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HERPESVIRUS REACTIVATION IN THE CONTEXT OF POST-COVID CONDITIONS
Janzakova Akerke Kurbanbekkizi, Kazakh Medical University "KSPH" Almaty, Republic of Kazakhstan E-mail: janzakova.akerke01@gmail.com Kurmanova Gaukhar Medeubaevna, Professor, Doctor of Medical Sciences, Head of the Department of "Clinical Disciplines", Kazakh National University named after Al-Farabi,
Almaty, Republic of Kazakhstan E-mail: gaukhar.kurmanova2000@gmail.com Buribaeva Janara Kuanishbekovna, associate professor, Doctor of Medical Sciences, Kazakh Medical University "KSPH" Almaty, Republic of Kazakhstan Janzakov Baurzhan Bidaibekovich, Master's in Public Health Head of the Pediatric surgery department, Almaty region, Republic of Kazakhstan E-mail: maladca@inbox.ru Doskozhaeva Saule Temirbulatovna, Professor, Doctor of Medical Sciences in Infectious Diseases, Almaty, Republic of Kazakhstan E-mail: sdoskojaeva@mail.ru Shin Anna Leonidovna, Doctor of Medical Sciences Department of "Clinical Disciplines", Kazakh National University named after Al-Farabi,
Almaty, Republic of Kazakhstan E-mail: annashin86@gmail.com
Abstract. The abstract presents a comprehensive overview of the interplay between herpesvirus reactivation and post-COVID conditions, exploring their impact on clinical outcomes. In the context of the prolonged and recurrent symptoms associated with the post-COVID syndrome, the study enters into the immune dysregulation induced by COVID-19, which has been identified as a contributing factor to the resurgence of latent herpesviruses, including herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Despite this understanding, the precise mechanisms through which herpesviruses reactivation influences the
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development of post-COVID syndrome remain elusive. The primary aim of this review is to provide a nuanced comprehension of this intricate relationship, evaluating the impact of herpesviruses reactivation on the clinical trajectory of COVID-19. The study also beginnings to identify the mechanisms underlying the potential worsening of the coronavirus infection by herpesviruses. By highlighting these interactions, this review seeks to offer valuable insights for developing effective strategies to manage the long-term health consequences of post-COVID conditions and to provide targeted support for individuals recovering from SARS-CoV-2 infection.
Key words: herpesvirus reactivation, post-COVID syndrome, herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), COVID-19.
Introduction/ As of today, there are more than 500 million registered cases of SARS-CoV-2 infection (Severe Acute Respiratory Syndrome Coronavirus 2) worldwide [1] Out of them 65 million cases develop post-covid conditions, however, because of the lack of clear diagnostic criteria the real number of these patients is unknown. The post-COVID syndrome includes a range of symptoms, including neurological and herpetic manifestations. [2]
In the context of post-COVID syndrome, prolonged and recurrent symptoms following the acute phase of COVID-19 may be associated with the reactivation of latent herpesviruses. [3]. Studies indicate that the immune dysregulation induced by COVID-19 contributes to the resurgence of herpesviruses, including HSV, CMV, and EBV. Understanding this relationship is pivotal for developing effective strategies to manage the long-term health consequences for those suffering from COVID-19. [4]
Aim of the Article.
The primary aim of this article is to thoroughly investigate and explain the intricate relationship between herpesvirus reactivation and post-COVID conditions. By getting into the interplay between immune dysregulation induced by COVID-19 and the resurgence of latent herpesviruses, including HSV, CMV, and EBV, the study aims to provide a nuanced comprehension of how herpesviruses impact the clinical trajectory of COVID-19 and contribute to the development of the post-COVID syndrome. Specifically, the review aims to identify the mechanisms through which herpesviruses may worsen the coronavirus infection and explores the potential long-term health consequences for individuals recovering from SARS-CoV-2 infection. By shedding light on these interactions, the article seeks to offer valuable insights for the development of effective strategies to manage the prolonged and recurrent symptoms associated with post-COVID conditions, ultimately contributing to the enhancement of diagnostic, therapeutic, and preventive approaches in the context of the global COVID-19 pandemic.
Prior research and studies: Post-COVID syndrome is defined as signs and symptoms that appear during or following a COVID-19 infection, last longer than 12 weeks, and cannot be attributed to any other illness [5].
The term 'long COVID' is often used to indicate symptoms and signs that persist or emerge after to acute COVID-19, in addition to the clinical case description
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guidelines. It encompasses both post-COVID syndrome (12 weeks or longer) and continuous symptomatic COVID-19 (from 4 to 12 weeks).
Post-covid syndrome demonstrates a wide range of symptoms that affect various body parts, including nausea, excessive fatigue, dyspnea or shortness of breath, cough, chest pain, palpitations, brain fog, short-term memory loss, joint pain, sensitivity to light and sound, coagulation, neurological, gastrointestinal, and gynecological issues [6; 7]. These persistent, chronic symptoms are indicative of damage to several organs. Examining the enduring health implications of COVID-19 in discharged patients, a recent study revealed concerning statistics: 26% experienced sleep issues, 23% reported anxiety or depression, and a staggering 63% faced exhaustion or physical weakness [8]. It is noteworthy that almost all adults globally have encountered at least one herpesvirus infection during their lifetime [9].
After the first infection, all herpesviruses have two alternate life-cycle programs called the dormant and lytic phases, which are crucial for the continuation of viral infections and the onset of illness [10]. Generally speaking, latency is the main state in which a virus lives on infected cells with little expression of its viral proteins. On the other hand, viral reactivation typically results in the production of mature virions, amplification of viral DNA, and strong expression of the majority of viral genes [11]. Herpesviruses show extensive cell tropism [12], and they operate like lytic pathogens during both the initial infection and reactivation, destroying the majority of the invasive cells [13]. At the same time, latently infected cells overcome immune monitoring by suppressing the expression and replication of viral genes [14]. Several factors might cause a viral transformation from a latent to a lytic phase, such as immunosuppression, co-infections, or psychological stress [15]. This switching is uncommon, often self-limiting, and has no impact on treatment. However, immunocompromised people or those whose immunological imbalance has been triggered by processes like COVID-19 may have long-term implications if they are unable to maintain latency due to T-cell failure [14].
Multiple pathogen activity may be the reason for failure to return to normal health, regardless of the role that autoimmune variables and longer persistence of SARS-CoV-2 fragments have been suggested to play in the development of worsened or long-term COVID-19 [15], [16]. Reactivation of previously acquired pathogens, such as herpesviruses, may be of special interest. Their reactivation may cause the production of distinct viral genes, infection of new tissues or organs, and the emergence of fresh acute or chronic symptoms [17].
A meta-analysis of the covid-19 population's prevalence of active HSV, CMV, and EBV infection was carried out. The population with COVID-19 had the greatest frequency of active EBV infection, at 41%. The prevalence of active HSV infection was found to be 28% in third place, with CMV at 25% and HSV1 at 18% [14]. In the sensitivity analysis of studies examining severe diseases, a notable disparity in the frequency of active EBV infection was observed between the severe COVID-19 and non-COVID-19 groups. Patients with a severe type of COVID-19 had a six-fold increased risk of having an active EBV infection compared to non-COVID-19 controls.
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Herpes simplex viruses, comprising HSV-1 and HSV-2, are globally prevalent infections affecting millions of individuals. The emergence of SARS-CoV-2 and its potential interaction with HSV have garnered attention in various clinical reports and studies, revealing the association between SARS-CoV-2 infection and HSV reactivation.
Studies, particularly in France and the United Kingdom, have highlighted the occurrence of Herpesviridae (HSV and/or CMV) pulmonary reactivations in COVID-19 patients. [18]. Notably, patients experiencing Herpesviridae reactivation had prolonged mechanical ventilation durations compared to those without reactivation, underscoring the potential impact on the clinical course of COVID-19. Additionally, a cross-sectional study demonstrated a notable prevalence of HSV infections in COVID-19 patients, with some experiencing more severe HSV reactivations during the viral infection [19].
Cytomegalovirus infection presents a complex interplay with severe COVID-19, particularly in immunocompromised or immunosuppressed individuals. While CMV-induced symptoms are generally mild in healthy individuals, congenital CMV infection can lead to severe organ disease and mortality, particularly in vulnerable populations such as HIV-infected patients, organ transplant recipients, and newborn infants [20].
Various studies across different regions have reported CMV reactivation in COVID-19 patients, with percentages ranging from 1.2% to 15%, especially in those receiving systemic corticosteroid treatment[21]. These findings highlight the heightened risk of CMV reactivation in critically ill COVID-19 patients, further emphasizing the need for vigilant monitoring and potential intervention in such cases [22].
The observed coinfection of SARS-CoV-2 and CMV, along with the development of CMV-related symptoms during severe COVID-19, suggests a potential link between immune suppression induced by the viral infection and subsequent CMV reactivation[23]. This association has led to speculations regarding the impact of COVID-19 treatments, such as glucocorticoids, anti-IL-6, and other immunobiological therapies, on CMV reactivation.
The evidence presented underscores the intricate relationship between Epstein-Barr virus (EBV) and COVID-19, shedding light on potential implications for disease severity and progression. The association between EBV reactivation and COVID-19 has been established through various studies, demonstrating a higher prevalence of EBV coinfection in SARS-CoV-2-positive individuals[24]. Moreover, the correlation between EBV reactivation and severity of COVID-19 symptoms, including fever and increased inflammatory markers, suggests a possible synergistic effect [25].
Notably, studies have revealed a higher mortality rate among COVID-19 patients with concurrent EBV reactivation, emphasizing the clinical significance of this interaction. The observed lytic reactivation of herpesviruses, particularly EBV, in critically ill COVID-19 patients further highlights the potential impact on patient outcomes, including prolonged ICU stays [21].
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Mechanistic studies have started to unravel the molecular basis of the interplay between SARS-CoV-2 and EBV, implicating mitochondrial dysfunction, inflammatory factors like Interleukin-6, and upregulation of ACE2 expression in the context of EBV reactivation [26]. These findings suggest potential avenues for therapeutic interventions, such as inhibiting EBV replication with antivirals to mitigate SARS-CoV-2 infectivity [27].
Conclusion. The global COVID-19 pandemic has posed a major challenge to global public health. This pandemic left a significant trail of lingering effects known, with the occurrence of long-lasting symptoms in approximately one in five infected adults.
One important aspect of the effects of COVID-19 was the reactivation of herpesviruses such as HPV, CMV and VEB in cured patients. This has raised concern because of the possible impact on overall health and disease course. Research suggests that COVID-19-induced immune dysregulation may promote the reactivation of latent herpesviruses, creating a favourable environment for their reproduction.
Risk factors for post-COVID include comorbidities, positive PCR for SARS-CoV-2, and detection of herpesvirus DNA in the blood. This emphasizes the need for careful monitoring and management of patients with coronavirus infection.
However, despite research, the understanding of the mechanisms of herpesvirus reactivation in the context of COVID-19 remains incomplete. Further research is needed to unravel these relationships and develop effective strategies to manage long-term health outcomes in patients. It is important to continue research in this area to improve diagnosis, treatment, and prevention to meet the multifaceted challenges presented by the COVID-19 pandemic.
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