Herpes Simplex Virus Reactivation Research Articles

At Early Rheumatoid Arthritis Stage, the Infectious Spectrum Is Driven by Non-Familial Factors and Anti-CCP Immunization.

Background/Objectives: Patients with rheumatoid arthritis (RA) are prone to develop infections. Methods: Accordingly, 195 untreated early (e)RA patients and 398 healthy controls were selected from women in Tatarstan's cohort to study infectious history in the anamnesis (four criteria) and in the previous year (16 criteria). Information about annual infections was collected face-to-face from year to year by a qualified rheumatologist/general practitioner and included the active use of information from medical records. Results: In the anamnesis, tuberculosis, and pneumonia, and in the previous year, respiratory tract infections, skin infections, and herpes simplex virus reactivation incidence were reported to be increased in eRA patients, as well as the event number and duration of acute and chronic tonsillitis. Moreover, more bacterial-suspected upper respiratory infections and urinary tract infections were retrieved in sporadic eRA patients as compared to familial eRA patients. An elevated immunization against CCP prevented respiratory tract infection in those with HSV exacerbation. Finally, associations were retrieved between infection (event number/delay) and RA indices: (i) chronic tonsillitis exacerbations with disease activity and health assessment (HAQ) in familial eRA; (ii) bacterial-suspected upper respiratory infections with the number of swollen and tender joints in sporadic eRA; and (iii) HSV exacerbation with inflammation in eRA patients with negative/low response against CCP. Here, we demonstrate the complex nature of the interplay of RA with specific infections. Conclusions: For the first time, differences in the patterns of annual trivial infections and their links with RA indices were found in cohorts of familial and sporadic cases of the disease. Additionally, for the first time, we identified a remarkable relationship between early RA and exacerbations of chronic tonsillitis, as well as tuberculosis in the patient's history. Altogether, this study supports the existence of a complex interplay between infections and RA at onset driven by familial status and the presence of anti-CCP Ab at elevated levels.

Herpes simplex virus reactivation among hematopoietic stem cell transplant recipients: re-evaluating acyclovir dosage

Herpes simplex virus reactivation among hematopoietic stem cell transplant recipients: re-evaluating acyclovir dosage

Interleukin 1β receptor and synaptic dysfunction in recurrent brain infection with Herpes simplex virus type-1.

Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer's disease. However, the molecular mechanisms underlying this association are not completely understood. Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role. Here, we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain, highlighting the role of interleukins and, in particular, interleukin 1β as a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.

Co-detection of Human Herpes Viruses in Cerebrospinal Fluid Samples of Pediatric Patients with Multi-System Inflammatory Syndrome: A Single Center Experience in Isfahan, Iran

Background: Since December 2019, the Coronavirus disease 2019 (COVID-19) pandemic has impacted the world, including neurologic manifestations among its effects. Additionally, some studies have reported the reactivation of various viruses in patients diagnosed with COVID-19. Objectives: This study aimed to investigate the viral infection patterns of common viruses that cause encephalitis in patients diagnosed with the concurrence of multi-system inflammatory syndrome in children (MIS-C) and encephalitis. Methods: This cross-sectional study was conducted from February 2020 to May 2021. Children diagnosed with both MIS-C and encephalitis were included. Cerebrospinal fluid (CSF) samples were collected from each participant for a biochemistry panel and polymerase chain reaction (PCR) assays for varicella-zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), adenovirus, and influenza virus. Furthermore, patients underwent neuroimaging studies, including magnetic resonance imaging and computed tomography. Results: Thirteen patients with MIS-C and encephalitis were enrolled. Viral detection in CSF samples through PCR assays was successful in six patients. EBV and HSV were detected in four and two patients, respectively. The median age of these six children was 44 months, with four being male. Follow-up visits after six months showed that their quality of life had returned to normal. Conclusions: This study highlighted the co-occurrence of HSV and EBV reactivation with MIS-C. Although viral reactivations, unlike primary infections, resolved spontaneously in our cohort. Consequently, the reactivation of viruses due to MIS-C may open new avenues for future research.

Herpes Simplex Virus Bronchopneumonitis in Critically Ill Patients with Acute on Chronic Liver Failure: A Retrospective Analysis.

(1) Background: Critically ill patients are frequently diagnosed with pulmonary Herpes simplex virus-1 (HSV) reactivation, which then can lead to HSV bronchopneumonitis and is associated with higher mortality and longer mechanical ventilation. For the particular subgroup of critically ill patients with acute on chronic liver failure (ACLF), however, the impact of HSV reactivation is unknown. We investigated the impact of HSV reactivation in these patients. (2) Methods: We conducted a retrospective analysis, evaluating data from 136 mechanically ventilated patients with ACLF between January 2016 and August 2023. Clinical parameters were compared between patients with and without HSV bronchopneumonitis. (3) Results: 10.3% were diagnosed with HSV bronchopneumonitis (HSV group). Mortality did not differ between the HSV and non-HSV group (85.7% vs. 75.4%, p = 0.52). However, the clinical course in the HSV group was more complicated as patients required significantly longer mechanical ventilation (14 vs. 21 days, p = 0.04). Furthermore, fungal superinfections were significantly more frequent in the HSV group (28.6% vs. 6.6%, p = 0.006). (4) Conclusions: Mortality of critically ill patients with ACLF with HSV bronchopneumonitis was not increased in spite of the cirrhosis-associated immune dysfunction. Their clinical course, however, was more complicated with significantly longer mechanical ventilation.

Histone H2A variant H2A.B is enriched in transcriptionally active and replicating HSV-1 lytic chromatin.

Herpes simplex virus 1 (HSV-1) transcription is epigenetically regulated during latent and lytic infections, and epigenetic inhibitors have been proposed as potential antiviral drugs to modulate latency and reactivation. However, the detailed epigenetic mechanisms of regulation of HSV-1 transcription have not been fully characterized and may differ from those regulating cellular transcription. Whereas lytic HSV-1 chromatin is unusually dynamic, latent silenced HSV-1 chromatin is not. The mechanisms resulting in the unique dynamics of the lytic chromatin remain unknown. Here we identify the enrichment of the highly dynamic histone 2A variant H2A in the most dynamic viral chromatin, which provides a mechanistic understanding of its unique dynamics. Future work to identify the mechanisms of enrichment in H2A.B on the viral chromatin may identify novel druggable epigenetic regulators that modulate HSV-1 latency and reactivation.

Two Waves of Specific B Cell Memory Immunoreconstruction Observed in Anti-HHV1-3 IgG Kinetics after Hematopoietic Stem Cell Transplantation.

Humoral memory and specific antibody levels depend on the kind of antigen and individual immunofactors. The presence of IgM antibodies or a fourfold rise in specific IgG levels are generally accepted as diagnostic factors in the serology of acute viral infections. This basic model is not adequate for the herpes virome, especially after hematopoietic stem cell transplantation (HSCT), due to continuous, usually multifocal antigenic stimulation, various donor serostatuses, immunosuppression, and individual immunoreconstitution. A case-control study was conducted to identify active infection cases of human herpesvirus (HHV) (from 300 diagnosed immunocompromised patients) and to evaluate historically associated humoral factors to look at outcomes. We considered only the data of patients with meticulous differential diagnosis to exclude other causes, and thereby to observe pathways and temporal relationships, not the statistical ones usually collected in cohorts. Despite the small number, such data collection and analysis methods avoid a number of biases and indicate cause and effect. In this observational study, a retrospective analysis of data from 300 patients with clinical diagnosis of herpes simplex virus (HSV) and varicella zoster virus (VZV) reactivation showed a number of biases. Two well-differentiated cases (confirmed by a Tzanck test) with various diseases and conditioning evolutions of immune parameters showed an interesting pathway. Exponential decreases in specific IgGs after HSCT preceded virus replication were observed, with a cytopathic effect (shingles, VZV encephalitis and HSV-induced mucositis). The minima (lowest IgG levels) before herpesvirus reactivation were 234.23 mIU/mL and 94 RU/mL for VZV and HSV, respectively. This coincided with a low CD4 titer, but without other infectious processes. Other immune response parameters such as Treg, cytotoxic T cells, and complement and total IgG level were the same as they were before the transplant procedure. Interestingly, a second wave of immunoreconstitution with an anamnestic antibody response was not always observed. It coincided with prolonged herpes viral infection. A patient with lymphocyte depletion in conditioning showed an earlier second wave of immunoreconstitution (6th vs. 14th month). As is typical for infancy, the kinetics of the IgG level is unique after HSCT (the decline phase is first). Host microbiome factors (e.g., HHV1-3-serostatus) should be taken into account to predict risk of non-relapse mortality and survival after HSCT. The levels of specific antibodies help in predicting prognoses and improve disease management. A lack of differentiation and the confusing bias of the assessor (i.e., observer selection bias) are the main obstacles in statistical HHV1-3 research. Such time-lapse case studies may be the first to build evidence of a pathway and an association between immune parameters and HHV disease.

Absence of CD80 reduces HSV-1 replication in the eye and delays reactivation but not latency levels.

Herpes simplex virus-1 (HSV-1) infections are among the most frequent serious viral eye infections in the U.S. and are a major cause of viral-induced blindness. HSV-1 infection is known to induce T cell activation, proliferation, and differentiation that play crucial roles in the development of virus-induced inflammatory lesions, leading to eye disease and causing chronic corneal damage. CD80 is a co-stimulatory molecule and plays a leading role in T cell differentiation. Previous efforts to limit lesion severity by controlling inflammation at the cellular level led us to ask whether mice knocked out for CD80 would show attenuated virus replication following reactivation. By evaluating the effects of CD80 activity on primary and latent infection, we found that in the absence of CD80, virus replication in the eyes and virus reactivation in latent trigeminal ganglia were both significantly reduced. However, latency in latently infected CD80-/- mice did not differ significantly from that in wild-type (WT) control mice. Reduced virus replication in the eyes of CD80-/- mice correlated with significantly expanded CD11c gene expression as compared to WT mice. Taken together, our results indicate that suppression of CD80 could offer significant beneficial therapeutic effects in the treatment of Herpes Stromal Keratitis (HSK).IMPORTANCEOf the many problems associated with recurrent ocular infection, reducing virus reactivation should be a major goal of controlling ocular herpes simplex virus-1 (HSV-1) infection. In this study, we have shown that the absence of CD80 reduces HSV-1 reactivation, which marks the establishment of a previously undescribed mechanism underlying viral immune evasion that could be exploited to better manage HSV infection.

C-Jun signaling during initial HSV-1 infection modulates latency to enhance later reactivation in addition to directly promoting the progression to full reactivation.

Herpes simplex virus-1 (HSV-1) establishes a latent infection in peripheral neurons and periodically reactivates to permit transmission, which can result in clinical manifestations. Viral transactivators required for lytic infection are largely absent during latent infection, and therefore, HSV-1 relies on the co-option of neuronal host signaling pathways to initiate its gene expression. The activation of the neuronal c-Jun N-terminal kinase (JNK) cell stress pathway is central to initiating biphasic reactivation in response to multiple stimuli. However, how host factors work with JNK to stimulate the initial wave of gene expression (known as Phase I) or the progression to full Phase II reactivation remains unclear. Here, we found that c-Jun, the primary target downstream of neuronal JNK cell stress signaling, functions during reactivation but not during the JNK-mediated initiation of Phase I gene expression. Instead, c-Jun was required to transition from Phase I to full HSV-1 reactivation and was detected in viral replication compartments of reactivating neurons. Interestingly, we also identified a role for both c-Jun and enhanced neuronal stress during initial neuronal infection in promoting a more reactivation-competent form of HSV-1 latency. Therefore, c-Jun functions at multiple stages during the HSV latent infection of neurons to promote reactivation but not during the initial JNK-dependent Phase I. Importantly, by demonstrating that initial infection conditions can contribute to later reactivation abilities, this study highlights the potential for latently infected neurons to maintain a molecular scar of previous exposure to neuronal stressors.IMPORTANCEThe molecular mechanisms that regulate the reactivation of herpes simplex virus-1 (HSV-1) from latent infection are unknown. The host transcription and pioneer factor c-Jun is the main target of the JNK cell stress pathway that is known to be important in exit of HSV from latency. Surprisingly, we found that c-Jun does not act with JNK during exit from latency but instead promotes the transition to full reactivation. Moreover, c-Jun and enhanced neuronal stress during initial neuronal infection promoted a more reactivation-competent form of HSV-1 latency. c-Jun, therefore, functions at multiple stages during HSV-1 latent infection of neurons to promote reactivation. Importantly, this study contributes to a growing body of evidence that de novo HSV-1 infection conditions can modulate latent infection and impact future reactivation events, raising important questions on the clinical impact of stress during initial HSV-1 acquisition on future reactivation events and consequences.

Metabolic signatures of tear extracellular vesicles caused by herpes simplex keratitis

PurposeHerpes simplex keratitis (HSK), caused by type 1 herpes simplex virus (HSV) reactivation, is a severe infectious disease that leads to vision loss. HSV can trigger metabolic reprogramming in the host cell and change the extracellular vesicles (EV) cargos; however, little is known about the EV metabolic signatures during ocular HSV infection. Here, we aimed to depict the EV-associated metabolic landscape in HSK patients’ tears. MethodsWe collected 82 samples from 41 participants with unilateral HSK (contralateral unaffected tears were set as negative control), including subtype cohorts of 13 epithelial, 20 stromal, and 8 endothelial HSK. We isolated tear EVs via our previously established platform and conducted metabolic analysis using LC-MS/MS. The metabolic signatures for recognizing HSK and subtypes were assessed through differential analysis and machine learning algorithms. ResultsHypopsia and increased extracellular CD63 levels were observed in affected eyes. We identified 339 metabolites based on sEVs isolated from tears. Differential analysis revealed alterations in energy and amino acid metabolism, as well as the infectious microenvironment. Furthermore, we observed dysregulated metabolite such as methyldopa, which is associated with inappropriate neovascularization and corneal sensation loss, contributing to the HSK severity particularly in the stromal subtype. Moreover, machine learning classification also suggested a set of EV metabolic signatures that have potential for pan-keratitis detection. ConclusionsOur findings demonstrate that tear EV metabolites can serve as valuable indicators for comprehending the underlying pathological mechanisms. This knowledge is expected to facilitate the development of liquid biopsy means and therapeutic target discovery.

Reactivation of Herpes Simplex Virus Following Sphenopalatine Ganglion Nerve Block: Case Report and Review of the Literature.

A 36-year-old woman with no significant past medical history underwent a sphenopalatine ganglion block for treatment of a month-long migraine headache refractory to conservative treatment protocols. The headache resolved initially, but 1 day following the procedure, the headache recurred. The patient also developed an erythematous and edematous rash which cultures confirmed to be herpes simplex virus (HSV). Following several unsuccessful treatment modalities, the patient received valacyclovir, which resulted in resolution of her headache. Underlying HSV-1 infection may cause intractable migraine headache and nerve blocks may potentiate reactivation of latent HSV infection that caused the skin lesion in this case.

Herpes simplex virus reactivation among severe COVID-19 patients: to treat or not to treat?

Background: Herpes simplex virus type 1 (HSV-1) reactivation in the airways is a common finding among patients admitted to the intensive care unit and has been more recently been reported in critically ill COVID-19 patients. Evidence suggests that HSV-1 reactivation in critically ill patients may be associated with higher morbidity and mortality rates. However, there is conflicting data about whether treatment with acyclovir impacts outcomes. Objectives: The primary aim of this study is to assess whether acyclovir improves survival in critically ill COVID-19 patients with concomitant HSV-1 reactivation. Additionally, we explore the effect of acyclovir on cardiorespiratory instability, biochemical markers of inflammation and renal function. Incidence, potential risk factors and outcomes of HSV-1 reactivation in COVID-19 ICU patients are studied last. Methods: A retrospective single-center cohort study set in a Belgian tertiary-care university hospital. All COVID-19 patients admitted to the ICU between March 1st, 2020, and April 15th, 2021, and were tested for HSV-1 using real-time PCR in airway samples were included for analysis. The administration of acyclovir for patients with HSV-1 reactivation was not randomized. Mortality and various markers of morbidity (cardiorespiratory instability, biochemical markers of inflammation, and renal function) were compared between patients that had received acyclovir and those that had not. Secondary outcome measures were respiratory and inflammatory markers of disease severity. Results: 34.7% (42/121) of patients had HSV-1 reactivation, of which 67% (28/42) received acyclovir. ICU mortality was 36% (n = 10) in the acyclovir group versus 0% in the untreated group. Multivariate analysis resulted in OR 3.82 (95% CI 1.37 – 10.68) for ICU mortality in the treated group. Patients treated with acyclovir had a longer length of stay (41.8 vs. 26.8 days, p = .018), longer duration of invasive mechanical ventilation (33.4 vs. 21.8 days, p = .050), and lower PaO2/FiO2 ratio (59.9 vs. 73.4 mmHg, p = .008). Conclusions: The role of acyclovir in patients with HSV-1 reactivation in the ICU remains controversial. According to this study, respiratory HSV-1 reactivation for this specific patient group might be better left untreated. Treatment selection bias, however, could not be fully excluded.

Interferon inhibits the release of herpes simplex virus-1 from the axons of sensory neurons.

Herpes simplex virus-1 (HSV-1) is a human pathogen known to cause cold sores and genital herpes. HSV-1 establishes lifelong infections in our sensory neurons, with no cure or vaccine available. HSV-1 can reactivate sporadically and travel back along sensory nerves, where it can form lesions in the oral and genital mucosa, eye, and skin, or be shed asymptomatically. New treatment options are needed as resistance is emerging to current antiviral therapies. Here, we show that interferons (IFNs) are capable of blocking virus release from nerve endings, potentially stopping HSV-1 transmission into the skin. Furthermore, we show that IFNγ has the potential to have widespread antiviral effects in the neuron and may have additional effects on HSV-1 reactivation. Together, this study identifies new targets for the development of immunotherapies to stop the spread of HSV-1 from the nerves into the skin.

Pathophysiology and treatment of pain in multiple myeloma

Most patients with multiple myeloma (MM) suffer from chronic pain of varying degrees of intensity at every stage of the natural disease process. Osteolytic bone lesions are one of the most common complications of MM. The bone disease visualized by PET/CT and MRI affects up to 90% of newly diagnosed MM patients, increasing the risk of the development of skeletal-related events. Pathological fractures and spinal cord compression occur in 17% and 6% of patients, respectively. Bone pain is explained by an increase in pressure in the bone marrow, the release of chemical mediators by myeloma plasma cells, and the occurrence of microcracks in the bones, indirectly to a violation of local metabolism. Management of myeloma bone disease includes anti-myeloma chemotherapy and radiotherapy, antiresorptive therapy with bisphosphonates or denosumab, and direct pharmacological pain correction. Patients with pathological vertebral fractures and without spinal cord compression should be considered for vertebroplasty or kyphoplasty. The use of proteasome inhibitors and monoclonal antibodies for the treatment of MM is associated with a risk of herpes simplex virus (HSV) and varicella-zoster virus (VZV) reactivation. The result of the healing of herpetic eruptions in some patients will be the development of postherpetic neuralgia, manifested by excruciating pain for months or years. Moreover, the treatment with proteasome inhibitor bortezomib is often associated with the development of long-term persistent peripheral neuropathy, often complicated by pain. According to their neurobiological and clinical features, pain is classified into nociceptive, neuropathic, and functional. Bone pain is nociceptive and for postherpetic and chemotherapy-induced neuropathy, the neuropathic component is more significant. Opioids are the drugs of choice for moderate to severe nociceptive pain, while anticonvulsants and antidepressants are the most commonly used adjuvants for neuropathic pain. This review summarizes information on the pathophysiology of various types of pain syndrome in patients with MM, as well as on modern approaches to the prevention and treatment of complications. The issues of the pharmacology of opioid analgesics are discussed. The review concludes with data from a clinical trial of a new domestic non-opioid μ1-opioid receptor agonist Tafalgin, considered a real alternative to narcotic analgesics.

Clinical Evaluation and Experience in Treatments Performed with Fractional CO2 Laser on Latin American Skin: An Observational Retrospective Study.

Background: The carbon dioxide (CO2) laser is an ablative system that evaporates, remodels, and coagulates tissues, becoming therefore a gold standard piece of equipment for the treatment of dermatological pathologies and esthetic imperfections. Objective: To evaluate the efficacy and safety of CO2 laser treatments in different patients' skin pathologies. Methods: A total of 705 patients with an age range between 18 and 70 years, with phototypes on the Fitzpatrick scale III, IV, V, and VI, were enrolled from October 2021 to May 2022, and were treated using the CO2 laser system. Results: Ninety-six patients were treated with fractional CO2 laser, used for skin rejuvenation and stretch marks. One patient presented reactivation of herpes simplex, 10 postinflammatory hyperpigmentation that resolved after 3 months with depigmenting agents, 6 with persistent erythema. A total of 13 patients with rhinophyma were treated, and no complications were observed; a total of 64 patients with wrinkles were treated. They improved in 6 months. A total of 340 patients were treated for seborrheic keratosis, papulosa nigra dermatosis, fibropapillomas, sebaceous hyperplasias, verruca vulgaris, and condylomata acuminata. One patient presented with a complication hypopigmented macule. A total of 136 patients underwent treatment for laser ablation of intradermal nevi and verrucous epidermal nevi, without complications. A total of 56 patients were treated with keloids and hypertrophic scars. One patient presented with ulceration of a keloid that resolved with the application of clostridiopeptidase A and chloramphenicol after 2 weeks. Conclusions: The use of the CO2 laser in any phototype and race, which are factors with a high incidence in Latin America, provides a safe and effective result for different dermatological pathologies.

Diagnosis and Treatment of Recurrent Herpes Labialis: A Case Report

Introduction:Reactivation of herpes simplex virus (HSV)-1 can cause recurrent herpes labialis. This is a lesion that clinically consists of multiple vesicles that can break into erosive areas covered with crusts on the vermilion and surrounding skin. The lesions may recur, be triggered by systemic factors including; stress, menstruation, and local stimuli such as injury; sun exposure, and are usually preceded by prodromal symptoms. Case: a 44-year-old woman came to the Department of Oral Medicine at the Dental and Oral Hospital of the University of Jember with complaints of small blisters and peeling on the outer right corner of her mouth. The patient has had these complaints since 3 days, feels pain especially when eating and talking accompanied by not feeling well. The patient had experienced the same illness several years ago and relapsed again when experiencing stress and fatigue. The patient has no history of allergies, either to drugs or food. Treatment: Topical antiviral drugs are given in the form of 5% acyclovir cream and supportive therapy in the form of multivitamin tablets. Conclusion: Recurrent Herpes labialis caused by HSV-1 can be treated with topical antivirals drugs and multivitamin tablets.

Multiple Organ Dysfunction Secondary to Herpes Simplex Virus -1 Reactivation After Treatment With Dexamethasone and Sarilumab for Covid-19 Disease.

The immunological response to the SARS-CoV-2 virus and the treatment of COVID-19 disease present a potential susceptibility to viral reactivation, particularly Herpes simplex virus-1 (HSV-1). A 49-year-old female presented to hospital with severe COVID-19 pneumonitis and was given sarilumab and dexamethasone. She was intubated and ventilated in the intensive care unit (ICU) and initially demonstrated biochemical and clinical evidence of improvement. This was followed by a severe acute deterioration in respiratory, renal, and cardiovascular function, accompanied by a vesicular rash on the face. Polymerase chain reaction confirmed HSV-1 reactivation and treatment with acyclovir was commenced. After 49 days in ICU the patient was successfully weaned from all organ support, and she made a satisfactory recovery. HSV-1 reactivation is common in COVID-19 and likely contributes to poorer clinical outcomes. The mechanism causing susceptibility to viral reactivation is not clearly defined, however, the development of critical illness induced immunosuppression via dysfunction of interferon and interleukin pathways is a likely mechanism. This effect could be perpetuated with immunosuppressant medications, although further research is needed to characterise this phenomenon.

Reactivation of herpesviruses during COVID-19: A systematic review and meta-analysis.

To provide a comprehensive systematic review and meta-analysis regarding the cumulative incidence (incidence proportion) of human herpesvirus (HHV) reactivation among patients with coronavirus disease 2019 (COVID-19), we searched PubMed/MEDLINE, Web of Science, and EMBASE up to 25 September 2022, with no language restrictions. All interventional and observational studies enrolling patients with confirmed COVID-19 and providing data regarding HHV reactivation were included. The random-effects model was used in the meta-analyses. We included information from 32 studies. HHV reactivation was considered a positive polymerase chain reaction result taken at the time of COVID-19 infection. Most of the included patients were severe COVID-19 cases. The pooled cumulative incidence estimate was 38% (95% Confidence Intervals [CI], 28%-50%, I2 =86%) for herpes simplex virus (HSV), 19% (95% CI, 13%-28%, I2 =87%) for cytomegalovirus (CMV), 45% (95% CI, 28%-63%, I2 =96%) for Epstein-Barr virus (EBV), 18% (95% CI, 8%-35%) for human herpesvirus 6 (HHV-6), 44% (95% CI, 32%-56%) for human herpesvirus 7 (HHV-7), and 19% (95% CI, 14%-26%) for human herpesvirus 8 (HHV-8). There was no evidence of funnel plot asymmetry based on visual inspection and Egger's regression test for the results of HSV (p=0.84), CMV (p=0.82), and EBV (p=0.27) reactivation. In conclusion, the identification of HHV reactivation in severe COVID-19 patients is helpful in the management of patients as well as the prevention of complications. Further research is required to elucidate the interaction between HHVs and COVID-19. Systematic review registration: PROSPERO CRD42022321973.

COVID-19, SARS-CoV-2 Vaccination, and Human Herpesviruses Infections.

There are several human herpesviruses. A common characteristic of infection by these viruses is latency, by which the virus assumes a non-replicative state, subverting the attentions of the host's immune response. In immunocompetent hosts, herpesviruses are immunologically controlled, although periodic virus shedding can occur. In situations where immunological control is lost, herpesviruses can reactivate and produce clinically apparent disease. It is now becoming apparent that COVID-19 or exposure to COVID-19 vaccines can exert several effects on the immune system. The pandemic of COVID-19 shows no sign of abating, with new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants continuing to evolve. Several COVID-19 vaccines have been developed, and much of the world's population has either experienced COVID-19 or been vaccinated against it. There are an increasing number of reports of associations between herpesvirus infections or reactivations and COVID-19 or COVID-19 vaccination. For instance, a positive cytomegalovirus serostatus may indicate a greater likelihood of severe COVID-19, and herpes simplex virus reactivation may be linked to increased mortality. Epstein-Barr virus reactivation appears to be associated with post-acute sequelae of COVID-19. Finally, herpes zoster has been reported to be associated with COVID-19 vaccination. This brief narrative review will provide several insights into associations between herpesvirus infections or reactivations and COVID-19 or SARS-CoV-2 vaccination.

Рецидивирующие респираторные заболевания и активные герпесвирусные инфекции у детей: проблемы и варианты их решения

Background: recurrent respiratory infections (RRI) in children are a relevant medical and social issue. Reactivation of latent herpes simplex virus (HSV) infections is recognized as one of the leading causes of recurrent respiratory infections. Its rate in children is up to 40%. Therapeutic options for recurrent respiratory infections in children are discussed given the activity of HSV infections and immune disorder treatment. Aim: to assess the efficacy of inosine pranobex (Normomed®) for recurrent respiratory infections and active HSV infection in children. Patients and Methods: we examined 96 children aged 1–17 years who requested medical care in an outpatient department with complaints typical of recurrent respiratory infections and laboratory-confirmed active HSV infection. Children received inosine pranobex (50–75 mg/kg/day) in three 10-day courses (10-day breaks). 5±1 weeks after finishing therapy, control clinical and laboratory tests and virology were performed. The nature of ARI episodes during the follow-up period and HSV infection activity over time were evaluated. Results: during treatment, a reduction in the rate and severity of respiratory diseases was reported in 94% of children. Fever severity decreased twice (p=0.035), oropharynx condition improved in 66.7% (p<0.01), and the severity of lymphoproliferative syndrome reduced in 62.5% (tonsil hypertrophy in 52.1%, lymphadenopathy in 50.6%, hepatomegaly in 55.3%, splenomegaly in 66.7%). During treatment with inosine pranobex, a decrease in HSV infection activity was reported in 88.6% of children. The active HSV count also decreased. A significant (p<0.01) reduction in the percentage of patients with active HHV 6A/B (from 78.1% to 12.5%), Epstein– Barr virus (from 45.8% to 7.3%), and HSV type 1 (from 14.6% to 1.0%) was reported. Conclusion: significant improvement in the somatic and virological status of children with recurrent respiratory infections and HSV infection after a course of inosine pranobex, which is characterized by antiviral and immunomodulatory effects, was established. KEYWORDS: monthly respiratory infections, recurrent respiratory infections, Epstein–Barr virus, human herpes virus 6A/B, children, inosine pranobex, Normomed. FOR CITATION: Melekhina E.V., Preobrazhenskaia D.V., Muzyka A.D., Soldatova E.Yu., Gorelov A.V. Recurrent respiratory infections and active herpesvirus infections in children: problems and solutions. Russian Medical Inquiry. 2023;7(11):704–712 (in Russ.). DOI: 10.32364/2587- 6821-2023-7-11-2.