Immune-mediated mechanisms of the inflammatory response in women with combined infections of the lower genital tract

Aim: to increase the effectiveness of combination therapy and reduce frequency of recurrences of inflammatory diseases in the lower genital tract of combined etiology.

Materials and Мethods. There was conducted a prospective, randomized, blind, comparative clinical study. 80 women with vaginal microbiota disorders were examined randomized into 2 groups: group I (n = 40) – antibiotic therapy was carried out in combination with the preparation Superlimph, group II (n = 40) – a standalone antibacterial therapy; group III consisted of 20 patients lacking gynecological diseases considered to provide with control laboratory parameters. Clinical and laboratory methods were used: microscopy of vaginal smears, detection of viruses and sexually transmitted infections, measurement of serum cytokine levels – interleukins (IL-1â, IL-2, IL-4, IL-6, IL-8, IL-10), tumor necrosis factor alpha, (TNF-á), interferon gamma (IFN-ã).

Results. It was found that clinical recovery occurred in 90.0 and 70.0 % of patients in group I and group II (р = 0.02), respectively. Microbiological recovery was observed in 100.0 and 67.5 % of patients, respectively (р = 0.003). In group I, the isolation of herpes simplex virus type 2 was found in 80.0 and 45.2 % of patients before and after treatment (p < 0.001), respectively, whereas in group II – in 82.5 and 77.5 %, respectively (p = 0.58), between groups – p < 0.001. Before treatment the level of all cytokines, excepting IFN-ã, was higher than the reference values in both groups: in group I, their magnitude decreased after treatment (p < 0.001) and corresponded to the reference values; in group II no changes occurred. Three months after treatment, no relapses were observed in group I, whereas frequency of relapses in group II was 22.5 %, within 1 year – 0 and 35.1 %, respectively. Predictors of recurrent dysbiosis (IL-2, IL-6 and TNF-á in increased concentrations after a course of treatment) were identified.

Conclusion. Treatment with a combined broad-spectrum antimicrobial drug along with topical immunomodulatory agent containing exogenous cytokines is an effective strategy for treating concomitant dysbiosis and preventing relapse.

1. Khryanin A.A., Reshetnikov O.V. Bacterial vaginosis. New concepts of microbial biological environment and treatment options. [Bakterial'nyj vaginoz. Novye predstavleniya o mikrobnom biosociume i vozmozhnosti lecheniya]. Medicinskij sovet. 2014;(17):128–32. (In Russ.). https://doi.org/10.21518/2079-701X-2014-17-128-133.

2. Shulzhenko A.E., Shchubelko R.V., Zuykova I.N. Recurrent mixed infections urogenital in women: correction strategy of mucosal immunity. [Recidiviruyushchie smeshannye infekcii urogenital'nogo trakta u zhenshchin: strategiya korrekcii mukozal'nogo immuniteta]. Consilium Medicum. 2016;18(6):87–93. (In Russ.).

3. Makarov I.O., Gomberg M.A., Borovkova E.I. et al. Bacterial vaginosis: state of exploration of the problem. [Bakterial'nyj vaginoz: sostoyanie izuchennosti problem]. Obstetrics, Gynecology and Reproduction. 2013;7(4):20–4. (In Russ.).

4. Prilepskaya V.N., Uruimagova A.T., Ivanova A.A. Recurrent vulvovaginitis and vaginosis. Possibilities of effective therapy. [Klinicheskie i laboratornye osobennosti recidiviruyushchih vul'vovaginitov i vaginozov. Vozmozhnosti effektivnoj terapii]. Ginekologiya. 2020;22(5):76–80. (In Russ.). https://doi.org/10.26442/20795696.2020.5.200361.

5. Mania-Pramanik J., Kerkar S.C., Salvi V.S. Bacterial vaginosis: A cause of infertility? Int J STD AIDS. 2009;20(11):778–81. https://doi.org/10.1258/ijsa.2009.009193.

6. Budilovskaya O. V., Shipitsyna E. V., Pereverzeva N.A. et al. Comparison of methods for assessing the inflammatory response of the lower parts of the female reproductive tract. [Sravnenie metodov ocenki vospalitel'noj reakcii nizhnih otdelov zhenskogo reproduktivnogo trakta]. Zhurnal akusherstva i zhenskih boleznej. 2018;67(5):13–20. (In Russ.). https://doi.org/10.17816/JOWD67513-20.

7. Ike A.C., Onu C.J., Ononugbo C.M. et al. Immune response to herpes simplex virus infection and vaccine development. Vaccines (Basel). 2020;8(2):302. https://doi.org/10.3390/vaccines8020302.

8. Kurt-Jones E.A., Orzalli M.H., Knipe D.M. Innate immune mechanisms and herpes simplex virus infection and disease. Adv Anat Embryol Cell Biol. 2017;223:49–75. https://doi.org/10.1007/978-3-319-53168-7_3.

9. Dikke G.B., Ostromenskii V.V. Immune dysfunction in chronic endometritis and the experience of its correction using local cytokine therapy. [Narushenie immunnogo statusa pri hronicheskom endometrite i opyt ego korrekcii posredstvom lokal'noj citokinoterapii]. Akusherstvo i ginekologiya. 2019;(9):139–46. (In Russ.). https://doi.org/10.18565/aig.2019.9.139-146.

10. Dikke G.B. Polymicrobial associations in the etiology of inflammatory diseases of the femail genital organs. [Polimikrobnye associacii v etiologii vospalitel'nyh zabolevanij polovyh organov u zhenshchin]. Akusherstvo i ginekologiya. 2017;(6):151–8. (In Russ.). https://doi.org/10.18565/aig.2017.6.151-8.

11. Mamchur V.I., Dronov S.N. Terzhinan through the eyes of a pharmacologist: an innovative approach to the treatment of vaginitis of various origins. [Terzhinan glazami farmakologa: innovacionnyj podhod k terapii vaginitov razlichnogo geneza]. Medicinskie aspekty zhenskogo zdorov'ya. 2015;(9):50–7. (In Russ.).

12. Ellermann-Eriksen S. Macrophages and cytokines in the early defense against herpes simplex virus. Virol J. 2005;2:59. https://doi.org/10.1186/1743-422X-2-59.

13. Cheng S.-C., Chai L.Y.A., Joosten L.A.B. et al. Candida albicans releases soluble factors that potentiate cytokine production by human cells through a protease-activated receptor 1- and 2-independent pathway. Infect Immun. 2009;78(1):393–9. https://doi.org/10.1128/IAI.01041-09.

14. Marconi C., Donders G.G.G., Bellen G. et al. Sialidase activity in aerobic vaginitis is equal to levels during bacterial vaginosis. Eur J Obstet Gynecol Reprod Biol. 2013;167(2):205–9. https://doi.org/10.1016/j.ejogrb.2012.12.003.

15. Rakhmatullaeva M.M. The level of proinflammatory cytokines in the diagnosis of bacterial vaginosis. [Uroven' provospalitel'nyh citokinov v diagnostike bakterial'nogo vaginoza]. Fundamental'nye i prakticheskie voprosy immunologii i infektologii. 2018;2:3–7. (In Russ.).

16. Hemalatha R., Ramalaxmi B.A., KrishnaSwetha G. et al. Cervicovaginal inflammatory cytokines and sphingomyelinase in women with and without bacterial vaginosis. Am J Med Sci. 2012;344(1):35–9. https://doi.org/10.1097/MAJ.0b013e318235597b.

17. Budilovskaya O.V., Krysanova A.A., Shipitsyna E.V. et al. The profiles of lactobacillus microflora and local immune response of the vaginal mucosa in the diagnosis of vaginal infections. [Diagnostika vaginal'nyh infekcij s uchetom profilej laktobacillyarnoj mikroflory i lokal'nogo immunnogo otveta slizistoj vlagalishcha]. Molekulyarnaya medicina. 2020;18(3):56–64. (In Russ.). https://doi.org/10.29296/24999490-2020-03-07.

18. Hedge S.R., Barrientes F., Desmond R.A., Schwebke J.R. Local and systemic cytokine levels in relation to changes in vaginal flora. J Infect Dis. 2006;193(4):556–62. https://doi.org/10.1086/499824.

19. Kremleva E.A., Sgibnev A.V. Proinflammatory cytokines as regulators of vaginal microbiota. Bull Exp Biol Med. 2016;162(1):75–8. https://doi.org/10.1007/s10517-016-3549-1.

20. Swidsinski A., Verstraelen H., Loening-Baucke V. et al. Presence of a polymicrobial endometrial biofilm in patients with bacterial vaginosis. PLoS One. 2013;8(1):e53997. https://doi.org/10.1371/journal.pone.0053997.

21. Marrazzo J.M., Wiesenfeld H.C., Murray P.J. et al. Risk factors for cervicitis among women with bacterial vaginosis. J Infect Dis. 2006;193(5):617–24. https://doi.org/10.1086/500149.

22. Discacciati M.G., Simoes J.A., Silva M.G. et al. Microbiological characteristics and inflammatory cytokines associated with preterm labor. Arch Gynecol Obstet. 2011;283(3):501–8. https://doi.org/10.1007/s00404-010-1427-z.

23. Karapetian T.E., Lomova N.A., Kesova M.I. Diagnostic significance of bacterial vaginosis. [Diagnosticheskaya znachimost' markerov vospaleniya v otdelyaemom cervikal'nogo kanala u beremennyh s bakterial'nym vaginozom]. Ginekologiya. 2018;20(1):71–4. (In Russ.). https://doi.org/10.26442/2079-5696_20.1.71-74.

24. Rukhlyada N.N., Taits A.N., Romanova L.A. et al. Bacterial vaginosis as a risk factor for preterm birth. [Bakterial'nyj vaginoz kak faktor riska prezhdevremennyh rodov]. Pediatr. 2019;10(4):97–101. (In Russ.). https://doi.org/10.17816/PED10497-101.

25. Murphy K., Mitchell C.M. The interplay of host immunity, environment and the risk of bacterial vaginosis and associated reproductive health outcomes. J Infect Dis. 2016;214(Suppl 1):29–35. https://doi.org/10.1093/infdis/jiw140.

26. Jasinski-Bergner S., Mandelboim O., Seliger B. Molecular mechanisms of human herpes viruses inferring with host immune surveillance. J Immuno Ther Cancer. 2020;8:e000841. https://doi.org/10.1136/jitc-2020-000841.

27. Marci R., Gentili V., Bortolotti D. et al. Presence of HHV-6A in endometrial epithelial cells from women with primary unexplained infertility. PLoS One. 2016;11(7):e0158304. https://doi.org/10.1371/journal.pone.0158304.

28. Pereira N., Kucharczyk K.M., Estes J.L.et al. Human papillomavirus infection, infertility, and assisted reproductive outcomes. J Pathog. 2015;2015:578423. https://doi.org/10.1155/2015/578423.

29. Esber А., Miguel R.D.V., Cherpes T.L. еt al. Risk of bacterial vaginosis among women with herpes simplex virus type 2 infection: a systematic review and meta-analysis. J Infect Dis. 2015;212(1):8–17. https://doi.org/10.1093/infdis/jiv017.

30. Nason M.C., Patel E.U., Kirkpatrick A.R. et al. Immunological signaling during herpes simplex virus-2 and cytomegalovirus vaginal shedding after initiation of antiretroviral treatment. Open Forum Infect Dis. 2016;3(2):ofw073. https://doi.org/10.1093/ofid/ofw073.