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1 Medical University – Varna Department of Obstetrics and Gynecology THESIS ABSTRACT ON THEME: Contemporary Approaches in the Pathogenesis, Diagnosis and Treatment of Genital Chlamydiosis in Infertile Patients by Assoc. Prof. Emil Georgiev Kovachev, MD PhD Scientific specialty “Obstetrics and gynecology” Submitted in fulfillment of the requirements for the degree “Doctor of Medical Sciences” 2016 2 1. INTRODUCTION Actuality of the problem. Sexually transmitted diseases (STD) are the main reason for infertility, longterm invalidity and mortality with serious medical and psychological consequences for millions of men, women and children. The attitude towards sexuality in the past 50 years has changed dramatically. Sexual revolution has led to an increasing number of STD and the widespread homosexuality has also contributed to this problem. So far, over 30 bacterial, viral and parasitic pathogens, that can be sexually transmitted, have been identified. In the last 15 - 20 years the proportion of inflammatory diseases with chlamydial or viral etiology (Herpes virus, CMV, HPV, Mycoplasma, Ureaplasma) as a monoinfection or associated with other microorganisms has raised dramatically, despite the successful treatment of bacterial and protozoic infections. These are not all etiology agents for STD, but the rest are rare and have no practical role. Nowadays, urogenital chlamydiosis is the most common sexually transmitted disease. About 50-60% of the cases are asymptomatic which leads to difficulties in detecting and diagnosing the infection. According to WHO, chlamydial infection strikes 89 millions of people all over the world every year and 4 millions of them are from Europe. The number of infected people in the USA is about 4,2 millions. Taking into consideration the above mentioned circumstances, scientists suggest that chlamydial infection has become a public threat. In the USA every year the direct and indirect material damage associated with it, is about 1,4 billion dollars, of which 80% is spent on the treatment of the female part of the population. In 2011 (data from 2005), WHO reported that in the group of patients ranged between 15-49 years, Chl. trachomatis is the most common cause of STD compared with the other three frequent causes like Neisseria gonorrhoeae, Syphilis and Trichomonas vaginalis. 3 It is known that Chlamydial infection covers mainly people in sexually active age (20-41 years) and 40% of them are female. But patients with clinical presentation are only about 5-10% of the cases from the gynecological departments, 1-8% of the pregnant women and 20-30% of the women on a first ambulatory review. In recent years, an increasing trend of the disease among young women and adolescent age patients has been reported. This fact is often linked to the changes in sexual behavior of young people. Often women who have experienced sexual violence are infected with chlamydia. It was found that the possibility of chlamydial infection is greater in women who lead promiscuous sex life, who do not use condoms or frequently change sexual partners. Chlamydia cervicitis in this group of women exceed 20-25 times the number of cases of cervicitis with the same etiology among women having one sexual partner and those avoiding casual intercource. Urogenital chlamydiosis can be accompanied with a variety of clinical manifestations, but commonly has mild or no symptoms. Often it causes inflammation in the urogenital system and extragenital complications resulting in disturbing the reproductive ability of men and women which leads to infertility. Chlamydial endocervicitis is recognized by all researchers as the most common clinical form of genital chlamydiosis in women. In this pathology, patients may have no symptoms or complain of minor genital fluor, dysuria or bleeding. Acute cervicitis is accompanied by adhesions of the cervix, erythema and a manifestation of pathological exudate. This genital fluor macerates the multilayered squamous epithelium lining on the external portion of the cervical canal and causes its partial desquamation which leads to an edema, haemorrhage and cervical erosions. As a result of a continuous ongoing, chlamydial cervicitis occurs hypertrophic erosions. According to WHO (2006), chlamydial urethritis in men is more than 60% of the cases. Chlamydia is identified in 60-70% of patients who developed gonococcal urethritis after effective treatment of gonorrhea. Chlamydia trachomatis leads to pregnancy complications, resulting in subclinical endometritis, horioamnionitis, increased risk of perinatal death of the fetus and premature birth and it also causes inflammation beyond the sexual sphere, for example: perihepatitis (syndrome of Fitz Hugh-Curtis) perisplenitis and perinephritis. It has been discovered that chlamydia leads to complications in the course of pregnancy, resulting in subclinical endometritis, horioamnionitis and increasing risk of perinatal death of the fetus and premature birth. 4 Neonatal infection is about 40-70% of the cases and occurs during the passage through the infected genital tract in the act of birth. Prenatal infection of the feto-placental complex can lead to uterine growth retardation or to the occurrence of conjunctivitis and pneumonia in infants. The role of chlamydia in the formation of brain circulation disorders in the neonatal period is already proven. The development of laboratory methods for diagnosing genital chlamydiosis is related to the knowledge of biology, antigenic structure, pathogenesis and infectious process. In the past, simple microscopic methods seemed to be sufficient and the application of various laboratory models to identify chlamydia in cell cultures was estimated as the "gold standard". However, the possibility of isolating the antigens of chlamydia directly into the tissue of the affected organ with immunofluorescence methods or DNA probes somewhat displaced the "gold standard" because they have a higher sensitivity. The method of direct immunofluorescence provides staight detection of marked Chlamydia antigens. Its great informative value is related to the possibility for discovery of soluble antibodies and nowadays this is one of the most important tests for diagnosing urogenital chlamydiosis. Its sensitivity with the use of monoclonal antibodies is 90-100% in the assay compositions of the urogenital tract with specificity 85-100%. The method of polymerase chain reaction (PCR) has been introduced in the clinical practice over the past 15 years. It represents one of the real contenders for the leading role in diagnosting of chlamydiosis, and in literature is called "method of last resort". The value of the existing diagnostic methods is still not determined and currently no clear criteria exist for laboratory control in the recovery period of chlamydiosis; there are not any defined terms for controls so far. It is a well-known fact that Chlamydia often causes a secondary immunodeficiency with not fully understood pathogenesis. In recent years, the idea of combined treating therapy, with antibiotics and immunomodulators is widely discussed. The main point of this concept is that Chlamydia is an intermediate phase between bacteria and viruses and possesses certain characteristics of viral agents. Immunostimulating therapy mainly activates the suppressed or impaired cell mediated immunity and leads to an increased production of interleukins and endogenous Y - interferon. 5 The estimated methods for treatment of chlamydia in modern science are constantly being filled by new preparations of specific antibiotic therapy. It should be noted that, despite the variety of antichlamydial medications, the preparations for stimulating the immune system are limited. Furthermore, the existing methods of treatment still require testing for comparison of clinical efficiency. It is not clear which treatment methods are optimal for women who are planning pregnancy, and how safe they are in terms of prevention of complications during pregnancy and perinatal infection of the fetus and the newborn. 2. PURPOSE AND OBJECTIVES OF THE STUDY The purpose of this study is to conduct comparative evaluation of diagnostic methods and the effectiveness of treatment for patients with urogenital chlamydiosis and fertility disorders. In order to achieve that objective, the following tasks have to be solved: 1. Comparison of the existing methods of diagnosis and assessment of the control of treatment. 2. Study of the hormonal status in patients with genital chlamydiosis before and after treatment. 3. Monitoring of the immune status in patients with urogenital chlamydiosis. 4. A comparative evaluation of the clinical effectiveness between the various methods of treatment of urogenital chlamydiosis. 5. Study of the particuliarities of the course of pregnancy, childbirth, postpartal and newborn period in women with urogenital chlamydiosis after application of different methods of treatment before pregnancy. 6. Evaluation of the effectiveness of the inclusion of isoprinosine in complex treatment in patients with urogenital chlamydiosis. 3. MATERIALS AND METHODS OF INVESTIGATION The study is retrospective and was conducted in the Department of "Obstetrics and Gynecology" - MU - Varna; SBAGAL - LTD - Varna and Medical Centre for Assisted Reproduction "Varna" Ltd. in the period between 30.11.2012 and 30.11.2015. The examination was performed on 224 patients in reproductive age 6 with different types of fertility disorders. In all cases the clinical complaints and the characteristics of menstrual, reproductive and sexual functions were evaluated. A variety of laboratory, hormonal, immunological and instrumental methods of diagnosis were attached. 4. OWN RESULTS AND DISCUSSION. 4.1 Clinical characteristics of the examined patients 224 infertile women in reproductive age were examined. In a complex clinicallaboratory approach it is found that 113 of them (50,5%) have chlamydiosis. In the other 111 women, chlamydial infection is not established (control group). Subsequently, the main group is divided into two representative subgroups differentiated by the treatment, respectively 74 patients treated by antibiotics in combination with immunomodulator (I - subgroup) and 39 patients - only with antibiotics. (II - subgroup). 5. CONCLUSION In 2011, WHO reported that Chl. trachomatis is the most common reason for STD in group of patients ranged between 15-49 years, compared with the other most probable causes as Neisseria gonorrhoeae, Syphilis and Trichomonas vaginalis. Chl. trachomatis can easily infect the ectopic zone of the immature cervix and probably in combination with other factors like oral contraceptives determines the fact that young females are more susceptible to the infection than adults. The level of sex steroid hormones during the different phases of menstrual cycle has a key role in the chlamydial infection, its chornification and asymphtomatic proceeding in about 75% of the infected women. The conducted endocrinologic researches enabled us to determine the characteristics of the hormonal status in patients with chlamydial infection, which concluded in the presence of relative hypoestrogenemic and significantly lower levels of progesterone. It can be assumed that these hormonal changes occur on the one hand as a result of the damage of the ovaries due to chlamydia, and on the other hand - they are the unfavorable background that contributes to the development and spread of genital chlamydiosis. Lower levels of steroid hormones have an adverse effect 7 on the local immunity, as well as some disorders in certain physiological processes. In conclusion, it should be noted that the analysis of the peculiarities of the course of birth, the postnatal period and the early neonatal period, proves the efficiency of the treatment of chlamydiosis in both the main and the comparison group. In some cases a specific treatment of chlamydiosis by using Isoprinosine is preferred. It is estimated that as a result of receiving that treatment, developed by us, before a planned pregnancy, the risk of horioamnionitis, premature rupture of membranes and infant signs of intrauterine infection is reduced twice. We assume that these differences in patients from the main and the control groups are related to the impact of isoprinosine on interferon status of women. Obviously, this not only improves the efficiency of treatment of chlamydiosis, but also affects other mechanisms contributing to the optimal course of pregnancy. It is possible that one of these mechanisms is the shortening of the phase of the stress-inducing mediators' activity. The comparative analysis of different methods of diagnosis of chlamydia convinced us in the high diagnostic value of the method of direct immunofluorescence, followed by PCR, the lower value of an enzyme immunoassay and the lowest - CFR (complement fixation reaction). We believe that the following research methods can be used in combination with significant success. According to our data, the optimal time to control the treatment should be considered from 3 to 6 months after the onset of the treatment. The conducted research convinced us that isoprinosine supplementation in complex treatment of chlamydial infection in infertile patients leads to a rapid regression of clinical manifestations, to an occurrence of planned pregnancy and reduces the risk of complications during pregnancy and childbirth with improved perinatal indicators. The significance of the problem and the high morbidity determines the need for targeted screening, obeying an algorithm to conduct the study of patients with suspicion of chlamydial endocervisitis, where already identified and statistically proven risk factors, clinical features and the differentiated groups can be used. So the proposed methodology for etiological diagnosis of reproductively significant infections allows conducting an early therapy. Screening for Chl. trachomatis is essential to prevent the consequences of pelvic inflammatory disease in a long term. According to WHO, every year chlamydia affects 89 million of people worldwide and about 4 million of them are Europeans. The annual cost of treatment and its consequences in the US are over $ 2 billion. Chl.trachomatis screening could reduce PID by over 50%. According to Burstein, due to the severity of the consequences of chlamydia, all sexually active women should be 8 screened in every six months, regardless of symptoms, previous infections, methods of contraception or partners. Nowadays urogenital chlamydiosis is the most common sexually transmitted disease. There are certain diagnostic difficulties due to poorly expressed or absent clinical symptoms in 50-60% of cases and complications are significant. New diagnostic methods make it possible to identify Chlamydia trachomatis easier, and new antibiotics contribute to a more successful treatment of genital chlamydiosis. Contemporary diagnostic methods make it possible to identify Chl.trachomatis at a greater rate, and recent therapeutic patterns results in a successful treatment. These factors, together with the high medical professionalism, help to reduce the prevalence of this infection in the population. According to modern medical practice, improvement and the imposition of standardized methods for diagnosis and evaluation is essential not only for the patient and the treating physician, but also for health, pharmacological companies and society in general. 6. CONSEQUENS 1. The frequency of incidence of genital chlamydiosis is determined, in group of 224 patients with various forms of infertility and clinical data on inflammatory diseases of FRS, 113 were positive (50.5%); 2. A comparative characterization of some of the methods of diagnosis and treatment of chlamydiosis in infertile patient was carried out; 3. A more sensitive methods for diagnosis of urogenital chlamydiosis than culture should be considered to be PCR (82.3%) and DIF (78.5%); 4. Urogenital chlamydiosis is accompanied by hipoestrogenimiya, reduced levels of progesterone, activation of T-Unit immunity, increasing the level of the CIC; 5. A combinated therapy with isoprinosine leads to a rapid regression of clinical symptoms of urogenital infection, and normalizes the hormonal status of the patient; 6. By an induction of endogenous interferon, isoprinosine in complex treatment of chlamydiosis manifests pronounced immunoregulatory 9 activities, which results in normalization of the ratio between subpopulations of T-lymphocytes (T-helper to T-suppressor); 7. Subsequent pregnancy should be recommended no sooner than 6 months after the treatment with Isoprinosine in the complex therapy; 8. Using isoprinosine in complex treatment of urogenital chlamydiosis before pregnancy, contributes to rational training of women and reducing the number of complications in gestation, birth and neonatal period; 9. The optimal period for monitoring of the effectiveness of the treatment takes place six months after its completion. The most sensitive method of control should be considered the method DIF (79.7%). 7. CONTRIBUTIONS 1. ELISA gives a number of false-positive results (20%) in the diagnosis of Chlamydia infection, which requires confirmation of the diagnosis by other methods (PCR, DIF); 2. This is the first study in our country which shows the effectiveness of treatment with isoprinosine in patients with chlamydial infection in the course of complex therapy; 3. For the first time in Bulgaria the changes of hormonal status in patients with urogenital chlamydiosis during the therapy have been studied and it was shown that the successful treatment of Chlamydia infection normalizes the hormonal status; 4. For the first time a comparative analysis of the performance of the immune status in patients with urogenital chlamydiosis before and after the treatment was carried out; 5. The effectiveness of the treatment, the frequency of the occurrence of pregnancy, the course of pregnancy, the clinical course of childbirth, postpartal and early neonatal period was observed; 6. For the first time the role of isoprinosine in the prevention of complications during pregnancy and childbirth in women with urogenital chlamydiosis, was described; 7. For the first time in the implementation of research results in clinical practice it is made possible to increase the effectiveness of treatment of patients with urogenital chlamydiosis, to reduce the number of the complications during pregnancy, childbirth, postpartum period. These 10 practices are embedded in clinical work in SBAGAL "Prof.. Dr. D. Stamatov "Ltd., Varna. 8. PUBLICATIONS RELATED TO THE PhD THESIS 1. I. Bakardzhiev, G. Pehlivanov, E. Kovachev. Correlations between contemporary methods in the diagnosis of Chlamydia Trachomatis urogenital infections. Journal of IMAB, 2011, vol. 17, book 1, pp. 158160. 2. E. Kovachev, I. Bakardzhiev, G. Pehlivanov, N. Kolev, E. Grueva. S. Anzhel. Some aspects in the diagnosis of urogenital infections caused by Chlamydia Trachomatis. Obstetrics and Gynecology, 2015, vol. 54, book 8, pp. 8-12. 3. S. Nikolaeva, E. Kovachev, S. Anzhel, D. Tonkova. Chlamydia and female steroid hormones. Varna Medical Forum, 2016, vol. 5, annex 1. 4. M. Angelova, Е. Kovachev, V.Tsankova, I.Koleva, S.Mangarovа. Role and importance of Chlamydia Trachomatis in pregnant patients. Open Access Macedonian Journal of Medical Sciences. 2016 Sep 15; 4(3):410412. 5. E. Kovachev, S. Ivanov, B. Bechev, N. Kolev, S. Kisyov, S. Anzhel. Relation between Chlamydia Trachomatis, the trophoblast and preterm delivery. Scripta Scientifica Medica Volume 48, number 1, 2016. 6. E. Grueva, E. Kovachev. The role of colposcopy as a method, part of the methodology of early and fast etiological diagnosis in examination of endocervicitis chlamydialis. Obstetrics and gynecology, 2016, vol. 55, book 5, pp. 32-40. 7. E. Kovachev, S. Ivanov, B. Bechev, M. Angelova, E. Grueva, N. Kolev, V. Ivanov. Sexual hormones – modulators of the immune response to the genital infection with Chlamydia Trachomatis. Obstetrics and gynecology, 2016, vol. 55, book 4, pp. 3-8. 8. E. Grueva, E. Kovachev. Characteristics of vaginal biocenosis in endocervicitis chlamydialis. Obstetrics and gynecology, 2016, vol. 55, book 1, pp. 3-13. 11 9. E. Kovachev, E. Grueva, S. Anzhel. Chlamydia trachomatis and tubal factor – the advantages of early screening and prevention of complications. Reproductive health, 2016, book 24, (in print). 10. E. Kovachev, E. Grueva. The role of Chlamydia trachomatis in pregnant women with endocervicitis, Obstetrics and gynecology, 2016, vol. 55, book 6, (in print)