Herpes Simplex Virus Reactivation Research Articles

Changes In Leukocyte Distribution And T-cell Reactivity During Initial Military Training

PURPOSE: Physiological stressors present during initial military training (IMT) may increase risk of illness and infection by suppressing immune function. This study aimed to improve insight into those relationships by characterizing changes in markers of innate and adaptive immune function during IMT. METHODS: Sixty U.S. Army infantry recruits (97% male) provided fasted blood and saliva samples at the beginning (PRE; week 0) and end (POST; week 22) of IMT. Peripheral leukocyte distribution was measured by flow cytometry, and T-cell and innate cell reactivity were measured by mitogen (anti-CD3/CD28 or lipopolysaccharide (LPS))-stimulated cytokine profiles in 48-hr whole blood culture. Latent reactivation of Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and herpes simplex virus 1 (HSV1) was measured in saliva by qPCR. RESULTS: Lymphocyte percentage increased (+28%) while granulocytes (-15%) and monocytes (-13%) decreased PRE to POST (all P < 0.01). This lymphocytosis was driven by an increase in natural killer cells (+19%), and accompanied by decreases in B-cells (-9%) and T-cells (-5%; all P < 0.01). Within T-cell subsets, terminally differentiated CD4+ (+22%) and CD8+ (+30%) cells increased while those of effector memory CD4+ cells (-11%), effector memory CD8+ cells (-54%) and central memory CD8+ cells (-15%) decreased (all P ≤ 0.02). T-cell production of most measured cytokines following anti-CD3/CD28 stimulation increased from PRE to POST (P < 0.05). Conversely, stimulation with LPS resulted in reduced production of most measured cytokines (P < 0.05). Prevalence of EBV reactivation was higher POST (n=30) relative to PRE (n=19; P = 0.01), but neither VZV nor HSV1 reactivation was observed at either time point. CONCLUSION: Lymphocytosis, maturation of CD4+/CD8+ T-cell subsets, and heightened T-cell reactivity at POST collectively suggests an appropriate immune response to pathogen challenges during IMT. Though EBV reactivation was increased at POST, no evidence of VZV or HSV1 reactivation, which are more common during severe stress, was observed. Findings suggest that EBV reactivation during IMT was likely appropriately controlled in recruits and that immune-competence was relatively uncompromised at the end of IMT. Supported by USAMRDC. Authors’ views not official DoD or Army policy

33521 Two cases of oral baricitinib associated papular eruption on face

Background: Janus kinase (JAK) inhibitors reduce inflammation by interrupting JAK-STAT pathway and are used for various disease. However, cutaneous adverse effects including reactivation of herpes simplex virus, herpes zoster, disseminated molluscum contagiosum, and acneiform eruptions were reported. In addition, few cases of granulomatous inflammation after JAK inhibitor use have been reported recently. Methods: Patient 1, a 40-year-old woman, presented with erythematous papules on periorbital and perioral area for 13 months. She had been taking prednisolone and hydroxychloroquine for rheumatoid arthritis (RA) for 1 year, but symptoms were not controlled. Thus, oral baricitinib was administered. After 2 months, facial lesions appeared. Patient 2, a 64-year-old woman, presented with erythematous papules on face developed 2 weeks ago. She has been taking baricitinib for RA because of inadequate response to methotrexate. Facial eruption occurred 4 months after initiation of baricitinib. Results: For patient 1, histopathologic examination showed dense dermal infiltration of lymphocytes, histiocyte and few plasma cells, which implicated granulomatous dermatitis. Doxycycline and topical gentamycin/prednicarbate were given and the lesions showed response. Patient 2 showed improvement after treatment with doxycycline, topical metronidazole, and topical ivermectin. However, lesions aggravated 7 months after doxycycline cessation with continuous baricitinib use. Conclusion: Although JAK inhibitors are known to be effective for the treatment of granulomatous diseases like sarcoidosis, granulomatous drug eruption has been reported. In our cases, facial skin lesions appeared 2 and 4 months after starting baricitinib, respectively. Our cases imply that dermatologists should be aware of the potential association between JAK inhibitors and cutaneous eruption.

33521 Two cases of oral baricitinib associated papular eruption on face

Background: Janus kinase (JAK) inhibitors reduce inflammation by interrupting JAK-STAT pathway and are used for various disease. However, cutaneous adverse effects including reactivation of herpes simplex virus, herpes zoster, disseminated molluscum contagiosum, and acneiform eruptions were reported. In addition, few cases of granulomatous inflammation after JAK inhibitor use have been reported recently. Methods: Patient 1, a 40-year-old woman, presented with erythematous papules on periorbital and perioral area for 13 months. She had been taking prednisolone and hydroxychloroquine for rheumatoid arthritis (RA) for 1 year, but symptoms were not controlled. Thus, oral baricitinib was administered. After 2 months, facial lesions appeared. Patient 2, a 64-year-old woman, presented with erythematous papules on face developed 2 weeks ago. She has been taking baricitinib for RA because of inadequate response to methotrexate. Facial eruption occurred 4 months after initiation of baricitinib. Results: For patient 1, histopathologic examination showed dense dermal infiltration of lymphocytes, histiocyte and few plasma cells, which implicated granulomatous dermatitis. Doxycycline and topical gentamycin/prednicarbate were given and the lesions showed response. Patient 2 showed improvement after treatment with doxycycline, topical metronidazole, and topical ivermectin. However, lesions aggravated 7 months after doxycycline cessation with continuous baricitinib use. Conclusion: Although JAK inhibitors are known to be effective for the treatment of granulomatous diseases like sarcoidosis, granulomatous drug eruption has been reported. In our cases, facial skin lesions appeared 2 and 4 months after starting baricitinib, respectively. Our cases imply that dermatologists should be aware of the potential association between JAK inhibitors and cutaneous eruption.

A Human Stem Cell-Derived Neurosensory-Epithelial Circuitry on a Chip to Model Herpes Simplex Virus Reactivation.

Both emerging viruses and well-known viral pathogens endowed with neurotropism can either directly impair neuronal functions or induce physio-pathological changes by diffusing from the periphery through neurosensory–epithelial connections. However, developing a reliable and reproducible in vitro system modeling the connectivity between the different human sensory neurons and peripheral tissues is still a challenge and precludes the deepest comprehension of viral latency and reactivation at the cellular and molecular levels. This study shows a stable topographic neurosensory–epithelial connection on a chip using human stem cell-derived dorsal root ganglia (DRG) organoids. Bulk and single-cell transcriptomics showed that different combinations of key receptors for herpes simplex virus 1 (HSV-1) are expressed by each sensory neuronal cell type. This neuronal–epithelial circuitry enabled a detailed analysis of HSV infectivity, faithfully modeling its dynamics and cell type specificity. The reconstitution of an organized connectivity between human sensory neurons and keratinocytes into microfluidic chips provides a powerful in vitro platform for modeling viral latency and reactivation of human viral pathogens.

Clinical features of herpes simplex virus reactivation after microvascular decompression for trigeminal neuralgia: Experience of 200 patients and a literature review.

Background: Herpes simplex virus (HSV) reactivation occasionally develops in the early postoperative period after microvascular decompression (MVD) for trigeminal neuralgia (TN). Therefore, the present study investigated the clinical features of this phenomenon.Methods: The study cohort comprised 200 patients with 125 women aged between 17 and 90 years (median age, 66 years) who underwent MVD for TN between January 2010 and December 2020. Characteristics were compared between patients with and without HSV reactivation and clinical features were analyzed.Results: Twenty patients had HSV reactivation: herpes labialis in 18 and herpes zoster (final diagnosis) in 2. A multivariate analysis revealed independent correlations between postoperative HV reactivation and a previous history of herpes labialis (odds ratios [OR]: 6.32, P = 0.0003) and reoperation for recurrent or persistent pain (OR: 5.06, P = 0.0211). No significant differences were observed in pain relief, postoperative facial numbness, or Barrow Neurological Institute Pain Intensity/Facial Numbness Scores in the past follow-up between patients with and without HSV reactivation. HSV reactivation manifested at a median of the 4th postoperative day (1–10 days) and its location was not related to the preoperative distribution of facial pain. All patients were treated with local acyclovir and were completely cured within 1–2 weeks.Conclusion: HSV reactivation occurred in 10% of patients after MVD including 1% of herpes zoster. A previous history of herpes labialis and reoperation was identified as risk factors for reactivation. Symptoms were completely cured by antiviral drugs within 1–2 weeks. It is important to note that cases of herpes zoster may be confused with cases of HSV after MVD.

Herpes Simplex Virus 1 (HSV-1) Reactivation in Critically Ill COVID-19 Patients: A Brief Narrative Review.

Systemic or pulmonary reactivations of herpes simplex virus 1 (HSV-1) have been reported in critically ill patients with COVID-19, posing a dilemma for clinicians in terms of their diagnostic and clinical relevance. Prevalence of HSV-1 reactivation may be as high as > 40% in this population, but with large heterogeneity across studies, likely reflecting the different samples and/or cut-offs for defining reactivation. There is frequently agreement on the clinical significance of HSV-1 reactivation in the presence of severe manifestations clearly attributable to the virus. However, the clinical implications of HSV-1 reactivations in the absence of manifest signs and symptoms remain controversial. Our review aims at providing immunological background and at reviewing clinical findings on HSV-1 reactivations in critically ill patients with COVID-19.

Long-term time trends in reactivated herpes simplex infections and treatment in Sweden

BackgroundOur aim was to describe the annual prevalence of herpes simplex virus (HSV) reactivation in relation to solar ultraviolet (UV) radiation and antiviral drug use in the Swedish adult population.MethodsThe study comprised 2879 anti-HSV-1 immunoglobulin (Ig) G positive subjects from five different cohorts who had donated serum from 1988 to 2010. The sera were analyzed for anti-HSV IgM using enzyme-linked immunosorbent assay. Associations between the presence of anti-HSV IgM antibodies, the apolipoprotein E ε4 allele and the serum sampling year were assessed by logistic regression. Seasonality of anti-HSV IgM was evaluated in a UV radiation model.Data of antiviral drugs for the entire Swedish population were compiled from two different nationwide databases: the Swedish Prescribed Drug Register and the Swedish Association of the Pharmaceutical Industry.ResultsCross-sectional and longitudinal analyses indicated that the prevalence of anti-HSV IgM antibodies declined between 1988 and 2010 (odds ratio [OR] = 0.912, p < .001), while the total annual use of antiviral drugs in Sweden gradually increased from 1984 to 2017. Higher UV radiation was associated with higher prevalence of anti-HSV IgM antibodies (OR = 1.071, p = .043).ConclusionThe declining time trend of HSV reactivation in a Swedish cohort coincides with a steady increase of antiviral drug use in the Swedish general population.

Clinical Response Difference between Acyclovir and Valacyclovir in Recurrent Intraoral Herpes: Adaptation Treatment in Pandemic Situation

Abstract: Recurrent intraoral herpes (RIH) is a reactivation of herpes simplex virus 1 (HSV 1) and is treated with an antiviral. In this pandemic situation, limited access to health care may lead to many consequences. This case report reports the difference in clinical response between acyclovir and valacyclovir in RIH and treatment in the pandemic situation. A 24 years old man complained of ulcers and pain in the mouth in the last two weeks. The patient had a history of recurrent ulcers since a year ago. Intraoral examination showed multiple ulcers, with erythema halo, 0.2-0.3 cm in diameters on the tongue, uvula, and pharynx. The patient had difficulty in eating. The IgG anti-HSV 1 test showed a positive result, and the lesions were diagnosed as RIH. The patient was treated with acyclovir, benzylamine HCl, and vitamin B12. One month after treatment, the lesions improved, but new lesions still emerged. Therefore, valacyclovir was substituted for acyclovir. Since the patient had difficulty in going to the hospital due to the lockdown policy, medication for two weeks was prescribed for him. One month after treatment with valacyclovir, there was no more new lesion emerging. In conclusion, there was a difference in clinical response between acyclovir and valacyclovir. It is assumed that the patient has resistancy to acyclovir which resulting in poor improvement. The pandemic condition forces us to be flexible in handling patients and adapting to government conditions and rules.Keywords: recurrent intraoral herpes; acyclovir; valacyclovir

DLK-Dependent Biphasic Reactivation of Herpes Simplex Virus Latency Established in the Absence of Antivirals.

Understanding the molecular mechanisms of herpes simplex virus 1 (HSV-1) latent infection and reactivation in neurons requires the use of in vitro model systems. Establishing a quiescent infection in cultured neurons is problematic, as any infectious virus released can superinfect the cultures. Previous studies have used the viral DNA replication inhibitor acyclovir to prevent superinfection and promote latency establishment. Data from these previous models have shown that reactivation is biphasic, with an initial phase I expression of all classes of lytic genes, which occurs independently of histone demethylase activity and viral DNA replication but is dependent on the cell stress protein DLK. Here, we describe a new model system using HSV-1 Stayput-GFP, a reporter virus that is defective for cell-to-cell spread and establishes latent infections without the need for acyclovir. The establishment of a latent state requires a longer time frame than previous models using DNA replication inhibitors. This results in a decreased ability of the virus to reactivate using established inducers, and as such, a combination of reactivation triggers is required. Using this system, we demonstrate that biphasic reactivation occurs even when latency is established in the absence of acyclovir. Importantly, phase I lytic gene expression still occurs in a histone demethylase and viral DNA replication-independent manner and requires DLK activity. These data demonstrate that the two waves of viral gene expression following HSV-1 reactivation are independent of secondary infection and not unique to systems that require acyclovir to promote latency establishment. IMPORTANCE Herpes simplex virus-1 (HSV-1) enters a latent infection in neurons and periodically reactivates. Reactivation manifests as a variety of clinical symptoms. Studying latency and reactivation in vitro is invaluable, allowing the molecular mechanisms behind both processes to be targeted by therapeutics that reduce the clinical consequences. Here, we describe a novel in vitro model system using a cell-to-cell spread-defective HSV-1, known as Stayput-GFP, which allows for the study of latency and reactivation at the single neuron level. We anticipate this new model system will be an incredibly valuable tool for studying the establishment and reactivation of HSV-1 latent infection in vitro. Using this model, we find that initial reactivation events are dependent on cellular stress kinase DLK but independent of histone demethylase activity and viral DNA replication. Our data therefore further validate the essential role of DLK in mediating a wave of lytic gene expression unique to reactivation.

Ex Vivo Herpes Simplex Virus Reactivation Involves a Dual Leucine Zipper Kinase-Dependent Wave of Lytic Gene Expression That Is Independent of Histone Demethylase Activity and Viral Genome Synthesis.

Herpes simplex virus 1 (HSV-1) maintains a lifelong latent infection in neurons and periodically reactivates, resulting in the production of infectious virus. The exact cellular pathways that induce reactivation are not understood. In primary neuronal models of HSV latency, the cellular protein dual leucine zipper kinase (DLK) has been found to initiate a wave of viral gene expression known as phase I. Phase I occurs independently of both viral DNA replication and the activities of histone demethylase enzymes required to remove repressive heterochromatin modifications associated with the viral genome. In this study, we investigated whether phase I-like gene expression occurs in ganglia reactivated from infected mice. Using the combined trigger of explant-induced axotomy and inhibition of phosphatidylinositide 3-kinase (PI3K) signaling, we found that HSV lytic gene expression was induced rapidly from both sensory and sympathetic neurons. Ex vivo reactivation involved a wave of viral late gene expression that occurred independently of viral genome synthesis and histone demethylase activity and preceded the detection of infectious virus. Importantly, we found that DLK was required for the initial induction of lytic gene expression. These data confirm the essential role of DLK in inducing HSV-1 gene expression from the heterochromatin-associated genome and further demonstrate that HSV-1 gene expression during reactivation occurs via mechanisms that are distinct from lytic replication. IMPORTANCE Reactivation of herpes simplex virus from a latent infection is associated with clinical disease. To develop new therapeutics that prevent reactivation, it is important to understand how viral gene expression initiates following a reactivation stimulus. Dual leucine zipper kinase (DLK) is a cellular protein that has previously been found to be required for HSV reactivation from sympathetic neurons in vitro. Here, we show that DLK is essential for reactivation from sensory ganglia isolated from infected mice. Furthermore, we show that DLK-dependent gene expression ex vivo occurs via mechanisms that are distinct from production replication, namely, lytic gene expression that is independent of viral DNA replication and histone demethylase activity. The identification of a DLK-dependent wave of lytic gene expression from sensory ganglia will ultimately permit the development of novel therapeutics that target lytic gene expression and prevent the earliest stage of reactivation.

Reply to: correspondence on “Herpes Zoster and Simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis​”

Reply to: correspondence on “Herpes Zoster and Simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis​”

Monocyte Signature Associated with Herpes Simplex Virus Reactivation and Neurological Recovery after Brain Injury.

Rationale: Brain injury induces systemic immunosuppression, increasing the risk of viral reactivations and altering neurological recovery. Objectives: To determine if systemic immune alterations and lung replication of herpesviridae are associated and can help predict outcomes after brain injury. Methods: We collected peripheral blood mononuclear cells in patients with severe brain injury requiring invasive mechanical ventilation. We systematically searched for respiratory herpes simplex virus (HSV) replications in tracheal aspirates. We also performed chromatin immunoprecipitation sequencing, RNA-sequencing, and invitro functional assays of monocytes and CD4 T cells collected on Day 1 to characterize the immune response to severe acute brain injury. The primary outcome was the Glasgow Outcome Scale Extended at 6 months. Measurements and Main Results: In 344 patients with severe brain injury, lung HSV reactivations were observed in 39% of the 232 patients seropositive for HSV and independently associated with poor neurological recovery at 6 months (hazard ratio, 1.90; 95% confidence interval, 1.08-3.57). Weighted gene coexpression network analyses of the transcriptomic response of monocytes to brain injury defined a module of 721 genes, including PD-L1 and CD80, enriched for the binding DNA motif of the transcriptional factor Zeb2 and whose ontogenic analyses revealed decreased IFN-γ-mediated and antiviral response signaling pathways. This monocyte signature was preserved in a validation cohort and predicted the neurological outcome at 6 months with good accuracy (area under the curve, 0.786; 95% confidence interval, 0.593-0.978). Conclusions: A specific monocyte signature is associated with HSV reactivation and predicts poor recovery after brain injury. The alterations of the immune control of herpesviridae replication are understudied and represent a novel therapeutic target.

Incidence and Outcome of Patients with Cardiogenic Shock and Detection of Herpes Simplex Virus in the Lower Respiratory Tract.

(1) Herpes simplex virus (HSV) reactivation in critically ill patients can cause infection in the lower respiratory tract, prolonging mechanical ventilation. However, the association of HSV reactivation with cardiogenic shock (CS) is unclear. As CS is often accompanied by pulmonary congestion and reduced immune system activity, the aim of our study was to determine the incidence and outcome of HSV reactivation in these patients. (2) In this retrospective, single-center study, bronchial lavage (BL) was performed on 181 out of 837 CS patients with mechanical ventilation. (3) In 44 of those patients, HSV was detected with a median time interval of 11 days since intubation. The occurrence of HSV was associated with an increase in C-reactive protein and the fraction of inspired oxygen at the time of HSV detection. Arterial hypertension, bilirubin on ICU admission, the duration of mechanical ventilation and out-of-hospital cardiac arrest were associated with HSV reactivation. (4) HSV reactivation could be detected in 24.3% of patients with CS on whom BL was performed, and its occurrence should be considered in patients with prolonged mechanical ventilation. Due to the limited current evidence, the initiation of treatment for these patients remains an individual choice. Dedicated randomized studies are necessary to investigate the efficacy of antiviral therapy.

Herpes simplex factors: Literature review

Herpes simplex virus, after the first infection, can remain dormant in the lymph nodes and reactivate at any time due to certain factors and/or stimuli causing effects in the patient. The purpose of this literature review is to update scientific information on the factors that predispose to the reactivation of herpes simplex virus. A comprehensive literature review was conducted in the LILACS, SciELO, PubMed, Scopus and the following keywords were used: herpes simplex, reactivation, latency and risks. A factor is reactivation by immunosuppression due to the intake of immunosuppressants or oncological therapy. Another factor is psychological stress, in which the hormones released act on mediating signs of reactivation. Sun exposure that reactivates the virus in infected neurons and infection in pregnant women can trigger complications in the fetus and delivery.

Viral exanthem following influenza vaccine

Abstract Introduction: Influenza vaccination (flu vaccine) is associated with some musculoskeletal and neurological complications despite its wide use and significant safety profile. Skin is one of the most common systems for drug reactions and side effects. Skin rashes such as bullous eruptions and vasculitis have been reported, but viral exanthem are seldom reported in association with the influenza vaccine. In particular, herpes simplex virus-2 reactivation and myelitis following influenza vaccination manifesting as severe herpes simplex virus type 2 and associated with blisters on the back of a single patient have been reported before. However, data on the rate of such complications are scarce in the literature. Patient concerns: A young woman complained of an unusual presentation of eruptive vesicular skin lesions following influenza vaccination complicated by allergic contact dermatitis to lemon soap applied to the lesions. Diagnosis: Viral exanthem were diagnosed based on clinical presentation and supported by a skin biopsy. Interventions: Medical treatment with antiviral and corticosteroids. Outcomes: The patient had a favorable outcome. Conclusion: Dermatologists should be vigilant to the association with any new medications and skin lesions, observe the progression of the lesions, and revisit the medical history to establish the correct relationships for any possible new causative agent to an evolving or new developing lesion.

Risk factors of herpes simplex virus reactivation after surgery for primary trigeminal neuralgia

The objective of this study is to investigate the risk factors of oral or facial herpes simplex virus (HSV-1) infection after primary trigeminal neuralgia (PTN). The clinical data of 33 PTN patients admitted by the same surgeon in the neurosurgery were retrospectively analyzed. Among the 33 patients, 26 patients underwent microvascular decompression (MVD), 6 patients who have not been found the clear offending vessels during the operation underwent partial sensory rhizotomy (PSR), and only one underwent adhesive band separation. Thirteen patients with postoperative oral and facial HSV-1 infection were selected as the herpes group, and the remaining 20 patients without postoperative oral and facial HSV-1 infection were selected as the non-herpes group. The differences between the two groups were compared by statistical analysis of factors such as gender, age, operation mode, operation time, and serum HSV-1 antibody titer value before surgery. Compared with the non-herpes group, there were no statistically significant differences in sex ratio (P = 0.930), age composition (P = 0.261), or disease profile (P = 0.226). Twenty-six patients underwent MVD operation, eight of whom were infected, and the difference between the two groups was statistically significant (P = 0.029). The operation time of the herpes group was 10-30min, which was significantly longer than that of the non-herpes group. The difference in operation time between the two groups was statistically significant (P = 0.023). Serum HSV-1-IgM was negative (< 0.9 COI) in all patients before surgery, but the positive rate of HSV-1-IgG (≥ 1.1 COI) was 97%, and the titer was greater than four times in 97% (32/33) of patients. The titer of IgG antibody in the herpes group was significantly lower than that in the non-herpes group, and the difference between the two groups was statistically significant (P = 0.017). The serum HSV-1-IgG in most of the PTN patients was positive. Latent HSV-1 in the trigeminal ganglion may be reactivate after PTN surgery to produce ipsilateral oral and facial herpes infection. The infection of HSV-1 reactivation after PTN surgery was positively correlated with the operation time but negatively correlated with the titer of HSV-1-IgG antibody before PTN surgery. The incidence of HSV-1 infection after PTN operation is related to different surgical procedures.

Reactivation of CMV and HSV-1 Among Severe COVID-19 Patients May be Triggered by Increased Level of Pulmonary Dioxin

PurposeReactivation of cytomegalovirus (CMV) infection was recently found to influence worse clinical outcome following SARS-CoV-2 infection (doi: 10.1186/s12979-020-00185-x). Other findings showed that CMV and herpes simplex virus 1 (HSV-1) reactivations are observed in patients with COVID-19 acute respiratory distress syndrome (ARDS) (HYPERLINK "https://doi.org/10.1186/s13054-020-03252-3" doi.org/10.1186/s13054-020-03252-3). Addressing occurrence of Herpesviridae reactivation in immunocompetent patients and still unspecified triggers of reactivation, we tested potent xenobiotic 2,3,7,8-tetrachrolodibenzo-p-dioxin (TCDD), which current body burden (DBB) ranges from 20 pg/g (TEQ in fat) in general population to 100 pg/g in older people.Methods & MaterialsIn silico quantitation of active dioxin response enhancers (DRE) in promoters of viral genes. Plaque assay of viral titer. Virus DNA hybridization assay. Clinico-epidemiological analysis.ResultsIn silico analysis revealed in regulatory region of CMV IE genes from 5 to 10 DRE, and from 6 to 8 DRE in regulatory region of HSV-1 IE genes. We established that a picomolar TCDD can trigger up-regulation of CMV and HSV-1 genes via AhR:Arnt transcription factor in macrophage (doi.org/10.1016/j.ijid.2012.05.265) and glial human cell lines (doi.org/10.1016/j.jalz.2016.06.1268), respectively. In fact, viral reactivation may be triggered in COVID-19 ARDS patients by higher pulmonary TCDD concentrations, as lipid storm within lungs of severe COVID-19 patients has been recently reported (doi.org/10.1101/2020.12.04.20242115). Due to hydrophobic character (Log PO/W: 7.05), TCDD partitions into inflammatory lipids in lung tissue thus augmenting its local concentration. Population-based epidemiological data on SARS-CoV-2 first wave of pandemic showed that picomolar TCDD can reactivate CMV (measured by high CMV seropositivity), as cumulative mortality rate 4.5 times was revealed in Lombardi region of Italy where after Seveso industrial accident TCDD plasma level in pre-exposed subjects still is 15 times the level in rest of Italy (doi.org/10.3389/fpubh.2020.620416). Also, Arctic Native (AN) peoples have TCDD body burden 7 times that in general population, as they consume dioxin-contaminated fat in seafood, and their COVID-19 mortality is 2.2 times of that among non-AN Alaskans (doi: 10.15585/mmwr.mm6949a3).ConclusionTCDD in picomolar range may trigger CMV expression in lung cells and commit virus to the lytic cycle, which can be applied to reactivation of Herpesviridae infection in immunocompetent patients with COVID-19 ARDS syndrome.

Herpes zoster and simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis

ABSTRACT Background A few cases of Herpes Zoster and Simplex reactivation following COVID-19 immunization have been recently described, but the real extent of this suspected adverse event has not been elucidated yet. Methods We performed a nested case/control study by using the U.S. Vaccine Adverse Event Reporting System database. We carried out a case-level clinical review of all Herpes reactivation cases following the administration of COVID-19 vaccines. For cases and controls, significance was set at P = 0.05, differential risk of reporting was assessed for each vaccine as reporting odds ratio and incidence was estimated based on the total number of vaccine doses administered. Results Of 6,195 cases included in the analysis (5,934 and 273 reporting Herpes Zoster and Herpes Simplex, respectively) over 90% were non-serious. We found a slightly higher risk of reporting both for Zoster (ROR = 1.49) and Simplex (ROR = 1.51) infections following the Pfizer-BioNTech vaccine. The estimated incidence was approximately 0.7/100,000 and 0.03/100,000 for Zoster and Simplex, respectively. Conclusions The paucity of cases (almost all of non-serious nature) makes the potential occurrence of this adverse effect negligible from clinical standpoints, thus supporting the good safety profile of the COVID-19 vaccination, which remains strongly recommended.

Herpes simplex virus reactivation in patients with COVID-19 and acute respiratory distress syndrome: a prospective cohort study

Background There is a paucity of data about the occurrence and risk factors of herpes simplex virus (HSV) reactivation among patients with severe COVID-19 presenting with acute respiratory distress syndrome (ARDS). Methods We performed a nested case-control study among a cohort of SARS-CoV-2 infected patients with ARDS. Between March and April 2020, all consecutive mechanically ventilated patients ≥18 years old with a positive PCR for SARS-CoV-2 on mucocutaneous samples were included in the study. We collected data on demographics, medical history, laboratory variables, administration of antivirals and other agents, respiratory and organ support procedures, microbiological results, and management of ARDS with prone positioning and the use of steroids. Univariate and multivariable Cox regression models were performed in order to identify predictors of HSV reactivation. Results Eighty-three patients with laboratory-confirmed SARS-CoV-2 infection were admitted to the ICU for mechanical ventilation. 18/83 (21.7%) patients developed mucocutaneous herpes simplex virus reactivation after a median of 17 days (IQR, 14–20). Prone positioning was the only independent risk factor for HSV reactivation (adj. hazard ratios, 1.60; 95% CI, 1.11–2.30; P = 0.009). All patients with mucocutaneous HSV reactivation were treated with antivirals. The outcome in terms of ventilator-associated pneumonia, catheter-related bloodstream infections, and in-hospital mortality was similar for patients with and without HSV reactivation. Conclusions HSV reactivation is frequent in COVID-19 patients with ARDS, especially if prolonged invasive mechanical ventilation with prone positioning is needed. Prompt testing for HSV and initiation of antiviral therapy should be performed in case of mucocutaneous lesions in this population.

Viral Ventilator-Associated Pneumonia/Hospital-Acquired Pneumonia.

Among the viruses possibly responsible for hospital-acquired and ventilator-associated pneumonia, herpes simplex virus (HSV) is probably the most often involved: HSV reactivation is frequent in intensive care unit patients, and lung parenchymal infection (HSV bronchopneumonitis) has been well described, either using cytological signs of parenchymal involvement in cells obtained during bronchoalveolar lavage or using HSV virus load in the lower respiratory tract. Although treating patients with HSV bronchopneumonitis may be recommended, based on expert opinion, prophylactic or preemptive treatment of HSV reactivation should be avoided. Ventilator-associated pneumonia due to cytomegalovirus (CMV) is less frequent than HSV bronchopneumonitis, and more difficult to diagnose. No data exists on the impact of antiviral treatment on CMV pneumonia. The involvement of respiratory viruses has been described in patients with healthcare-associated pneumonia and hospital-acquired pneumonia, but their role in ventilator-associated pneumonia is not clear.