections and the widespread unjustified use of antibiotics that suppress the commensal flora. An important role is also played by the almost constant use of antipyretics at any increase in temperature, which also suppress the production of cytokines that cause the Th-1 type response: γ-interferon, IL-1 and IL-2, TNF-a. Suppression of the Th-1 type response prevents the development of a more stable response to infection and the formation of immunological memory.

Bacterial lysates stimulate the production of Th-1 type cytokines, they also increase the production of IgA, slgA, lysozyme in the mucous membranes of the respiratory tract, simulate the activity of natural killers, normalizing the number of CD4+ cells when they decrease, and also suppress the production of IgE and antibodies of this class. It is this action of lysates that is currently considered the main one, contributing to the formation of a mature immune response and a decrease in respiratory morbidity.

IRS 19 - bacterial lysate of predominantly local action stimulates the production of endogenous lysozyme and SIgA, increases the phagocytic activity of macrophages (qualitative and quantitative enhancement of phagocytosis), indirectly normalizing the number of CD4+ cells when they decrease. The desensitizing effect of IRS 19 has also been proven due to polypeptides that prevent the formation of sensitizing antibodies. When using IRS 19, swelling of the nasopharyngeal mucosa also decreases, exudate is liquefied and its outflow is facilitated.

Imudon increases the concentration of lysozyme, endogenous interferon, SIgA and antibodies of this class in saliva, including in relation to Candida albicans - the main causative agent of thrush and pharyngomycosis. Imudon quickly and effectively relieves sore throat, normalizes the composition of the oropharynx microflora.

Preparations of predominantly general action, in addition to stimulating the formation of specific antibodies to microorganisms included in their composition, activate humoral activity characteristic of the Th-1 response. For VP-4 and Bronchomunal, correction of the content of T-lymphocytes (CD3, CD4, CD 16, CD20) and a decrease in the level of immunoglobulin E are also indicated. Ribomunil also stimulates the function of T- and B-lymphocytes, the production of serum and secretory immunoglobulins, IL-1, and alpha-interferon. The drug has both general and local action, increasing the level of secretory IgA. Lysates are included in the ARI Program of the Union of Pediatricians.

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Efficiency

Meta-analysis of the effectiveness of imported lysates shows that in the treatment groups the frequency of ARI decreases compared to the placebo group by an average of 42% (95% CI 40-45%). The use of VP-4 in frequently ill children led to a reduction in the duration of ARI, a 3-fold decrease in morbidity, and a reduction in episodes of obstruction.

Controlled studies of a 6-month course of Ribomunil in frequently ill children showed a 3.9-fold decrease in the incidence of ARIs and a 2.8-fold decrease in the use of antibiotics. In placebo-controlled studies, a positive effect was achieved in 30-74% of children, and the number of days of incapacity for work among parents significantly decreased. A 3-month course of Ribomunil is also effective: already in the 1st year, the incidence of ARIs decreased by 45.3%, and the need for antibacterial therapy by 42.7%. In the 2nd year, the number of ARIs per child was 2.17+0.25, in the control - 3.11+0.47. These differences are smoothed out by the end of the 2nd year.

It has been shown that the use of IRS 19 also leads to a reduction in the number of acute respiratory viral infections. Thus, asthma patients treated with IRS 19 had 3 times fewer episodes of acute respiratory viral infections (2.1 per child) during the year than in the previous year, while in the control group there were only 25% fewer (4.5 per child). A good effect of IRS 19 was also noted in adults, as well as at the beginning of treatment in the acute period of acute respiratory viral infections.

In children who get sick frequently (more than 6 times a year), Imudon reduced the frequency of acute respiratory viral infections by half over the next 3 months compared to the previous 3 months, and exacerbations of chronic pharyngitis by 2.5 times, the carriage of beta-hemolytic streptococcus decreased by 3 times, and Candida fungi by 4 times. Despite the fairly high costs of bacterial lysates, they provide significant savings.

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Routes of administration and dosage

VP-4 is administered to children over 2.5 years old by the nasally-oral method. The vaccine is diluted with 4 ml of saline. In this form, it can be stored for 5 days at 2-6°. The first 3 days, the vaccine is administered only nasally in the following dose: 1 drop on the 1st day, 2 drops on the 2nd day, 4 drops on the 3rd day. Oral administration begins after 3 days: at intervals of 3-5 days, 1 ml/day and 2 ml/day are given once, then 4 ml/day - 6 times. If the effect is insufficient, the course of oral administration can be extended to 10 times at a dose of 4 ml. Food intake is 1 hour before and 2 hours after administration of the vaccine.

Bronchomunal is prescribed orally, in the morning, on an empty stomach, one capsule for 10-30 days. For preventive purposes - 1 capsule per day for 10 days in a row per month; course - 3 months. (it is advisable to start therapy every month on the same day). 1 capsule of Bronchomunal P contains 3.5 mg for children 6 months-12 years old, for older children and adults 1 capsule contains 7 mg. Bronchovacsom is also available in capsules of 3.5 and 7 mg and is used in the same way.

IRS 19 is an intranasal spray in 20 ml bottles (60 doses), prescribed to children from 3 months of age, 1 dose 2 to 5 times a day for 2 weeks.

Imudon - tablets (0.05 g of dry matter) for resorption with a pleasant taste should be kept in the mouth until completely resorbed (without chewing). Prescribed 6 tablets per day for acute (10 days) and chronic (more than 20 days) pharyngitis, for severe purulent-inflammatory diseases of the oral cavity with bone damage

Bacterial lysates

Preparation	Compound
VP-4, Mechnikov Research Institute of Vaccines and Serum Syndrome, Russian Academy of Medical Sciences, Russia	Acellular multicomponent vaccine - antigens and associated lipopolysaccharides of S. aureus, K. pneumoniae, Proteus vulgaris, E. coli, as well as teichoic acid
Bronchovacsom, OM form, Switzerland	Lyophilized lysate of 8 bacteria: S. pneumoniae, H. influenzae, K. pneumoniae, K. ozenae, S. aurens, S. viridans, St. pyogenes, M. catarrhalis
Bronchomunal Lek, Slovenia
Imudon, Solvay Pharma, France	A mixture of lysates of 13 bacteria: Streptococcus pyogenes group A, Enterococcus faecalis, Enterococcus faecium, Sptreptococcus sanguis, Staphylococcus aureus, K. pneumoniae, Corynebacterium pseudodiphtheriticum, Fusobacterium nucleatum, Lactobacillus acidophilus, L. fermentatum L. heheticus, L. delbrueckiis, Candida, albicans,
IRS 19, Solvay Pharma, France	Lysates of 18 bacteria: S. pneumoniae (6 serotypes), S. pyogenes (groups A and C), H. influenzae, K. pneumoniae, N. perflava, N. flava, M. Catarrhalis, Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Streptococcus group G, Acinetobacter
Ribomunil, Pierre Fabre, France	Ribosomal fractions of K. pneumoniae (35 lobes), S. pneumoniae (30 lobes), S. pyogenes (30 lobes), H. influenzae (5 lobes) + proteoglycans of the membrane part of Klebsiella

Imudon is combined with antibiotics; for ENT surgeries, 8 tablets are given per day for 1 week before and after surgery. It is recommended to take 2-3 courses per year.

Ribomunil is available in tablets of 0.25 mg ribosomal fractions and 0.375 mg proteoglycans of the membrane part of Klebsiella pneumoniae (1/3 of a single dose) or 0.75 and 1.125 mg (1 single dose), respectively, and in the form of sachets with 500 mg granulate for the preparation of a drinking solution. Dosage: 3 tablets (0.25 mg) or 1 tablet (0.75 mg) or 1 sachet (after dilution in a glass of water) 4 days a week for 3 weeks in the first month of treatment, then the first 4 days of each month for the next 5 months.

Side effects and contraindications

When VP-4 is administered, the temperature may increase to subfebrile levels for 12-24 hours, nasal congestion, cough (at a temperature of 38.5° or other side effects, the administration is stopped). Broyusomunal may cause dyspepsia. IRS 19 may in rare cases increase rhinorrhea, which helps eliminate pathogenic agents. Imudon has no side effects. Hypersalivation is noted among the side effects of Ribomunil.

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Combined use with other vaccines

Ribomunil, IRS19 were successfully used together with influenza vaccines, which increased their effectiveness against ARI. The combined administration of Ribomunil with measles vaccination reduced the frequency of ARI in the post-vaccination period; Ribomunil accelerates the immune response to vaccination, which indicates its pronounced immunomodulatory effect.

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