Urogenital endogenic Bacterial Infection

This article presents the terminology and modern views regarding the formation of vaginal dysbiosis and urogenital endogenous infection. The characteristic of endogenous and exogenous trigger factors leading to a violation of the vaginal microbiocenosis is given. The mechanisms for the occurrence of some obstetric pathology in this infectious process are considered. Diagnostic and therapeutic approaches for the correction of dysbiosis with determining the place of systemic enzyme therapy in the complex treatment of this pathology are presented.

Endogenous bacterial infections (EBI) are nonspecific infectious and inflammatory diseases caused by commensal auto-flora, which under certain conditions manifests its pathogenic potential either in its natural habitats (urogenital tract) or in other organs when the internal environment of the macroorganism is infected, which is accompanied by its homeostasis with the development of an inflammatory reaction of a local and / or systemic nature.

Vaginal dysbiosis, like dysbiosis in other abdominal organs, can be considered as the initial stage of the formation of an endogenous infection. Stage formation of endogenous bacterial infection can be represented as follows. At the initial stage, under the influence of endogenous and / or exogenous trigger factors, a dysbiotic process is formed, accompanied by a decrease in the number of obligate microbiota, which may be limited by bacteremia and antigenemia associated with excessive (threshold) accumulation of facultative pathogenic endogenous bacterial microflora.

The endogenous microflora, or microbiota of biotopes of the female urogenital system, forming its endogenous microbiocenosis, is heterogeneous. In our opinion, it includes a constant (autochthonous, resident) component (99%) and a transient (allochton, random) component - 1%. Constant microflora, in turn, subdivided into obligate (obligatory, basic or indigenic) - 80–90% and optional (optional, additional) - 10–20%. The facultative part of the resident microbiota, including opportunistic microorganisms (mainly bacteria), often together with exogenous genital infection participates in the formation of inflammatory foci in the organs of the genitourinary system. Therefore, in the overwhelming majority of cases (about 90%), their etiological factor is mixed (exogenous-endogenous) microflora.

Obligate part of the resident microbiota, which is represented in women Lactobacillus spp. and Bifidobacte rium spp. and is predominantly in the vaginal biotope, is that “normal” microflora that does not participate in the formation of inflammatory foci due to the absence of pathogenicity factors and creates that bacterial “buffer” that normally prevents colonization of the genital tract by conditional pathogens and the spread of exogenous infection. The facultative part of the endogenous vaginal microbiota includes numerous opportunistic bacteria belonging to different groups. Under the influence of various exogenous and / or endogenous factors, they can colonize the genital tract and, when they reach a certain (critical) amount of microbial mass, realize their pathogenic potential, causing dysbiotic and inflammatory foci.

In dysbiosis, immunopathological and anti-apoptotic effects can occur, as well as chromosomal aberrations associated with the effects of certain facultative microbiota (in particular, mycoplasmas), leading to the formation of autoimmune reactions, tumor transformation and the addition of secondary infection.

At the next stage, the inflammatory process in the organs of the urogenital system (as a variant of a local non-generalized endogenous infection) with dysfunction of these organs may join. With the spread of pathogens outside the urogenital system and the formation of inflammatory foci in the organs of other systems, we can speak of a generalized endogenous infection. At the same time, there may be no proliferation of bacteria in the blood and transient bacteremia and antigenemia in the absence of other clinical and laboratory signs of sepsis. However, with a pronounced weakening of immunoresistance, septicemia and septicopyemia with all their manifestations and consequences can be formed.

From the variety of reasons involved in the formation of endogenous sexual infection and dysbiotic process of the vagina as its initial stage, the following can be singled out as the main ones: 1) a change in the pH of the vaginal contents (the causes are both endogenous and exogenous); 2) infection with pathogens of exogenous genital infections (chlamydia, trichomonads, neisseriya, viruses); 3) violations in the system of general and local immunity; 4) induction of lysogeny in lactoflora, leading to the destruction of the pool of obligate lactoflora and, as a result, to a decrease in colonization resistance.

From exogenous genital infections or sexually transmitted infections, the most relevant in terms of the impact on the endogenous microbiota are urogenital chlamydial (pathogen - Chlamydia trachomatis 15 serotypes from A to K), urogenital trichomonas (pathogen - Trichomonas vaginalis) and a heart infection infection, a heart infection infection, a heart infection pattern, a heart infection pattern, a heart infection pattern, a heart infection pattern, a heart infection pattern, a heart infection pattern, a heart infection pattern and a heart infection pattern, a heart infection pattern, a heart infection infection, a heart infection infection, a heart infection infection, a heart infection infection, a heart infection infection, a heart infection infection, a heart infection infection, a heart infection infection and an infection that has a heart attack. - Neisseria gonorrhoeae). The causative agents of these genital infections as a type of exogenous factors can also affect the vaginal microbiocenosis not only directly, but also indirectly through endocrine-immune mechanisms. Using the example of chlamydial infection, the direct effect of hormones and cytokines on the exopathogen genome, leading to the formation of aberrant forms and persistence, has been proven.

The concept of "dysbiosis" is much broader than "dysbacteriosis." Dysbacteriosis characterizes the violation of the qualitative and quantitative composition of bacterial microflora. Dysbiosis includes disorders related not only to bacterial microflora, but also to other representatives of the microbiocenosis (fungi, viruses, protozoa).

Basically, there are several main options for vaginal dysbiosis:

• ■ anaerobic dysbacteriosis (anaerobic bacterial dysbiosis or vaginal dysbiosis with a predominance of anaerobic bacterial microflora; or bacterial vaginosis) - only anaerobic facultative pathogenic bacteria dominate over obligate bacterial microflora;
• ■ aerobic dysbacteriosis (aerobic bacterial dysbiosis or vaginal dysbiosis with predominance of aerobic bacterial microflora) - only aerobic facultative opportunistic bacteria predominate over obligate bacterial microflora;
• ■ mixed dysbacteriosis (aerobic-anaerobic bacterial dysbiosis or vaginal dysbiosis with predominance of aerobic and anaerobic bacterial microflora) - aerobic and anaerobic facultative pathogenic bacteria over obligate bacterial microflora predominate to the same extent.

In all three cases, the proportion of obligate bacterial microflora is below 80%, and the number of fungi of the genus Candida is normal (< 104 CFU). Individual types of vaginal dysbiosis are variants in which there is an increased accumulation of Candida fungi (> 104 CFU) with a normal amount of obligate bacterial microflora, as well as with a concomitant decrease in obligate bacterial microflora and the prevalence of optional microflora in various species presented above.

Thus, it is possible to speak about several variants of dysbiosis (variants of mixed dysbiosis):

• ■ fungal dysbiosis (vulvovaginal candidiasis) - in the case of the predominance of fungi of the genus Candida against the background of a sufficient amount of obligate bacterial microflora;
• ■ Fungal and bacterial dysbiosis - the predominance of Candida fungi against the background of a decrease (< 80%) of obligate bacterial microflora.

This option can be in 3 varieties:

a) fungal anaerobic dysbiosis - the accumulation of Candida fungi (> 104 CFU) and the prevalence (> 20%) of facultative anaerobic bacterial microbiota over the obligate;

b) fungal aerobic dysbiosis - the accumulation of fungi Candida genus (> 104 CFU) and the prevalence (> 20%) of the optional aerobic bacterial microbiota over the obligate;

c) fungal-anaerobic-aerobic disbiosis – accumulation of fungi of the genus Candida (> 104 CFU) and the prevalence (> 20%) of facultative aerobic and anaerobic bacterial microflora over the obligate microflora; and there is a predominance of both groups of bacteria to the same degree.

Depending on the nature of the dysbiotic process in the vagina, several types of endogenous infection can be considered: urogenital anaerobiosis, urogenital aerobiosis and urogenital candidiasis or vulvovaginal candidiasis, and their various combinations.

Of the presented variants of dysbiosis, anaerobic dysbacteriosis of the vagina or (as it is also called) bacterial vaginosis, which forms the initial stage of urogenital anaerobiosis as a type of urogenital endogenous infection, is the most frequent.

In anaerobic dysbacteriosis or anaerobic bacterial dysbiosis (bacterial vaginosis) from the optional part of the endogenous microbiota the most common bacteria are from the genera Gardnerella, Atopobium and Prevotella.

Vaginal dysbiosis, like dysbiosis in other abdominal organs, can be considered as the initial stage of endogenous infection

Of the newly added “participants” (Atopobium vaginae, Mycoplasma genitalium, Leptotrichia and Mega sphaera species, unidentified Clostridium species), all but mycoplasmas turned out to be strict anaerobes.

In about 84% of cases, bacterial vaginosis is combined with intestinal dysbacteriosis. In this case, vaginosis can be considered as a manifestation of a systemic dysbiotic process, which affects not only the urogenital system microbiota, but also the endogenous microflora in various cavities of the microorganism when exposed to any exogenous and endogenous factors. In this case, when confirming the prevalence of anaerobes in its various biotopes, this violation in a global sense can be called "anaerobiosis" and regarded as one of the variants of endogenous infection with the formation of dysbiotic foci not only in the urogenital tract, but (most often) and in the digestive system.

Bacterial infections realize their pathogenic potential through the formation of inflammatory foci in the reproductive system with a violation of their function, the effects of endo and exotoxins. Moreover, not only pathogens of exogenous genital infections are often involved in the infectious process, but also representatives of the endogenous microflora that form dysbiosis of the vagina and other organs. This is facilitated by the specificity of the metabolism of some bacteria, which causes the characteristic manifestations of this dysbiotic process and the appearance of a number of complications.

For example, in bacteroids, fuzobacteria, as well as in anaerobic streptococci and gardnerella, a high ability to produce phospholipase A2 was detected. The latter, in turn, activates the production of prostaglandins by releasing arachidonic acid from its ester form.

In pregnant women, bacterial proteases and lipases can affect the chorioamniotic membrane, leading to its rupture. Violation of the integrity of the chorioamniotic membrane in conjunction with increasing concentrations of prostaglandins in the amniotic fluid initiate preterm labor. Organic acids produced by gram-negative anaerobes, as well as bacteria of the genus Mobiluncus (in particular, succinic acid), inhibit the functional activity of polynuclear neutrophils, with which a small amount of the latter or their complete absence in vaginal discharge during bacterial vaginosis is associated. G. vaginalis can produce toxic bioproducts, which include mucolytic enzymes and hemolysin. By acting on red blood cells, hemolysin causes the formation of numerous pores in the erythrocyte membrane.

Hemolysin is also a leukotoksichesky factor causing structural and functional disorders of leukocytes in the form of their swelling and reduction of directional leukotaxis. One of the factors of leukocyte suppression is succinate, a product of the metabolism of bacteria of the genus Bacteroides, also present in large quantities in vaginal specimens of women with bacterial vaginosis. Succinate inhibits the chemotactic ability of leukocytes and their phagocytic ability.

Levels of endotoxinemia and proinflammatory cytokines are markers of chronic endogenous infectious and inflammatory diseases of different parts of the genital tract with damage to the network of organs of the reproductive system of women

Thus, the functions of leukocytes can be suppressed by the synergistic effect of hemolysin gardnerell and bacteroid succinate.

A number of studies of different years confirm the participation of lipopolysaccharides (LPS) of gram-negative bacteria in the pathogenesis of a separate obstetric-gynecological pathology, including embryonic resorption, intrauterine growth retardation and antenatal fetal death, premature birth, preeclampsia, placental dysfunction. Levels of endotoxinemia and pro-inflammatory cytokines are markers of chronic endogenous infectious and inflammatory diseases of different parts of the genital tract with damage to the network of organs of the reproductive system of women.

In the dysbiotic state of the vaginal biotop in women, an increase in the concentration of LPS in the systemic circulation is 7 times, the level of endotoxin-binding protein (LBP - lipopolysaccharide-binding protein) - 2 times and IgG titers to the core-LPS region - 1.7 times compared to normobiocenosis. The involvement of LPS in the pathogenesis of bacterial vaginosis is consistent with the fact that this syndrome occurs without signs of an inflammatory reaction, which is based on a decrease in the functional activity of neutrophils, manifested by incomplete phagocytosis. The latter may be due to the effect of ultra-high concentrations of LPS of gram-negative bacteria, which are dominant in vaginosis, on leukocytes, leading to a decrease in phagocytic activity and a cytotoxic effect.

A more than tenfold increase in serum LPS concentration in women with infertility against the background of chronic nonspecific inflammatory diseases of the pelvic organs leading to a decrease in the level of antiendotoxin antibodies and inhibition of the activity of granulocyte antiendotoxin immunity has also been established.

Endotoxin-induced immunopathological changes in homeostasis, manifested by endothelial dysfunction, are largely identical to those in the development of preeclampsia, which indicates the universality of the mechanisms of their formation and allows us to consider preeclampsia as a model of systemic endotoxinemia. The latter is a modern concept explaining the phenomenon of preeclampsia from the standpoint of the realization of negative biological effects of LPS against the background of insufficiency of LPS-binding and LPS-elimination systems. Thus, it was shown that in severe pre-eclampsia, the level of LPS in serum increases many times against the background of inhibition of the synthesis of immunoglobulins to the Lore sore-region. It is known that the main source of LPS in preeclampsia may be the intestinal microbiota. Under conditions of reduced tissue perfusion due to peripheral generalized vasospasm with preeclampsia, enhanced translocation of gram-negative bacteria and their endotoxin through the ischemic intestinal wall can occur.

Along with intestinal biocenosis, other reserve LPS is vaginal habitat, especially when vaginosis, when the proportion of gram-negative microorganisms increases by thousands of times, and atrophic changes of the vaginal mucosa due to the influence of the shell bacterial enzymes contribute LPS penetration of venous and lymphatic vascular reproductive organs network system in the period of gestation.

When pregnancy occurs, autoimmune reactions and activation of infection can lead to the development of disseminated intravascular coagulation, the occurrence of local microthrombosis in the area of placentation with the formation of heart attacks, followed by placental abruption

It has been shown that hemocirculation of LPS against the background of suppression of anti-endotoxin immunity may be manifested by the frequent development of preeclampsia in the first half of pregnancy, the threat of termination of pregnancy in the early stages, as well as anomalies of labor activity. Proven miscarriage in dysbiotic conditions of the genital and intestinal tracts. In 30–40% of cases, the cause of preterm labor is infectious.

To exclude some exogenous sexual infection (chlamydia, trichomonas, neural), it is advisable to additionally use modern diagnostic (laboratory) approaches

Another, no less significant consequence of infectious and inflammatory diseases of the mother is the formation of placental insufficiency, the frequency of which against the background of infection reaches 50-60%. Proinflammatory cytokine IL-1 is considered to be the main “mediator” of the damaging effect of LPS on the placenta. It has been proven that abnormalities in the hemostasis system during pregnancy towards increased blood coagulation potential subsequently lead to thrombosis of the spiral arteries, villi vessels, choriological plate, and umbilical vessels, which is clinically manifested by the development of placental disorders, hypoxia and fetal hypotrophy. Perhaps it is the LPS of gram-negative bacteria that triggers the coagulation cascade, which ends up with thrombus formation in utero-placental vessels, since the ability of LPS to cause disturbances in the hemostasis system and microcirculation, which has been confirmed in animal experiments, has been previously established.

In some cases, poor pregnancy outcomes are due to concomitant disorders in the hemostasis system, including the antiphospholipid syndrome characterized by multiple thrombosis of vital organs against the background of high titers of antiphospholipid antibodies. The experiments demonstrated that intraamniotic administration of LPS entails serious consequences for the maternal organism, contributing to the development of chorionamnionitis, and for the fetus, causing damage to the central nervous system and the formation of congenital malformations and anomalies.

A special role in the formation of reproductive complications during endogenous bacterial infection is played by a viral persistent infection. With endogenous infection, special favorable conditions are created for its activation. Prolonged persistence of viral infection leads to a state of immunodeficiency. In addition, long-term persistence of viral-bacterial infection can lead to changes in the antigenic structure of infected cells due to both the actual infectious antigens included in the structure of the surface membranes and the formation of new cellular antigens determined by the cellular genome. This leads to the appearance of autoantibodies, which can have a destructive effect on the cells of their own organism. When pregnancy occurs, autoimmune reactions and activation of the infection can lead to the development of disseminated intravascular coagulation, the occurrence of local microthrombosis in the area of ​​placentation with the formation of heart attacks, followed by placental abruption. Infection can directly affect the fetus, possibly due to the activation of pro-inflammatory cytokines, which have a cytotoxic effect. Loss of pregnancy can be associated with hyperthermia, elevated levels of prostaglandins, with premature rupture of the membranes due to microbial proteases and other mechanisms.

According to T.I. Dolgikh et al., Indirect clinical signs of congenital malformations in the fetus are the presence of a long-term threat of termination of pregnancy, the development of placental insufficiency, and pathology of amniotic fluid. The presence of congenital malformations of the fetus is associated with the formation of placental insufficiency, accompanied by signs of activation of intravascular coagulation. With ultrasound markers of intrauterine infection, there is a reliably frequent determination of signs of activation of intravascular coagulation (hyperfibrinogenemia, a decrease in the activity of antithrombin III). In addition, the active course of herpes virus infections contributes to the activation of intravascular coagulation of blood with a tendency to the formation of chronic DIC.

Diagnosis of urogenital endogenous infections in women, in our opinion, should include the following components: 1) a statement of vaginal dysbiosis (the establishment of its varieties); 2) diagnosis of inflammatory lesions in the urogenital system and other systems; 3) determination of sexually transmitted (sexual) infection as one of the most important exogenous trigger factors of endogenous infection; 4) identification of other exogenous and endogenous factors (diseases) leading to the start of an infectious process with the formation of dysbiosis and inflammatory foci.

Thanks to the introduction of molecular genetic methods, the diagnosis of various types of vaginal dysbiosis does not cause great difficulties. Today, Femoflor technology has been created (Femoflor-16 or 17 is optimal) based on the use of real-time PCR (PCR real-time). This technology allows to give the most complete quantitative and qualitative characteristics of the normal and conditionally pathogenic flora of the urogenital tract in women.

To exclude some exogenous genital infection (chlamydia, trichomonas, neural), it is advisable to additionally use modern diagnostic (laboratory) approaches. It should also be remembered that the success of the diagnosis and treatment of exogenous sexually transmitted infections in women depends on the quality realization of these components in their sexual partners. Identification of other trigger factors for endogenous infection includes examination of related specialists in order to identify endocrine, therapeutic, neurological, immune and other pathologies, as well as factors that can lead to the launch of an endogenous infection.

Correction of endogenous infection should include several stages: 1) elimination of inflammatory foci in the organs of the urogenital system, in other systems and related complications; 2) elimination of the dysbiotic process, taking into account its variety (as a source of bacteremia and antigenemia) and the root causes of inflammatory foci; 3) identification and elimination of all trigger factors (including exogenous infections and endocrinopathies), which have led to the development of dysbiosis and the formation of endogenous infections at the present time and may lead to them in the future.

In the treatment of inflammatory foci, it is necessary to apply the well-known complex, including etiotropic antibiotic therapy, enzyme therapy (for potentiation of antibiotics), immunomodulating, symptomatic therapy, psychotherapy, anti-adhesive and anti-inflammatory drug and physical therapy; justified the use of organoprotectors, as well as pro-and synbiotics - with the aim of correcting the vaginal and intestinal microflora after the end of antibiotics.