Recurrent Herpes Simplex Research Articles

Breaching the Barrier: Investigating Initial Herpes Simplex Viral Infection and Spread in Human Skin and Mucosa

Herpes simplex virus (HSV) is sexually transmitted via the anogenital mucosa where it initially infects epidermal keratinocytes and mononuclear phagocytes (MNPs). It then spreads to the dorsal root ganglion via sensory nerve endings, to remain latent for life with periodic reactivation. Currently, there is no cure or vaccine. Initial or recurrent HSV infection can produce serious complications and mediate acquisition of HIV. This review outlines the initial events after the HSV infection of human anogenital mucosa to determine the optimal window to target the virus before it becomes latent. After infection, HSV spreads rapidly within the mid-layers of epidermal keratinocytes in the explanted human inner foreskin. Infected cells produce chemokines, which modulate nectin-1 distribution on the surface of adjacent keratinocytes, facilitating viral spread. Epidermal Langerhans cells and dendritic cells become infected with HSV followed by a “viral relay” to dermal MNPs, which then present viral antigen to T cells in the dermis or lymph nodes. These data indicate the need for interruption of spread within 24 h by diffusible vaccine-induced mediators such as antiviral cytokines from resident immune cells or antibodies. Intradermal/mucosal vaccines would need to target the relevant dermal MNPs to induce HSV-specific CD4+ and CD8+ T cells.

USO DE VACINA IMUNOESTIMULANTE PARA HERPES SIMPLES DE REPETIÇÃO: UMA REVISÃO INTEGRATIVA DA LITERATURA

Infection with the herpes simplex virus is considered common throughout the world and clinically manifests signs and symptoms in the oral and genital regions. The natural history of the disease comprises the phases of primary infection, latency and recurrent infection. Although many people infected with the herpes virus may be asymptomatic or have mild symptoms, active outbreaks can be intensely uncomfortable, characterized by lesions on the skin or mucous membranes, accompanied by pain, itching and a burning sensation. In addition to the physical symptoms, the emotional impact of herpes should not be underestimated. Among the therapeutic alternatives are antivirals, natural therapies and low-power laser therapy. However, in cases of patients with recurrent herpes this therapy is not always effective, so a new alternative to control the virus is the immunostimulating vaccine. The present study aimed to evaluate the effectiveness of the immunostimulant vaccine in the treatment of patients with recurrent herpes simplex, through an integrative review of the literature. A search was carried out for articles in electronic databases, such as MEDLINE, via PubMed, LILACS, via VHL, and Scielo, published between 2011 and 2024 that addressed studies of herpes simplex with randomized clinical trials, associating the descriptors: “recurrent herpes simplex”, or “immunostimulating vaccine”, or “recurrent herpes treatment”, without language restrictions. 17 studies were found, of which, after excluding duplicates and those that did not meet the inclusion criteria, 10 were selected for analysis. Thus, this review highlights that the immunostimulating vaccine is an effective therapeutic resource, reducing healing time, symptoms and recurrence of lesions.

Novel Mouse Model of Recurrent Sublethal Herpes Simplex Virus Infection Recapitulates Human Antibody Responses to Primary and Chronic Infection.

Background: Herpes simplex virus (HSV) vaccine development has been impeded by the absence of predictive preclinical models and defined correlates of immune protection. Prior candidates elicited neutralizing responses greater than natural infection but no antibody-dependent cellular cytotoxicity (ADCC) and failed to protect in clinical trials. Primary HSV infection also elicits only neutralizing responses, but ADCC and an expanded antigenic repertoire emerge over time. This evolution may contribute to the decreased frequency and severity of recurrences. To test this notion, we developed a recurrent HSV infection mouse model and evaluated changes in humoral immunity with repeated challenges. Methods: Mice were repeatedly infected intranasally with clinical isolates of HSV-1 or HSV-2 for four months. HSV binding IgG, neutralizing (with or without complement) and ADCC-mediating antibodies were quantified prior to each round of infection. Viral targets were assessed by western blotting. Pooled immune serum (750 μg IgG per mouse) was passively transferred into naïve wild-type or Hvem knockout mice 24 h prior to lethal skin challenge. Results: Repeated exposure to HSV-1 or HSV-2 induced an increase in total HSV-binding IgG but did not boost neutralizing titers. In contrast, ADCC-mediating responses increased significantly from the first to the fourth viral exposure (p < 0.01). The increase was associated with an expanded antigenic repertoire. Passive transfer of fourth round immune serum provided significant protection whereas first round serum failed to protect (p < 0.01). However, protection was lost when serum was transferred into Hvem knockout mice, which are impaired in mediating ADCC killing. Conclusion: This novel model recapitulates clinical responses, highlights the importance of ADCC in protecting against recurrent infection, and provides a strategy for evaluating therapeutic vaccines.

Joint British Association for Sexual Health and HIV and Royal College of Obstetricians and Gynaecologists national UK guideline for the management of herpes simplex virus (HSV) in pregnancy and the neonate (2024 update).

This updated national UK guideline offers recommendations on the management of genital herpes simplex virus (HSV) in mothers and pregnant people during pregnancy and within 4 weeks following birth. It includes recommendations for first episode and recurrent HSV, HSV in preterm pre-labour rupture of membranes and in co-infection with HSV and HIV. Recommendations around management of the neonate are made, on prevention of postnatal transmission, management of breastfeeding, and the management of clinically discordant couples. This guideline is aimed at healthcare professionals working in sexual health clinics, maternity units, and those working on postnatal wards and neonatal units in the UK. However, the principles of the recommendations should be adopted across all services, including community care.

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.

Is the level of varicella-zoster virus IgG associated with symptomatic status of genital herpes simplex virus infection? A case-control study.

Herpes simplex virus (HSV) is a common infection, affecting the majority of the population by age of 50. Recurrent symptomatic outbreaks, experienced by a minority, have significant psychological and psychosexual effects. The varicella zoster virus (VZV), resembling HSV, shows potential for a functional cure via vaccination. This study seeks to investigate if there is an association between low VZV antibody levels and recurrent HSV outbreaks. A total of 110 patients with symptomatic and asymptomatic HSV were recruited during their sexual health screen. Serum samples were collected between Aug 2019 - July 2022; breaks in the study occurred due to COVID. The primary outcome measure was the serological status of HSV and VZV IgG titre level. The average age was 37.3years (range 21-65years). For people with asymptomatic genital HSV2 the average VZV IgG titre was 2373.9IU/mL (n = 17); and 1219.0IU/mL for the symptomatic group (n = 67); p ≤ 0.00001), with similar results for HSV1. There is a strong association between average higher varicella-zoster virus (VZV) IgG level and being an asymptomatic carrier of herpes simplex sirus (HSV)1&2. A feasibility study to assess the use of the VZV vaccine as a treatment of HSV is planned.

A cost-effective label-free biosensor for rapid detection of multiple viral respiratory infections base on liquid crystals: Fabrication and modeling

The high transmission rate and incurability of recurrent Herpes Simplex Virus (HSV) infection require an accurate and fast detection approach for its efficient prevention. In an attempt to find a novel sensitive and simple optical diagnostic technique which enables on-spot testing, here we developed label-free biosensors based on E7 nematic liquid crystals (LCs) for specific detection of HSV DNA. For this purpose, homeotropically oriented LCs as smart materials are spread on the textile grid to make their both upper and lower surfaces be in contact with ambient air. HSV DNA of concentration between 1.4 nM and 5.5 nM is added to the platform, and DNA elution buffer is used as a control. Then, the reorientation of LCs occurs due to the coupling of electrical dipoles between LCs and DNA molecules. Creating a unique pattern that is projected onto CCD by putting the sample in a cross-polarizer and using white light. To model the LC's director distribution, LC's free energy equation is solved using the variational method and finite difference method (FDM). Overall, our LC-based sensor is a user-friendly, cost-effective, highly sensitive, and fast way for specific detection of HSV without the need for experts and expensive equipment.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial

Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n=38) or control (n=46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p=0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p=0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p=0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p=0.02). There were no safety concerns. BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Dual impacts of a glycan shield on the envelope glycoprotein B of HSV-1: evasion from human antibodies in vivo and neurovirulence.

Identification of the mechanisms of viral evasion from human antibodies is crucial both for understanding viral pathogenesis and for designing effective vaccines. Here we show in cell cultures that an N-glycan shield on the herpes simplex virus 1 (HSV-1) envelope glycoprotein B (gB) mediated evasion from neutralization and antibody-dependent cellular cytotoxicity due to pooled γ-globulins derived from human blood. We also demonstrated that the presence of human γ-globulins in mice and immunity to HSV-1 induced by viral infection in mice significantly reduced replication in their eyes of a mutant virus lacking the glycosylation site but had little effect on the replication of its repaired virus. These results suggest that an N-glycan shield on a specific site of HSV-1 envelope gB mediated evasion from human antibodies in vivo and from HSV-1 immunity induced by viral infection in vivo. Notably, we also found that an N-glycan shield on a specific site of HSV-1 gB was significant for HSV-1 neurovirulence and replication in the central nervous system of naïve mice. Thus, we have identified a critical N-glycan shield on HSV-1 gB that has dual impacts, namely evasion from human antibodies in vivo and viral neurovirulence. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latent and recurrent infections in humans. To produce recurrent infections that contribute to transmission of the virus to new human host(s), the virus must be able to evade the antibodies persisting in latently infected individuals. Here, we show that an N-glycan shield on the specific site of the envelope glycoprotein B (gB) of HSV-1 mediates evasion from pooled γ-globulins derived from human blood both in cell cultures and mice. Notably, the N-glycan shield on the specific site of gB was also significant for HSV-1 neurovirulence in naïve mice. Considering the clinical features of HSV-1 infection, these results suggest that the glycan shield not only facilitates recurrent HSV-1 infections in latently infected humans by evading antibodies but is also important for HSV-1 pathogenesis during the initial infection.

Contactin-associated protein-2 and anti-aquaporin-4 antibody positive autoimmune encephalitis secondary to herpes simplex encephalitis: A case report.

Recurrent herpes simplex encephalitis (HSE) can easily induce autoimmune encephalitis (AE). However, there are few reports of anti-contactin-associated protein-2 (CASPR2)-related encephalitis, especially with positive anti-aquaporin 4 (AQP4) antibodies. A 14-year-old boy was admitted to the Department of Neurology of the First Affiliated Hospital of Kunming Medical University for "headache, dizziness, and fever for four days" with positive anti-CASPR2 and anti-AQP4 antibodies in the cerebrospinal fluid. Cranial MRI showed lesions in the right hippocampus, amygdala, and insular lobe, with local sulcus enhancement in the right insular, temporal, and frontal lobes. The fluid-attenuated inversion recovery was significantly enhanced. Human herpes virus type I was detected by cerebrospinal fluid metagenomic testing. The patient was diagnosed with AE secondary to HSE, with positive anti-CASPR2 and anti-AQP4 antibodies. After 2 weeks of immunoglobulin and methylprednisolone immunomodulatory therapy, acyclovir antivirus, mannitol dehydration, reducing intracranial pressure, and other symptomatic support therapy. The patient's symptoms significantly improved, with no complaints of discomfort, and he was discharged for observation. The patient was followed up a month after discharge and had no complaints of discomfort. CASPR2 and anti-aquaporin-4 antibody-positive AE have not been reported to be positive. This case will raise awareness of CASPR2 and anti-aquaporin-4 antibody-positive AE secondary to HSE, strengthen diagnostic capacities, and provide advice to treat it.

IFIH1 deficiency causing neonatal herpes simplex virus encephalitis and recurrent retinitis

Homozygous loss-of-function variants in Interferon induced with helicase C domain 1 (IFIH1) leads to immunodeficiency with early onset recurrent and severe viral respiratory infections (Immunodeficiency 95; MIM 619773). Severe respiratory infections with RNA viruses such as rhinovirus and respiratory syncytial virus (RSV) are most characteristic of IFIH1 deficiency. IFIH1 encodes melanoma differentiation-associated protein 5 (MDA5), an intracellular sensor of mainly long double-stranded RNA (ds-RNA), a viral replication intermediate. When activated, MDA5 triggers antiviral pathways including increased transcription of Type 1-interferon. The antiviral role of MDA5 is best described for positive (+) RNA viruses such as Picornavirus family which produce long ds-RNA as a replication intermediate. We present a patient with neonatal herpes simplex virus (HSV) encephalitis and recurrent retinitis with homozygous variant of unknown significance (VUS) in IFIH1, c.2062A>G (p.Lys688Glu).Patient is a 10-year-old male, born of consanguineous parents from the United Arab Emirates. Past medical history is notable for neonatal HSV encephalitis, grade 3 intraventricular hemorrhage, cerebral palsy, epilepsy, optic atrophy and recurrent HSV retinitis. Patient has no additional history of severe or recurrent infections. No family history of recurrent or severe infections, malignancy, autoimmunity or autoinflammation.Immune evaluation demonstrated anemia with elevated mean corpuscular volume and mild elevation of platelets and monocytes. Patient had normal lymphocyte subsets, normal T and B cell subset distributions, protective vaccine titers and normal immunoglobins apart from mildly elevated immunoglobulin G. An Invitae primary immunodeficiency panel demonstrated homozygous VUS in IFIH1, c.2062A>G (p.Lys688Glu). This variant is not found in gnomAD or ClinVar and has a Combined Annotation Dependent Depletion score of 22.6. Functional testing demonstrated decreased interferon induction after stimulation with intracellular RNA, intracellular DNA and agonists of both Toll-like receptor 7 and 9. These findings are consistent with MDA5 deficiency given decreased interferon response with known MDA5 agonists.In summary, we describe a patient with recurrent and severe infections with a DNA virus and no known infections with respiratory RNA viruses. Both DNA and RNA viruses produce long ds-RNA as replication intermediates, an MDA5 agonist. This patient highlights the anti-viral role of MDA5 for both DNA and RNA viruses.

Corneal epithelial scarring secondary to recurrent herpes simplex keratitis

Corneal epithelial scarring secondary to recurrent herpes simplex keratitis

Role of tear exosomes in the spread of herpes simplex virus type 1 in recurrent herpes simplex keratitis.

Herpes simplex keratitis (HSK) is the most common but serious infectious keratitis with high recurrence. It is predominantly caused by herpes simplex virus type 1 (HSV-1). The spread mechanism of HSV-1 in HSK is not entirely clear. Multiple publications indicate that exosomes participate in the intercellular communication process during viral infections. However, there is rare evidence that HSV-1 spreads in HSK by exosomal pathway. This study aims to investigate the relationship between the spread of HSV-1 and tear exosomes in recurrent HSK. Tear fluids collected from total 59 participants were included in this study. Tear exosomes were isolated by ultracentrifugation, then identified by silver staining and western blot. The size was determined by dynamic light scattering (DLS). The viral biomarkers were identified by western blot. The cellular uptake of exosomes was studied using labelled exosomes. Tear exosomes were indeed enriched in tear fluids. Collected exosomes own normal diameters consistent with related reports. The exosomal biomarkers existed in tear exosomes. Labelled exosomes were successfully taken up by human corneal epithelial cells (HCEC) in large numbers in a short time. After cellular uptake, HSK biomarkers were detectable by western blot in infected cells. Tear exosomes should be the latent sites of HSV-1 in recurrent HSK and might be involved in the spread of HSV-1. Besides, this study verifies HSV-1 genes can be indeed transferred between cells by exosomal pathway, providing new inspiration for the clinical intervention and treatment as well as the drug discovery of recurrent HSK.

An Adenovirus-Based Recombinant Herpes Simplex Virus 2 (HSV-2) Therapeutic Vaccine Is Highly Protective against Acute and Recurrent HSV-2 Disease in a Guinea Pig Model

Genital herpes (GH) has become one of the most common sexually transmitted diseases worldwide, and it is spreading rapidly in developing countries. Approximately 90% of GH cases are caused by HSV-2. Therapeutic HSV-2 vaccines are intended for people already infected with HSV-2 with the goal of reducing clinical recurrences and recurrent virus shedding. In our previous work, we evaluated recombinant adenovirus-based vaccines, including rAd-gD2ΔUL25, rAd-ΔUL25, and rAd-gD2, for their potency as prophylactic vaccines. In this study, we evaluated these three vaccines as therapeutic vaccines against acute and recurrent diseases in intravaginal challenged guinea pigs. Compared with the control groups, the recombinant vaccine rAd-gD2ΔUL25 induced a higher titer of the binding antibody, and rAd-gD2 + rAd-ΔUL25 induced a higher titer of the neutralizing antibody. Both rAd-gD2ΔUL25 and rAd-gD2 + rAd-ΔUL25 vaccines significantly enhanced the survival rate by 50% compared to rAd-gD2 and reduced viral replication in the genital tract and recurrent genital skin disease. Our findings provide a new perspective for HSV-2 therapeutic vaccine research and provide a new technique to curtail the increasing spread of HSV-2.

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&lt;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&lt;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.

The Pathogenesis of Oral Manifestations of COVID-19

The COVID-19 pandemic which causes the SARS-CoV-2 opens the way to more than thousand serious pathological conditions of various organs and systems, including those in the oral cavity. Objective: To perform a systematic analysis of scientific articles and identify the main pathogenetic factors of COVID-19 affected the oral cavity. The search was performed on the PubMed and Google Scholar platforms using the following strategy: "COVID-19" + "Oral cavity". All articles presented in the open access, published before 01/04/2022 in the format of Case Reports, Clinical Studies, Clinical Trial Protocols, Clinical Trials, Multicentre Studies were analysed. 135 publications were included in the study after exclusion, 33.518 cases were analysed. Damage to the teeth, tongue, hard palate and oral mucosa, dysgeusia, xerostomia and ageusia are the most common manifestations of COVID-19 (17.137 reported cases). Suggested mechanisms of dysgeusia in patients with COVID-19 include direct cytotoxic effects of the virus on ACE-2-expressing receptors, angiotensin II imbalance, and peripheral taste and olfactory neurotropism. Salivary glands with increased expression of ACE-2 are also a target for COVID-19, they progress to xerostomia with the development of dysgeusia. The primary lesion of the oral mucosa was manifested in the form of multiple erythema and oedema (29 cases). Ulcers happened due to mucosal bite caused by muscle contraction, irritation by a foreign object during intubation were shown to lead to the development of neoplasms from benign fibroma to an aggressive form of cancer, especially against the background of corticosteroids (3 cases). Vitamin D deficiency lead to a decrease in the density of the maxillofacial bone and serves as a factor for tooth migration and periodontitis. The addition of a secondary infection is observed in connection with the suppression of the immune system, both by the virus itself and by medications. Pseudomembranous candidiasis (3 cases), recurrent herpes simplex (3 cases), saccharomyces cerevisiae (2 cases) and others have been registered. The analysis demonstrated that damage of the oral cavity can occur both because of the direct action of COVID-19, and indirectly, through psycho-emotional stress, antibacterial drugs, co-infection, neglect of hygiene measures, vitamin D and zinc deficiency.

Primary Herpetic Gingivostomatitis.

An 82-year-old female presented with painful oral lesions associated with fever and dysphagia since 3 days. Examination revealed multiple grouped tender white to yellow plaques and few discrete vesicles on an erythematous base over the tongue and palate [Figure 1] with tender cervical lymphadenopathy. Tzanck smear from the vesicles showed multinucleate epidermal giant cells [Figure 2]. A diagnosis of primary herpetic gingivostomatitis was made and the lesions resolved following treatment with oral valacyclovir 1 g twice daily for 7 days [Figure 3]. Herpetic gingivostomatitis is typically caused by Herpes simplex virus type-1 (HSV-1), but cases caused by HSV-2 have also been reported. HSV-1 spreads by direct contact, via droplets, or by sexual contact. Primary herpetic gingivostomatitis usually presents with yellow to white plaques and vesicles which rupture and coalesce to form ulcers over the buccal mucosa, tongue, palate, gingiva, and the lips. Severe cases can have associated fever, malaise, myalgia, and local lymphadenopathy. Following the primary episode, the virus being neurotropic may become latent in the peripheral nerves and ganglions, with subsequent reactivations causing recurrent infections in around one-thirds of patients. Recurrent herpes simplex infections can present as localized vesicles commonly on the vermillion border of the lips, perioral skin, or the hard palate.[1] The diagnosis of herpes gingivostomatitis is primarily clinical. The differential diagnoses include aphthous stomatitis, oral candidiasis, herpangina, Behcet disease, erythema multiforme, Steven–Johnson syndrome, hand, foot and mouth disease and immunobullous disorders.[2] Tzanck smear from vesicles demonstrating viral cytopathic changes can support the diagnosis; however, it cannot distinguish between HSV-1, HSV-2, or varicella zoster virus. Crusted or ulcerative lesions are diagnosed by more accurate tests like direct fluorescent antibody test, polymerase chain reaction, and viral cultures. Serological tests are useful but not generally indicated for acute infections; also many people exposed to HSV may demonstrate asymptomatic seroconversion.[12]Figure 1: Multiple grouped tender white to yellow plaques and discrete vesicles on an erythematous base over the tongue and palateFigure 2: Tzanck smear showing multinucleate epidermal giant cellFigure 3: Complete resolution post treatmentMost cases of herpes gingivostomatitis are self-resolving, requiring only supportive measures. Severe cases may require systemic antiviral therapy – oral Acyclovir 15 mg/kg five times a day; or valacyclovir, 1g twice daily; or famciclovir, 500 mg twice daily; for 5 to 7 days. In case of frequent recurrences, prophylactic suppressive acyclovir (400 mg twice daily), valacyclovir (500 mg orally once daily), or famciclovir (250 mg twice daily) may be considered.[23] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

2125. Determinants of Placental Transfer of HSV-specific Antibodies and the Impact of SARS-CoV-2 Coinfection

Abstract Background Primary versus recurrent herpes simplex virus 1 or 2 (HSV-1 or HSV-2) infection during pregnancy carries a higher risk of neonatal herpes. Murine and clinical studies demonstrate that antibody dependent cellular cytotoxicity (ADCC) provides greater protection against disseminated neonatal disease. To quantify relative transfer of HSV specific Abs with different functions and targets and whether SARS-CoV-2 coinfection modified transfer, we conducted a prospective cohort study of mother-infant dyads prior to and during COVID-19. Methods Total and HSV lysate, glycoprotein D (gD) and glycoprotein B (gB)-specific IgG, IgG1 and IgG3, nAbs and ADCC were quantified in paired 3rd trimester maternal and cord blood. IgG1 and IgG3 subclass and gD or gB-specific Abs were isolated by column purification and glycan profiles were assessed using mass spectrometry. The pre-COVID study population included 21 term and 15 preterm dyads who were HSV seropositive and the pri-COVID cohort included 25 HSV seropositive term dyads whose mothers were also SARS-CoV-2 PCR and COVID Ab positive at delivery. Results HSV-specific Ab and neutralizing Ab transfer ratio (TR) were higher in term compared to preterm pre-COVID dyads (all p&amp;lt; 0.05), but the ADCC TR was &amp;lt; 1.0 for both groups. To determine if the low ADCC TR reflected antigenic target, subclass and/or glycans, we enriched for anti-gD and anti-gB specific and IgG1 and IgG3 Abs. The anti-gD Abs were exclusively IgG, had only neutralizing activity and had glycans associated with FcRn binding. In contrast, anti-gB Abs were both IgG1 and IgG3; had both neutralizing and ADCC activity and expressed glycans associated with both FcRn and FcγRIIIa binding. There was no significant difference in HSV-specific IgG TR in pre-COVID vs COVID dyads (0.42) but the nAb TR was lower (p=0.018) and ADCC TR higher (p&amp;lt; 0.001) in COVID compared to pre-COVID patients. Placental immunohistochemistry showed an increased colocalization of FcRn and FcγRIIIA in SARS-CoV-2 positive mothers, which would favor transfer of ADCC Abs. Conclusion Defining the determinants of ADCC transfer has implications for future vaccine and monoclonal Ab strategies to prevent/treat neonatal herpes. We speculate that increasing the transfer of ADCC may be a key element in providing immune protection Disclosures Betsy Herold, MD, Viracor (Eurofins): Advisor/Consultant|X-Vax, Technologies: Advisor/Consultant|X-Vax, Technologies: Grant/Research Support|X-Vax, Technologies: Serve on Scientific Advisory Board for X-Vax, Technologies and receiving reserach funding for related worl. Betsy Herold, MD, Viracor (Eurofins): Advisor/Consultant|X-Vax, Technologies: Advisor/Consultant|X-Vax, Technologies: Grant/Research Support|X-Vax, Technologies: Serve on Scientific Advisory Board for X-Vax, Technologies and receiving reserach funding for related worl.

PSAT327 Can Cannabis Use Lead to Central Hypothyroidism

Abstract Background Marijuana has been legalized for medical use in 36 states and for recreational use in 18 states. Its effects on thyroid function and hypothalamic-pituitary-thyroid axis in humans is not known. Clinical Case 72 years old male presented to his primary care physician with occasional difficulty swallowing. He reported fatigue for 4-5 years, trouble falling asleep for 2 months, weight gain 8 pounds over last few weeks, occasional diarrhea, and intermittent episodes of heat intolerance. His past medical history included controlled type 2 diabetes mellitus, recurrent herpes simplex infection, arthritis of hip joints, short-term memory loss, anemia, carpal tunnel syndrome and benign prostatic hyperplasia. Medications included glimepiride, lisinopril, acyclovir, tamsulosin, finasteride, escitalopram. He had been smoking marijuana regularly since he was a teenager. He denied using any other supplements. His physical exam was normal with stable vital signs and normal BMI. His labs showed a low TSH (0.096 mcIU/mL, n: 0.358-3.8 mcIU/mL), normal free T4 (0.90 ng/dL, n: 0.76-1.46 ng/dL), normal total T3 (70 ng/dL, n: 60-180 ng/dL). Review of his labs showed low TSH for last 4 years progressively getting worse with normal free T4 levels. TSH-receptor antibody and TPO Antibody level were negative. His white cell count, hemoglobin and platelets were normal. His electrolytes, kidney function and liver function tests were also normal. Thyroid Ultrasound showed 2 small sub-centimeter hypoechoic nodules in the left thyroid lobe. Two years ago, a radioactive Iodine scan showed normal iodine uptake. A recent radioactive iodine uptake scan showed generalized decreased iodine uptake with no evidence of graves’ disease or toxic multinodular goiter. Conclusion Currently there are no controlled studies on the effect of marijuana use on thyroid function in humans. A cross-sectional analysis using National Health and Nutrition Examination Survey (NHANES) from 2007 to 2012 showed recent marijuana use was significantly associated with lower levels of TSH but was not associated with thyroid dysfunction (1). This study suggests that marijuana use is associated with low TSH levels. This could be due to hypothalamic suppression of TSH or may indicate a protective role against hypothyroidism. Older studies in rodents showed that cannabis exposure may lead to suppression of TSH and hypothalamic function (2). The data related to human subjects is scarce. Therefore, pathophysiologic mechanisms are speculative, although animal data support potential mechanism of hypothalamic suppression.

Impact of the use of anti-glaucoma medications on the risk of herpetic keratitis recurrence.

Numerous case reports have associated anti-glaucoma medications with recurrence of herpes simplex virus (HSV) and herpes zoster virus (HZV) keratitis. The aim of our study was to determine whether different anti-glaucoma agents are associated with recurrence of herpetic keratitis. This was a retrospective cohort study using health databases from a Canadian province from January 2001 to December 2012. A new cohort of users on topical prostaglandins (PGs), beta blockers (BBs), alpha-2 agonists (AAs) and carbonic anhydrase inhibitors (CAIs) was created. The date of the third anti-glaucoma drug dispensation within 90days was deemed the index date of the case. Herpetic keratitis events, as defined by an ICD-9/10 code for HSV or HZV keratitis, or the dispensation of an anti-viral medication by either an ophthalmologist or an optometrist, were examined prior to and following the index date. Risk ratios (RRs) were computed to compare the risk of HSV/HZV keratitis among the PG, BB, AA, and CAI groups individually and collectively while adjusting for age and sex. Among 19,986 users of glaucoma medications identified, there were 684 cases of HSV/HZV keratitis. There was no increased risk of HSV/HZV keratitis recurrence for any of the four glaucoma medications classes individually or collectively when adjusted for age and sex. There was also no increased risk for redeveloping either HSV keratitis only or HZV keratitis only amongst all anti-glaucoma users. There is no association between the use of topical ocular hypotensive therapies and HSV/HZV keratitis recurrence. Further studies are needed to confirm these findings.