Atypical chronic active herpesvirus infections: Etiological structure, frequency of occurrence, clinical syndromes associated with them

Abstract

BACKGROUND: Every year, a steady, progressive increase in the number of atypical chronic, active forms of infections caused by herpesviruses is recorded. Diagnosing and selecting adequate therapeutic strategies for treating these infections present significant difficulties for physicians due to the polysyndromicity and many clinical manifestations.

AIMS: This study determines the prevalence of atypical chronic, active infections caused by herpesviruses among patients infected with herpesvirus infections and studies the etiological structural features and clinical manifestations/criteria and signs of atypically occurring chronic forms of herpes viral infections.

MATERIALS AND METHODS: Under our supervision at the Clinical and Diagnostic Center “Medsi in Belorusskaya” (Moscow), 98 patients of both sexes aged 23 to 60 years suffering from atypical chronic, active forms of infections caused by herpesviruses comprised the herpesviruses group. The comparison group consisted of 30 conditionally healthy subjects comparable in sex and age to patients. In addition to traditional methods (history collection, physical examination, general blood test, and others), serodiagnostic methods with ELISA were used to detect herpesvirus infections. ELISA was also used for detecting the genome of viruses in biomaterials. The study was approved by the ethics committee, and all patients received informed consent to participate in the study. Statistical analysis was performed using adequate methods.

RESULTS: The study of the etiological structure of herpesvirus infections in patients with atypical chronic, active forms of infections caused by herpesviruses, mixed herpesvirus infections were shown to occur in 83.4% of patients, and mono herpesvirus infections in 16.6% of cases. It was shown that the Epstein–Barr virus was the dominant virus among patients with mono and mixed herpesvirus infections. A high rate of Epstein–Barr virus DNA detection was demonstrated in saliva (84.2%), posterior pharyngeal wall scrapings (73.5%), tonsils (42.9%), urine (12.6%), and blood (8.3%) is a marker of the high replicative activity of the virus. The primary clinical syndromes associated with mono and mixed atypical chronic and active forms of infections caused by herpesviruses were identified.

CONCLUSIONS: This study identified and quantitatively assessed the viral load associated with the severity of the course and clinical manifestations of atypical chronic, active forms of infections caused by herpesviruses. Clarifying the features of clinical manifestations and syndromes in patients suffering from various mono and mixed herpesvirus infections will allow us to outline the goals for the further development of an adequate diagnostic algorithm for these atypical forms of herpesvirus infections and the concept of targeted, personalized etio- and immunopathogenetic therapy.

Keywords

herpesvirus infections / Epstein–Barr virus / immunocompromised patient

References

[1] Arai A. Chronic active Epstein-Barr virus infection: A bi-faceted disease with inflammatory and neoplastic elements. Immunol Med. 2018;41(4):162–169. doi: 10.1080/25785826.2018.1556030

[2] Arai A. Chronic active Epstein-Barr virus infection: a bi-faceted disease with inflammatory and neoplastic elements // Immunol Med. 2018. Vol. 41, N 4. Р. 162–169. doi: 10.1080/25785826.2018.1556030

[3] Isakova VA, Isakov DV, Arkhipova EI. Human herpesvirus infections. A guide for doctors. Saint Petersburg; 2015. 677 р. (In Russ).

[4] Исакова В.А., Исаков Д.В., Архипова Е.И. Герпесвирусные инфекции человека. Руководство для врачей. Санкт-Петербург, 2015. 677 c.

[5] Ning S. Innate immune modulation in EBV infection. Herpesviridae. 2010;2(1):1. doi: 10.1186/2042-4280-2-1

[6] Ning S. Innate immune modulation in EBV infection // Herpesviridae. 2010. Vol. 2, N 1. Р. 1. doi: 10.1186/2042-4280-2-1

[7] Liu X, Li Y, Peng S, et al. Cao Epstein-Barr virus encoded latent membrane protein 1 suppresses necroptosis through targeting RIPK1/3 ubiquitination. Cell Death Dis. 2018;9(2):1–14. doi: 10.1038/s41419-017-0081-9

[8] Liu X., Li Y., Peng S., et al. Cao Epstein-Barr virus encoded latent membrane protein 1 suppresses necroptosis through targeting RIPK1/3 ubiquitination // Cell Death Dis. 2018. Vol. 9, N 2. Р. 1–14. doi: 10.1038/s41419-017-0081-9

[9] Wu L, Fossum E, Joo CH, et al. Epstein-Barr virus LF2: An antagonist to type I interferon. J Virol. 2009;83(2):1140–1146. doi: 10.1128/JVI.00602-08

[10] Wu L., Fossum E., Joo C.H., et al. Epstein-Barr virus LF2: An antagonist to type I interferon // J Virol. 2009. Vol. 83, N 2. Р. 1140–1146. doi: 10.1128/JVI.00602-08

[11] Randall RE, Goodbourn S. Interferons and viruses: An interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol. 2008;89(Pt 1):1–47. doi: 10.1099/vir.0.83391-0

[12] Randall R.E., Goodbourn S. Interferons and viruses: An interplay between induction, signalling, antiviral responses and virus countermeasures // J Gen Virol. 2008. Vol. 89, Pt 1. Р. 1–47. doi: 10.1099/vir.0.83391-0

[13] Charostad J, Nakhaie M, Dehghani A, Faghihloo E. The interplay between EBV and KSHV viral products and NF-κB pathway in oncogenesis. Infect Agents Cancer. 2020;15:62. doi: 10.1186/s13027-020-00317-4

[14] Charostad J., Nakhaie M., Dehghani A., Faghihloo E. The interplay between EBV and KSHV viral products and NF-κB pathway in oncogenesis // Infect Agents Cancer. 2020. N 15. Р. 62. doi: 10.1186/s13027-020-00317-4

[15] Eligio P, Delia R, Valeria G. EBV chronic infections. Mediterr J Hematol Infect Dis. 2010;2(1):e2010022. doi: 10.4084/MJHID.2010.022

[16] Eligio P., Delia R., Valeria G. EBV Chronic Infections // Mediterr J Hematol Infect Dis. 2010. Vol. 2, N 1. Р. e2010022. doi: 10.4084/MJHID.2010.022

[17] Merlo A, Turrini R, Dolcetti R, et al. The interplay between Epstein-Barr virus and the immune system: A rationale for adoptive cell therapy of EBV-related disorders. Haematologica. 2010;95(10): 1769–1777. doi: 10.3324/haematol.2010.023689

[18] Merlo A., Turrini R., Dolcetti R., et al. The interplay between Epstein-Barr virus and the immune system: A rationale for adoptive cell therapy of EBV-related disorders // Haematologica. 2010. Vol. 95, N 10. Р. 1769–1777. doi: 10.3324/haematol.2010.023689

[19] Babcock JG, Hochberg D, Thorley-Lawson AD. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity. 2000;13(4):497–506. doi: 10.1016/s1074-7613(00)00049-2

[20] Babcock J.G., Hochberg D., Thorley-Lawson A.D. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell // Immunity. 2000. Vol. 13, N 4. Р. 497–506. doi: 10.1016/s1074-7613(00)00049-2

[21] Tracy SI, Kalacheva K, Lunemann JD, et al. Persistence of Epstein-Barr virus in self-reactive memory B cells. J Viorol. 2012;88(22):12330–12340. doi: 10.1128/JVI.01699-12

[22] Tracy S.I., Kalacheva K., Lunemann J.D., et al. Persistence of Epstein-Barr virus in self-reactive memory B cells // J Viorol. 2012. Vol. 88, N 22. Р. 12330–12340. doi: 10.1128/JVI.01699-12

[23] Nesterova IV, Kovaleva SV, Chudilova GA, et al. Congenital and acquired interferonopathies associated with atypical viral infections and COVID-19 (monograph). Saint-Petersburg: Dialog; 2022. 600 р.

[24] Нестерова И.В., Ковалева С.В., Чудилова Г.А., и др. Врожденные и приобретенные интерферонопатии, ассоциированные с нетипично протекающими вирусными инфекциями и COVID-19 (монография). Санкт-Петербург: Диалог, 2022. 600 с.

[25] Jiang J, Zhao M, Chang C, et al. Type I interferons in the pathogenesis and treatment of autoimmune diseases. Clin Rev Allergy Immunol. 2020;59(2):248–272. doi: 10.1007/s12016-020-08798-2

[26] Jiang J., Zhao M., Chang C., et al. Type I interferons in the pathogenesis and treatment of autoimmune diseases // Clin Rev Allergy Immunol. 2020. Vol. 59, N 2. Р. 248–272. doi: 10.1007/s12016-020-08798-2

[27] Lusso P. HHV-6 and the immune system: Mechanisms of immunomodulation and viral escape. J Clin Virol. 2006;37(Suppl 1): S4–10. doi: 10.1016/S1386-6532(06)70004-X

[28] Lusso P. HHV-6 and the immune system: Mechanisms of immunomodulation and viral escape // J Clin Virol. 2006. Vol. 37, Suppl 1. Р. S4–10. doi: 10.1016/S1386-6532(06)70004-X

[29] Hislop AD, Taylor GS, Sauce D, Rickinson AB. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol. 2007;(25):587–617. doi: 10.1146/annurev.immunol.25.022106.141553

[30] Hislop A.D., Taylor G.S., Sauce D., Rickinson A.B. Cellular responses to viral infection in humans: Lessons from Epstein-Barr virus // Annu Rev Immunol. 2007. N 25. Р. 587–617. doi: 10.1146/annurev.immunol.25.022106.141553

[31] Kuzushima K, Matsuoka H. Impaired cytotoxic T lymphocyte response to Epstein-Barr virus-infected NK cells in patients with severe chronic active EBV infection. J Med Virol. 2001;64(2):141–148. doi: 10.1002/jmv.1029

[32] Kuzushima K., Matsuoka H. Impaired cytotoxic T lymphocyte response to Epstein-Barr virus-infected NK cells in patients with severe chronic active EBV infection // J Med Virol. 2001. Vol. 64, N 2. Р. 141–148. doi: 10.1002/jmv.1029

[33] Mardanly SS, Mardanly SG, Kazakov AA, et al. Development of a PCR test system for the detection of human herpes virus type 7. Clin Laboratory Diagnostics. 2022;67(11):658–662. (In Russ). doi: 10.51620/0869-2084-2022-67-11-658-62

[34] Марданлы С.С., Марданлы С.Г., Казаков А.А., и др. Разработка ПЦР тест-системы для детекции вируса герпеса человека 7 типа // Клиническая лабораторная диагностика. 2022. Т. 67, № 11. С. 658–662. doi: 10.51620/0869-2084-2022-67-11-658-62

[35] Cohen JI, Jaffe ES, Dale JK, et al. Characterization and treatment of chronic active Epstein-Barr virus disease: A 28-year experience in the United States. Blood. 2011;117(22):5835–5849. doi: 10.1182/blood-2010-11-316745

[36] Cohen J.I., Jaffe E.S., Dale J.K., et al. Characterization and treatment of chronic active Epstein-Barr virus disease: A 28-year experience in the United States // Blood. 2011. Vol. 117, N 22. Р. 5835–5849. doi: 10.1182/blood-2010-11-316745

[37] Shestakova IV. To treat or not to treat Epstein-Barr virus infection: a detailed overview of the various tactics. Infectious Disease. 2013;(4):12–23. (In Russ).

[38] Шестакова И.В. Лечить или не лечить Эпштейна–Барр-вирусную инфекцию: подробный обзор различных тактик // Инфекционные болезни. 2013. № 4. С. 12–23.

[39] Nesterova IV, Khalturina EO. Algorithm of clinical, immunological and laboratory diagnostics of atypical chronic active Epstein-Barr herpesvirus infection. Russ Immunol J. 2018;12(2):170–177. (In Russ).

[40] Нестерова И.В., Халтурина Е.О. Алгоритм клинико-иммунологической и лабораторной диагностики атипичной хронической активной Эпштейн-Барр герпесвирусной инфекции // Российский иммунологический журнал. 2018. Т. 12, № 2. С. 170–177.

[41] Mardanly SG, Mardanly SS. Herpes virus type 7 (literature review). Clin Laboratory Diagnostics. 2023;68(2):117–122. (In Russ). doi: 10.51620/0869-2084-2023-68-2-117-122

[42] Марданлы С.Г., Марданлы С.С. Вирус герпеса 7-го типа (обзор литературы) // Клиническая лабораторная диагностика. 2023. Т. 68, № 2. С. 117–122. doi: 10.51620/0869-2084-2023-68-2-117-122

Funding

РоспотребнадзорRospotrebnadzor

RIGHTS & PERMISSIONS

Khalturina E.O., Mironov A.Y., Suranova T.G.