Features of the Immunoinflammatory Process in Genital Herpes Infection

The dissertation is dedicated to the study of features of the immunoinflammatory process in genital herpes infection of various clinical forms — acute course and exacerbation of chroniс-recurrent genital herpes. The study evaluates levels of proinflammatory cytokines (interleukin-1β, interleukin-6), an inducer of antiviral immunity (interferon-γ), specific antibodies to herpes simplex virus types 1 and 2, and circulating immune complexes in the blood serum of patients. The object of study is an immunomodulatory preparation based on echinacea, compared by immunomodulatory properties with polyoxidonium. The objective of the work is to identify patterns in the development of immunoinflammatory processes and to evaluate the effectiveness of immunomodulatory therapy in converting a weak immune response into a full-fledged strong one, which is significant for improving the treatment of genital herpes and reducing the frequency of recurrences.

Relevance of the Topic

The World Health Organization (WHO) notes a sharp increase in morbidity associated with herpes simplex virus types 1 and 2, emphasizing that morbidity has reached 20 million cases per year, and mortality from herpes simplex virus infection ranks second after influenza among viral diseases. According to data from various researchers, herpesviruses have infected 65–90 percent of the world's population. In Russia, official registration of patients with genital herpes was introduced in reporting forms in the mid-1990s, which explains the low morbidity indicators (Gomberg M.A., 1996; Kubanova A.A., 2000; Kungurov N.V. et al., 2001). The total number of patients with genital herpes in the Russian Federation amounts to approximately 8 million people.

By the present time, a number of studies have been conducted addressing questions of the clinical course, treatment, and, to a lesser extent, pathogenesis of genital herpes (Kubanova A.A., 2000; Kungurov N.V., Gerasyanova N.M., Zudin A.B., Kuzovkova T.V., 2001; Batkaev E.A. et al., 2001; Samgin M.A., Khaldin A.A., 2002).

The greatest significance in the spread of genital herpes has the sexual route of transmission. Infection more often occurs through contact with patients suffering from asymptomatic forms of genital herpes. This disease becomes a significant pathology in young adulthood (Nikonov A.P., 1995; Marchenko L.A., 1997; Brown Z.A. et al., 1993; Bryson Y. et al., 1993; Corey L., 1994). In Russia, there is an increase in the severity of the disease course, and the significance of affecting reproductive-age individuals is growing in connection with severe consequences for the fetus and newborn: miscarriages, congenital anomalies, etc. (Nikonov A.P., 1995; Sukhikh G.T., 1997; Khakhalin L.N., 1997; Zaidieva Z.S., 1998; Kungurov N.V., 2001; Isakov V.A., 2004). Of particular importance is the sharp increase in so-called subclinical and asymptomatic forms of genital herpes (Khakhalin L.N., 1999; Kungurov N.V., Gerasyanova N.M., Kuzovkova T.V., 2001).

An important aspect of the pathogenesis of genital herpesvirus infection is latency and persistence of the virus in the patient's organism even after conducted treatment (Sukhikh G.T. et al., 1997; Shulzhenko A.E., 2002). This is due to the fact that modern aetiotropic therapy does not provide complete cure, and in 30–50% of patients with genital herpes, recurrences of the disease develop within the first 2–3 years (Khaldin A.A., Samgin M.A. 2004). The consequence of this is a sharp increase in the processes of chronicization of herpes infection in the population, noted by the WHO at the end of the 20th and beginning of the 21st centuries.

The solution of this problem is associated with an understanding of the pathogenesis of genital herpesvirus infection and establishing the mechanisms of development of the phenomenon of virus persistence, which at the present time is associated with the development of an incomplete immune response to the action of weakly immunogenic antigens of the aetiological factor (Mayansky D.N., 1991, 1992; Petrov R.V., Khaityov P.M. 1998–2005; Bukharin O.V., 1998, 1999). The phenomenon manifests itself in the absence of firm binding of antigens to corresponding low-affinity antibodies, which does not lead to the formation of circulating immune complexes and their elimination from the organism (Kuznetsov V.P. 1994, 1996; Medunitsin N.V. 1995, 1998; Petrov R.V., Khaityov R.M., Pinegin B.V. 1995–2000; Trunova L.A., Trunov A.N., Efremov A.V. 1996–2003; Zinkernagel R.M., 2001–2005). This was soon confirmed by a group of scientists led by academicians R.V. Petrov and P.M. Khaityov during the creation of a highly effective anti-influenza vaccine, in which the virus was combined with an artificially created immunostimulator polyoxidonium (1996–2000). The fact of extraordinary importance was also established: polyoxidonium could be used in combination with any weakly immunogenic antigen, which led to the development of a strong immune response contributing to the elimination of the causative agent of the disease from the organism (Khaityov P.M., Pinegin B.V., 2000).

At the present time, the use of polyoxidonium has received a positive evaluation for many diseases and, in particular, for genital herpesvirus infection: treatment with polyoxidonium leads to a decrease in the number of recurrences per year and an increase in the duration of remission (Shulzhenko A.E., 2002).

From the literature, it is known that similar immunomodulatory properties are possessed by a preparation obtained from the plant echinacea (Coegnit E.G., Kuhnast R. 1986; Bauer R., Reminger P. 1989, 1990; Bauer R., Wagner H. 1991; Bauer R., 1998; Smirnov P.N., Gorskij A.N., Trunova L.A., 1999; Dennehy C., 2001). The preparation was used to convert a weak immune response into a full-fledged strong one in nonspecific infectious-inflammatory diseases of various organs and systems by the Novosibirsk school of clinical immunopathophysiologists (Trunov A.N., Trunova L.A., Efremov A.V., Antonov A.R., 1999–2005; Tikhonova O.V., 2001; Chmyreva N.V., 2001; Yanova I.V., 2004; Naymushena N.V., 2004; Avdyuk-Kovalenko G.A., 2005).

The wide spread of herpes infection of different serotypes in recent years raises the question of the necessity of developing fundamental and applied aspects of combating clinically manifested, subclinical, and asymptomatic forms of genital herpes. Of particular importance is the testing and interpretation of processes of interaction between the aetiological factor and the immune system that do not lead to complete liberation of the patient's organism from prolonged virus persistence.

At the present time, it appears important to develop new comprehensive approaches to the treatment of herpesvirus infections using immunomodulatory therapy with the aim of converting the weak immune response characteristic of the studied infection into a strong one.

The above has become the basis for planning and executing the goal and objectives of the dissertation work submitted for consideration.

Objective of the Study.

To identify features of immunoinflammatory processes in different clinical forms of genital herpes and against the background of immunomodulatory therapy.

Tasks of the Study:

1. To determine levels of proinflammatory cytokines IL-1β and IL-6 in the blood serum of patients with acute and exacerbation of chronic genital herpes.

2. To study concentrations of IFN-γ as an inducer of antiviral immunity in the blood serum of patients in the examined groups.

3. To evaluate the state of the humoral component of the immune system in patients of the examined groups by determining levels of specific antibodies to herpes simplex virus and circulating immune complexes in the blood serum of patients with acute and exacerbation of chronic genital herpes.

4. To identify dynamics of changes in the studied indicators against the background of immunomodulatory therapy with echinacea.

5. To study the influence of the developed echinacea immunorehabilitation scheme on the dynamics of studied immunobiochemical and certain clinical indicators in individuals with chroniс-recurrent genital herpes infection in the stage of clinical remission.

Scientific Novelty.

For the first time, a comparative evaluation of features in the development of the immunoinflammatory process in the mechanisms of development of acute genital herpes and exacerbation of chronic genital herpes was conducted. It was established that both forms of the pathological process are characterized by a reliable increase in concentrations of proinflammatory cytokines (interleukin-1β, interleukin-6), an inducer of antiviral immunity interferon-γ, levels of specific antibodies to herpes simplex virus, and circulating immune complexes, which indicates the pronounced nature of the immunoinflammatory process.

For the first time, it was shown that a pathogenic feature of the development of the acute form of the disease is the presence of significantly lower concentrations of the main proinflammatory cytokine interleukin-1β and lower, compared with exacerbation of the chronic pathological process, levels of circulating immune complexes, which reflects a clinically more prolonged course of the acute process in comparison with exacerbation.

It was established that the use of the immunomodulator echinacea leads to a decrease in the severity of inflammatory processes, which manifests itself in a reliable decrease in concentrations of the main proinflammatory cytokines interleukin-1β and interleukin-6 on the 7th day after immunomodulation in both forms of genital herpes. In the acute variant of the disease course, a more pronounced decrease in interleukin-6 levels was revealed, whereas in the exacerbation process, a more pronounced decrease in interleukin-1β was observed on the 7th day of observation. An increase in interleukin-6 concentrations on the 14th and 21st days after immunomodulation in both forms of the disease was established, which is associated with its role in the processes of activation of specific antibody formation.

For the first time, it was shown that the use of the developed scheme of immunomodulatory therapy with echinacea in acute and exacerbation of chronic genital herpes leads to activation of the immune response, which manifests itself in a reliable increase in concentrations of the inducer of antiviral immunity interferon-γ, levels of specific antibodies to herpes simplex virus, and an integral indicator of activation of the humoral component of the immune system — circulating immune complexes — in the dynamics of observation.

Practical Significance.

The obtained data on the dynamics of changes in the studied indicators allowed the conclusion about the uniformity of the influence of immunomodulatory therapy in acute processes and exacerbations of chroniс-recurrent genital herpes, about the similarity of immunological mechanisms of development of these forms of the pathological process.

The use of the immunomodulator of the first phase of the immune response — echinacea — in acute conditions and exacerbations of chroniс-recurrent genital herpes leads to a decrease in the severity of inflammatory processes and activation of the immune response with development of the specific phase of the immune response.

The results obtained in the study of the immunoinflammatory process in genital herpes infection pathogenetically justify the conduct of a randomized prospective clinical investigation of the effectiveness of the application of the immunomodulator echinacea as an addition to standard virolytic therapy of genital herpes.

Statements Submitted for Defense:

1. Genital herpesvirus infection is characterized by a predominant violation of the first phase of the immune response of the organism.

2. The use of an immunomodulator in both forms of the pathological process leads to an increase in antiviral immunity and a decrease in the activity of inflammatory processes.

3. The developed immunorehabilitation scheme for chronic herpes infection extends the duration of remission and reduces the frequency of recurrences.

Implementation of Research Results.

Theoretical and practical provisions developed in the dissertation research were introduced into the scientific-pedagogical activity of the Department of General Pathology of NGMU MZ i SP RF and into the practical activity of the dermatovenerological department of the Central City Hospital of the city of Berdsk.

Validation of Dissertation Research Materials.

The main provisions of the dissertation were presented at the 5th Congress of Immunologists and Allergologists of the CIS (2003), the 10th International Congress on Rehabilitation in Medicine and Immunorehabilitation (2005), at an interlaboratory seminar at the Laboratory of Reproductive Immunology of the Central Research Institute of Epidemiology and Microbiology of the Siberian Branch of the Russian Academy of Medical Sciences (2006), at a joint session of the Department of Pathophysiology and the Problem Commission «Functional Foundations of Homeostasis» of NGMU MZ i SP RF (Novosibirsk, 2006).