Download E. Kovachev

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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
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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.
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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.
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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.
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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
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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
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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
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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
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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
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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.
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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)