Varicella Zoster Virus Disease Research Articles

Varicella-Zoster Virus Pretransplant Vaccination and Posttransplant Infections Among Pediatric Solid Organ Recipients in the Two-Dose Varicella Era: A Single-Center, Multi-Organ Retrospective Study.

Varicella-zoster virus (VZV) pretransplant immunization rates, exposures, and posttransplant disease are poorly characterized among pediatric solid organ transplant (SOT) recipients in the two-dose varicella vaccine era. A retrospective analysis of the electronic health records among children <18 years old who received SOT from January 1, 2011 through December 31, 2021, was performed at a single center to assess for missed pretransplant varicella vaccination opportunities, characterize VZV exposures, and describe posttransplant disease. Among 525 children, 444 were ≥6 months old (m.o.) at SOT with a documented VZV vaccine status. Eighty-five (19%) did not receive VZV Dose One; 30 out of 85 (35%) could have been immunized. Infants 6-11 m.o. accounted for 14 out of 30 (47%) missed opportunities. Among children ≥12 m.o. with documented Dose Two status (n = 383), 72 had missed vaccination opportunities; 57 out of 72 (79%) were children 1-4 years old. Most children had unclassifiable pre-SOT serostatus as varicella serology was either not obtained/documented (n = 171) or the possibility of passive antibodies was not excluded (n = 137). Of those with classified serology (n = 188), 69 were seroimmune. Forty-seven of 525 (9%) children had recorded VZV exposures; two developed varicella-neither had documented pre-SOT seroimmunity nor had received post-exposure prophylaxis. Nine additional children had medically attended disease: four primary varicella and five zoster. Of the 11 cases, 10 had cutaneous lesions without invasive disease; one had multi-dermatomal zoster with transaminitis. Seven (64%) received treatment exclusively outpatient. VZV exposure and disease still occur. Optimizing immunization among eligible candidates and ensuring patients have a defined VZV serostatus pretransplantation remain goals of care.

Exploring the Link between Varicella-Zoster Virus, Autoimmune Diseases, and the Role of Recombinant Zoster Vaccine.

The varicella-zoster virus (VZV) is a human neurotropic herpes virus responsible for varicella and herpes zoster (HZ). Following primary infection in childhood, VZV manifests as varicella (chickenpox) and enters a period of latency within the dorsal root ganglion. A compromised cellular immune response due to aging or immunosuppression triggers viral reactivation and the development of HZ (shingles). Patients with autoimmune diseases have a higher risk of developing HZ owing to the immunodeficiency associated with the disease itself and/or the use of immunosuppressive agents. The introduction of new immunosuppressive agents with unique mechanisms has expanded the treatment options for autoimmune diseases but has also increased the risk of HZ. Specifically, Janus kinase (JAK) inhibitors and anifrolumab have raised concerns regarding HZ. Despite treatment advances, a substantial number of patients suffer from complications such as postherpetic neuralgia for prolonged periods. The adjuvanted recombinant zoster vaccine (RZV) is considered safe and effective even in immunocompromised patients. The widespread adoption of RZV may reduce the health and socioeconomic burdens of HZ patients. This review covers the link between VZV and autoimmune diseases, assesses the risk of HZ associated with immunosuppressant use, and discusses the benefits and risks of using RZV in patients with autoimmune diseases.

Varicella zoster virus-induced autophagy in human neuronal and hematopoietic cells exerts antiviral activity.

Autophagy is a degradational pathway with pivotal roles in cellular homeostasis and survival, including protection of neurons in the central nervous system (CNS). The significance of autophagy as antiviral defense mechanism is recognized and some viruses hijack and modulate this process to their advantage in certain cell types. Here, we present data demonstrating that the human neurotropic herpesvirus varicella zoster virus (VZV) induces autophagy in human SH-SY5Y neuronal cells, in which the pathway exerts antiviral activity. Productively VZV-infected SH-SY5Y cells showed increased LC3-I-LC3-II conversion as well as co-localization of the viral glycoprotein E and the autophagy receptor p62. The activation of autophagy was dependent on a functional viral genome. Interestingly, inducers of autophagy reduced viral transcription, whereas inhibition of autophagy increased viral transcript expression. Finally, the genotype of patients with severe ocular and brain VZV infection were analyzed to identify potential autophagy-associated inborn errors of immunity. Two patients expressing genetic variants in the autophagy genes ULK1 and MAP1LC3B2, respectively, were identified. Notably, cells of both patients showed reduced autophagy, alongside enhanced viral replication and death of VZV-infected cells. In conclusion, these results demonstrate a neuro-protective role for autophagy in the context of VZV infection and suggest that failure to mount an autophagy response is a potential predisposing factor for development of severe VZV disease.

Management of a major varicella zoster exposure in a pediatric oncology population

Management of the exposure of pediatric oncology patients to varicella zoster virus (VZV) is controversial. We report the exposure of 56 patients to a single child with chicken pox at a pediatric cancer housing facility and describe our strategic approach for their management. We reviewed the immune and clinical status of 56 children with cancer receiving ongoing treatment at Memorial Sloan Kettering Cancer Center (MSK) who, while living at a pediatric cancer housing facility, were exposed to the index patient. The management of patients exposed included: (1) determination of immune status, (2) availability of vaccination history or VZV disease prophylaxis, (3) exposure status and subsequent isolation during the period of incubation, and (4) VZV disease prophylaxis. In addition to the 56 patients exposed to the index case, eight children with cancer treated at other facilities and 11 healthy siblings living in the facility were exposed. Of the 56 MSK patients, 21 were classified as immunosuppressed and received varicella zoster immune globulin (human), intravenous standard immune globulin, or acyclovir based on serostatus and immune function. The cohort was followed for 4 weeks after the exposure and no secondary infections were diagnosed. We performed a risk assessment and created a management plan to control and prevent further exposure and development of disease. No secondary cases developed. This strategic approach could serve as a model for the management of VZV exposure for other pediatric oncology centers.

Impaired STING Activation Due to a Variant in the E3 Ubiquitin Ligase AMFR in a Patient with Severe VZV Infection and Hemophagocytic Lymphohistiocytosis

Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, causing two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, VZV can give rise to more severe clinical manifestations, including disseminated infection, pneumonitis, encephalitis, and vasculopathy with stroke. Here, we describe a 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, hemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. Hemophagocytic lymphohistiocytosis (HLH) was strongly suspected and as the condition deteriorated, HLH therapy was initiated. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy. We found that the patient carries a rare monoallelic variant in autocrine motility factor receptor (AMFR), encoding a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase–stimulator of IFN genes (cGAS-STING) pathway. Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-β reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans. In conclusion, we describe a novel genetic etiology of severe VZV disease in childhood, also representing the first inborn error of immunity related to a defect in the cGAS-STING pathway.

Prodrug Strategies for the Development of β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU) against Varicella Zoster Virus (VZV).

Varicella zoster virus (VZV) establishes lifelong infection after primary disease and can reactivate. Several drugs are approved to treat VZV diseases, but new antivirals with greater potency are needed. Previously, we identified β-l-5-((E)-2-bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU, 1), which had significant anti-VZV activity. In this communication, we report the synthesis and evaluation of numerous l-BHDU prodrugs: amino acid esters (14-26), phosphoramidates (33-34), long-chain lipids (ODE-l-BHDU-MP, 38, and HDP-l-BHDU-MP, 39), and phosphate ester prodrugs (POM-l-BHDU-MP, 41, and POC-l-BHDU-MP, 47). The amino acid ester l-BHDU prodrugs (l-phenylalanine, 16, and l-valine, 17) had a potent antiviral activity with EC50 values of 0.028 and 0.030 μM, respectively. The phosphate ester prodrugs POM-l-BHDU-MP and POC-l-BHDU-MP had a significant anti-VZV activity with EC50 values of 0.035 and 0.034 μM, respectively, and no cellular toxicity (CC50 > 100 μM) was detected. Out of these prodrugs, ODE-l-BHDU-MP (38) and POM-l-BHDU-MP (41) were selected for further evaluation in future studies.

CLINICAL FEATURES, COMPLICATIONS AND TREATMENT RESULTS OF VARICELLA ZOSTER VIRUS IN BACHMAI HOSPITAL

Objectives: Describing clinical features, complications and evaluation of treatment results caused by Varicella Zoster Virus (VZV) at Bachmai Hospital from January 1, 2018 to December 31 2019. &#x0D; Subjects and methods: retrospective study. 67 patients Admitted at Bachmai Hospital, having realtime PCR - VZV with positive test result and VZV - IGM positive diagnostic serum test. &#x0D; Results: Among 67 cases of VZV disease, the majority were females, accounting for 61.2%, the median age was 29 years old, 56.7% had background disease, of which 16.4% of systemic lupus erythematosus, 4.5% cancer. There are 64.2% of cases remember not being vaccinated. Only 3.0% remember having had chickenpox before. The disease caused by VZV is clinically diverse, 70.1% (47 cases) showed chickenpox disease, 25.37% (17 cases) showed water burn injury in the shingles scene and 4.5 % (3 cases) showed meningitis with no burn lesions on the skin. Uncomplicated chickenpox 29.8%, complications of chickenpox commonly encountered dermatitis and soft tissue 19.4%, complications of meningitis combined with cord paralysis 7 or common in shingles scene. As a result of treatment, 86.6% (58 cases) had no sequelae, 3.0% (2 cases) had no sequelae of consciousness disorder, and up to 10.4% (7 cases). Consolidation) serious request for return, death is recorded. &#x0D; Conclusion: Disease caused by VZV in people with underlying systemic lupus erythematosus, cancer or pregnant women. The clinical picture is diverse, has many complications on the research group and high mortality.

#71 Post-Exposure Prophylaxis for Varicella-Zoster Virus Exposure in High-Risk Children

Abstract Background Despite universal childhood vaccination, Varicella-Zoster virus (VZV) remains a cause of severe infection following varicella exposure for immunocompromised children and high-risk infants. Post-exposure prophylaxis (PEP) is recommended to minimize this risk; however, providers may not consistently administer Varicella-specific immune globulin (VariZIG) as recommended in guidelines or may choose alternative regimens. The purpose of this study was to determine patterns of PEP for Varicella-Zoster Virus (VZV) at children’s hospitals. Method Using the Pediatric Health Information Systems database, clinical encounters with the ICD-9/10 codes for VZV exposure from 2009-2019 were reviewed. Only the first VZV exposure encounter for a given patient in the study period was included. Patients receiving prophylaxis or intravenous immunoglobulin (IVIG) within 30 days of the index encounter were also excluded. Presence of chronic illness or conditions at risk of progression to severe varicella disease was identified by reviewing ICD-9/10 codes for encounters in the prior 12 months. Choice and timing of PEP regimen exposure were identified, classified into the following categories: VZIG, intravenous immunoglobulin (IVIG), acyclovir, or combination prophylaxis. Clinical encounters for subsequent varicella disease within 30 days of exposure were recorded. Results There were 1770 children with first clinical encounters for VZV during the study period of which, 66 were excluded due to recent prior receipt of anti-viral therapy or IVIG. Of these 1704 children, 509 (29.9%) were prescribed PEP after VZV exposure, while 65 (3.8%) ultimately developed VZV disease. Of patients who received PEP, acyclovir was most frequently prescribed (n=195, 38.3%), divided between administration between1-4 days (n=132), 5-10 days (n=19), and both time periods (n=44), post-exposure. The proportion who received the other regimens was VariZIG (n=146, 28.7%), IVIG (n=115, 22.6%), and combination therapy (n=53, 10.4%). From 2009-2019, the proportion of children receiving acyclovir declined from 56% to 36%, VariZIG increased from 10 to 15%, IVIG decreased from 32 to 7%, while a similar percentage (8-9%) received a combination of Acyclovir and IG. The proportion of patients who subsequently had clinical encounters for varicella disease was highest for Acyclovir (30/195, 15.4%) followed by VariZIG (5/146, 3.4%), combination therapy (2/53, 3.8%), and IVIG alone (0/115). (p&amp;lt;0.0001). Of the 65 patients that developed VZV disease, 24/65 (36.9%) had at least one high-risk condition. Conclusion Varicella PEP in high-risk children was highly varied among children’s hospitals and often diverged from guideline recommendations. Use of acyclovir was associated with a higher rate of breakthrough infection. More consistent use of guideline-recommended agents like VariZIG may lead to less varicella disease and complications in high-risk children.

Simian Varicella Virus Pathogenesis in Skin during Varicella and Zoster.

Primary simian varicella virus (SVV) infection and reactivation in nonhuman primates is a valuable animal model in the study of varicella zoster virus disease [varicella (chickenpox) and herpes zoster (shingles)]. To understand SVV pathogenesis in skin, we inoculated 10 rhesus macaques with SVV, resulting in varicella rash. After the establishment of latency, eight of the monkeys were immunosuppressed using tacrolimus with or without irradiation and prednisone and two monkeys were not immunosuppressed. Zoster rash developed in all immunosuppressed monkeys and in one non-immunosuppressed monkey. Five monkeys had recurrent zoster. During varicella and zoster, SVV DNA in skin scrapings ranged from 50 to 107 copies/100 ng of total DNA and 2–127 copies/100 ng of total DNA, respectively. Detection of SVV DNA in blood during varicella was more frequent and abundant compared to that of zoster. During varicella and zoster, SVV antigens colocalized with neurons expressing β-III tubulin in epidermis, hair follicles, and sweat glands, suggesting axonal transport of the virus. Together, we have demonstrated that both SVV DNA and antigens can be detected in skin lesions during varicella and zoster, providing the basis for further studies on SVV skin pathogenesis, including immune responses and mechanisms of peripheral spread.

Fraternal Twins: The Enigmatic Role of the Immune System in Alphaherpesvirus Pathogenesis and Latency and Its Impacts on Vaccine Efficacy.

Although the establishment, maintenance and reactivation from alphaherpesvirus latency is far from fully understood, some things are now manifestly clear: Alphaherpesvirus latency occurs in neurons of the peripheral nervous system and control of the process is multifactorial and complex. This includes components of the immune system, contributions from non-neuronal cells surrounding neurons in ganglia, specialized nucleic acids and modifications to the viral DNA to name some of the most important. Efficacious vaccines have been developed to control both acute varicella and zoster, the outcome of reactivation, but despite considerable effort vaccines for acute herpes simplex virus (HSV) infection or reactivated lesions have thus far failed to materialize despite considerable effort. Given the relevance of the immune system to establish and maintain HSV latency, a vaccine designed to tailor the HSV response to maximize the activity of components most critical for controlling reactivated infection might limit the severity of recurrences and hence reduce viral transmission. In this review, we discuss the current understanding of immunological factors that contribute to HSV and VZV latency, identify differences between varicella-zoster virus (VZV) and HSV that could explain why vaccines have been valuable at controlling VZV disease but not HSV, and finish by outlining possible strategies for developing effective HSV vaccines.

Long-Term Incidence of Varicella Zoster Virus Disease in Adults Receiving Single-Unit Cord Blood Transplantation

Although varicella zoster virus (VZV) disease is a common complication after allogeneic hematopoietic cell transplantation (HCT), research into the long-term incidence of VZV disease in adults receiving cord blood transplantation (CBT) has been limited. The objective of this study was to evaluate the incidence, risk factors, and clinical impact of VZV disease after CBT with long-term follow-up in our institution. We retrospectively analyzed the data for 156 adult patients who received single-unit CBT at our institution between 2007 and 2020 and who achieved neutrophil engraftment and survived at least 100 days without recurrence of the underlying disease. VZV disease occurred in 61 patients at a median of 608 days (range, 36 to 4090 days) after CBT. The cumulative incidence of VZV disease was 14% (95% confidence interval [CI], 9% to 20%) at 1 year post-CBT and 40% (95% CI, 31% to 48%) at 5 years post-CBT. Multivariate analysis identified the cessation of antiviral prophylaxis as an independent risk factor for an elevated risk of VZV disease (hazard ratio, 15.65; 95% CI, 6.59 to 37.21; P < .001). The cumulative incidence of VZV disease was significantly lower in the long-term antiviral prophylaxis group (who received prophylaxis for approximately 1 year after CBT or to the end of immunosuppressive therapy) compared with the short-term antiviral prophylaxis group (who received prophylaxis for 35 days after CBT) (P=.005). Among the patients who developed VZV disease, the median time to onset of VZV disease was significantly delayed in the long-term antiviral prophylaxis group compared with the short-term antiviral prophylaxis group (694 days versus 130 days; P < .001), but the median onset of VZV disease after the cessation of antiviral prophylaxis was not significantly different between the 2 groups (166 days versus 95 days; P=.087). These data demonstrate that the long-term incidence of VZV disease is relatively high in adult patients undergoing CBT. Given that the incidence of VZV disease remained high after the cessation of antiviral prophylaxis, additional interventions, such as recombinant zoster vaccine administration, could be required to prevent VZV disease in long-term adult survivors after CBT.

An acyclic phosphonate prodrug of HPMPC is effective against VZV in skin organ culture and mice

Varicella zoster virus (VZV) causes chicken pox and shingles and is prevalent worldwide. Acyclovir and penciclovir (and its prodrugs) are first-line treatments for VZV infections, but they are not highly potent against VZV and resistance may arise in immunocompromised people on long-term therapy. HPMPC (cidofovir) is active against VZV, but cidofovir is not approved for treating VZV diseases, is nephrotoxic, and is not orally bioavailable. Here, we present the synthesis and evaluation of USC-373, a phosphonate prodrug of HPMPC with activity against VZV and other DNA viruses. In cultured fibroblasts, it was potent against VZV Ellen laboratory strain and was not overtly toxic, with EC50 of 4 nM and CC50 of 0.20 μM, producing a selectivity index of 50. In ARPE-19 cells, USC-373 was effective against VZV-ORF57-Luc wild type strain and the acyclovir-resistant isogenic strain. In human skin organ culture, USC-373 formulated in cocoa butter and applied topically prevented VZV-ORF57-Luc spread without toxicity. In NuSkin mice with human skin xenografts, one daily dose of 3 mg/kg was effective by the subcutaneous route, and one daily dose of 10 mg/kg was effective by the oral route. Remarkably, a 10 mg/kg oral dose given every other day was also effective. USC-373 was well tolerated and mice did not lose weight or show signs of distress. The prodrug modifications of USC-373 increase the potency and oral bioavailability compared to its parent nucleoside analog, HPMPC.

Antiviral Targeting of Varicella Zoster Virus Replication and Neuronal Reactivation Using CRISPR/Cas9 Cleavage of the Duplicated Open Reading Frames 62/71.

Varicella Zoster Virus (VZV) causes Herpes Zoster (HZ), a common debilitating and complicated disease affecting up to a third of unvaccinated populations. Novel antiviral treatments for VZV reactivation and HZ are still in need. Here, we evaluated the potential of targeting the replicating and reactivating VZV genome using Clustered Regularly Interspaced Short Palindromic Repeat-Cas9 nucleases (CRISPR/Cas9) delivered by adeno-associated virus (AAV) vectors. After AAV serotype and guide RNA (gRNA) optimization, we report that a single treatment with AAV2-expressing Staphylococcus aureus CRISPR/Cas9 (saCas9) with gRNA to the duplicated and essential VZV genes ORF62/71 (AAV2-62gRsaCas9) greatly reduced VZV progeny yield and cell-to-cell spread in representative epithelial cells and in lytically infected human embryonic stem cell (hESC)-derived neurons. In contrast, AAV2-62gRsaCas9 did not reduce the replication of a recombinant virus mutated in the ORF62 targeted sequence, establishing that antiviral effects were a consequence of VZV-genome targeting. Delivery to latently infected and reactivation-induced neuron cultures also greatly reduced infectious-virus production. These results demonstrate the potential of AAV-delivered genome editors to limit VZV productive replication in epithelial cells, infected human neurons, and upon reactivation. The approach could be developed into a strategy for the treatment of VZV disease and virus spread in HZ.

Modelling varicella vaccination – What does a lack of surge in herpes zoster incidence tell us about exogenous boosting?

BackgroundFor decades, assessments of the impact of universal varicella vaccination on the epidemiology of varicella and herpes zoster (HZ) have been made using mathematical modelling. Decreased virus circulation and the resulting diminished exogenous boosting have been predicted to lead to a surge in HZ incidence. Lately, the exogenous boosting hypothesis has been challenged due to a lack of an extensive surge in HZ incidence in countries with, by now long-standing universal varicella vaccination. MethodsIn a deterministic compartmental transmission model of varicella zoster virus disease, we model various levels and duration of protection from boosting to explore the impact of successful childhood varicella vaccination on HZ incidence. ResultsConsidering total HZ incidence, lifelong and strong protection from boosting give a stable incidence of HZ for about 60 years followed by a decline, whereas lifelong intermediate protection leads to a decline. So does weak protection of intermediate duration. Full and short protection, lead to a small surge, while full and intermediate protection lead to the largest HZ surge. HZ incidence by age group show that total incidence is the result of opposing increasing and decreasing trends in the various age groups over time. ConclusionsThe absence of an extensive surge in HZ incidence after varicella vaccination can, especially during the first 20–30 years, occur in either strong, intermediate or weak boosting scenarios. The impact seems to depend on an interplay of the protective level and duration of the protection in determining the basic reactivation rate and the proportion of the population that is susceptible at the start of vaccination. However, the picture depends on whether the entire population or specific age groups are observed.

The architecture of the simian varicella virus transcriptome.

Primary infection with varicella-zoster virus (VZV) causes varicella and the establishment of lifelong latency in sensory ganglion neurons. In one-third of infected individuals VZV reactivates from latency to cause herpes zoster, often complicated by difficult-to-treat chronic pain. Experimental infection of non-human primates with simian varicella virus (SVV) recapitulates most features of human VZV disease, thereby providing the opportunity to study the pathogenesis of varicella and herpes zoster in vivo. However, compared to VZV, the transcriptome and the full coding potential of SVV remains incompletely understood. Here, we performed nanopore direct RNA sequencing to annotate the SVV transcriptome in lytically SVV-infected African green monkey (AGM) and rhesus macaque (RM) kidney epithelial cells. We refined structures of canonical SVV transcripts and uncovered numerous RNA isoforms, splicing events, fusion transcripts and non-coding RNAs, mostly unique to SVV. We verified the expression of canonical and newly identified SVV transcripts in vivo, using lung samples from acutely SVV-infected cynomolgus macaques. Expression of selected transcript isoforms, including those located in the unique left-end of the SVV genome, was confirmed by reverse transcription PCR. Finally, we performed detailed characterization of the SVV homologue of the VZV latency-associated transcript (VLT), located antisense to ORF61. Analogous to VZV VLT, SVV VLT is multiply spliced and numerous isoforms are generated using alternative transcription start sites and extensive splicing. Conversely, low level expression of a single spliced SVV VLT isoform defines in vivo latency. Notably, the genomic location of VLT core exons is highly conserved between SVV and VZV. This work thus highlights the complexity of lytic SVV gene expression and provides new insights into the molecular biology underlying lytic and latent SVV infection. The identification of the SVV VLT homolog further underlines the value of the SVV non-human primate model to develop new strategies for prevention of herpes zoster.

Advances and Perspectives in the Management of Varicella-Zoster Virus Infections

Varicella-zoster virus (VZV), a common and ubiquitous human-restricted pathogen, causes a primary infection (varicella or chickenpox) followed by establishment of latency in sensory ganglia. The virus can reactivate, causing herpes zoster (HZ, shingles) and leading to significant morbidity but rarely mortality, although in immunocompromised hosts, VZV can cause severe disseminated and occasionally fatal disease. We discuss VZV diseases and the decrease in their incidence due to the introduction of live-attenuated vaccines to prevent varicella or HZ. We also focus on acyclovir, valacyclovir, and famciclovir (FDA approved drugs to treat VZV infections), brivudine (used in some European countries) and amenamevir (a helicase-primase inhibitor, approved in Japan) that augur the beginning of a new era of anti-VZV therapy. Valnivudine hydrochloride (FV-100) and valomaciclovir stearate (in advanced stage of development) and several new molecules potentially good as anti-VZV candidates described during the last year are examined. We reflect on the role of antiviral agents in the treatment of VZV-associated diseases, as a large percentage of the at-risk population is not immunized, and on the limitations of currently FDA-approved anti-VZV drugs. Their low efficacy in controlling HZ pain and post-herpetic neuralgia development, and the need of multiple dosing regimens requiring daily dose adaptation for patients with renal failure urges the development of novel anti-VZV drugs.

Occupational Exposure to Varicella Zoster in a Tertiary-Care Healthcare Setting

Background: Disseminated varicella zoster virus (dVZV) infection is a feared complication of varicella zoster virus (VZV) reactivation in immunocompromised patients. The CDC recommends contact and airborne precautions for localized VZV in immunocompromised patients until dissemination has been ruled out. Pre-emptive isolation can be problematic for medical centers without access to negative-pressure rooms. When we identify a case of dVZV at our facility, we perform an investigation to identify occupational exposures. Methods: We conducted a retrospective, descriptive review of occupational exposure investigations related to dVZV from January 2016 to December 2018. We collected baseline characteristics of the dVZV patient, and we evaluated whether the exposure occurred due to a delay in diagnosis or a progression from “localized” to disseminated VZV disease. Results: We identified 21 immunosuppressed patients with dVZV whose infection resulted in an occupational exposure during the specified study period. Average age was 58.6 years, with 10 males and 12 females. The immunocompromised patients included 11 with hematologic malignancy, 5 with solid-organ malignancy, 3 with rheumatologic disease on immunosuppressive therapy, and 2 with a solid-organ transplant. Most of the exposures (72.7%) occurred in an inpatient setting. The exposures resulted from either delayed recognition of dVZV or delayed initiation of appropriate precautions for all of the immunosuppressed patients. Two additional exposures occurred as a result of a change from “localized” to “disseminated” VZV. These patients whose diagnosis changed from localized to dVZV were considered previously immunocompetent, and dissemination took place 2 days after seeking healthcare evaluation. Conclusions: Most occupational exposures to varicella zoster are the result of delayed initiation of appropriate isolation precautions due to delayed diagnosis of dVZV infection or failure to recognize the need for instituting precautions in disseminated disease. Instituting preemptive airborne precautions for immunocompromised patients with localized varicella zoster would be unlikely to reduce occupational exposures.Funding: NoneDisclosures: Consulting fee- Merck Priya Sampathkumar

Acyclovir-induced neurotoxicity with a positive cerebrospinal fluid varicella zoster PCR result creating a management dilemma: a case report

BackgroundVaricella zoster virus central nervous system infections can present as aseptic meningitis, encephalitis, myelitis, and vasculopathy. Diagnosis is based on identification of varicella zoster virus deoxyribonucleic acid (DNA) in the cerebrospinal fluid by polymerase chain reaction. Therapy for these infections is acyclovir or valacyclovir. However, acyclovir can have neurotoxic effects that can mimic the presentation of varicella zoster virus central nervous system disease. We present a rare presentation of a patient who had acyclovir-induced neurotoxicity who also had a false-positive cerebrospinal fluid varicella zoster virus polymerase chain reaction result, creating a management dilemma. We review the clinical characteristics of acyclovir-induced neurotoxicity. In addition, we present the diagnostic characteristics of the cerebrospinal fluid viral polymerase chain reaction and alternative methods to diagnose central nervous system varicella zoster virus disease.Case presentationA 68-year-old Hispanic man with end-stage renal disease was diagnosed with cutaneous zoster at an outside facility and was started on acyclovir 4 days prior to admission. His family noted worsening confusion, agitation, speech difficulty, and hallucinations, leading them to bring him to the emergency department. His cerebrospinal fluid varicella zoster virus polymerase chain reaction result was positive, indicating the presence of varicella zoster virus deoxyribonucleic acid in the cerebrospinal fluid; however, he did not have cerebrospinal fluid pleocytosis typical of varicella zoster virus meningoencephalitis. Pharmacy records from the outside hospital revealed supratherapeutic acyclovir dosing. This led to a diagnostic dilemma over whether this patient had varicella zoster virus encephalitis or acyclovir-induced neurotoxicity. Acyclovir was discontinued, and the patient underwent two sessions of hemodialysis to remove acyclovir, which led to a full neurologic recovery.ConclusionsVaricella zoster virus encephalitis and acyclovir-induced neurotoxicity can have similar presentations. Varicella zoster virus deoxyribonucleic acid can be present in the cerebrospinal fluid during active cutaneous zoster in the absence of central nervous system disease. If concern for central nervous system varicella zoster virus disease remains high, additional testing with cerebrospinal fluid serology can be performed. Compared with central nervous system varicella zoster virus disease, acyclovir-induced neurotoxicity has a more predictable clinical resolution once drug therapy is discontinued or the patient undergoes hemodialysis, which can aid in making the diagnosis. Clinicians should be aware of this rare and dangerous complication of acyclovir. In addition, clinicians should have an understanding of the diagnostic limitations of cerebrospinal fluid viral polymerase chain reaction and have alternative approaches available to diagnose central nervous system varicella zoster virus disease when it is suspected.

Biosocial Study of the Causes Spread the Varicella-zoster Virus Disease among School Students in Diyala Governorate

Biosocial Study of the Causes Spread the Varicella-zoster Virus Disease among School Students in Diyala Governorate

S1639 SAFETY AND EFFICACY OF LIVE ATTENUATED VARICELLA VACCINE FOR PREVENTING VARICELLA ZOSTER VIRUS DISEASE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: A PROSPECTIVE SINGLE‐CENTER STUDY

Background:Varicella‐zoster virus (VZV) disease commonly occurs after allogeneic hematopoietic stem cell transplantation (allo‐HCT). Although long‐term acyclovir prophylaxis can prevent reactivation of VZV during acyclovir administration, VZV disease still remains a major problem after discontinuation of acyclovir. Thus, reconstitution of VZV‐specific T‐cell immunity may be necessary for allo‐HCT patients to prevent VZV disease completely. Vaccination against VZV has been considered as the method for accelerating VZV‐specific immune recovery. However, limited data is available on VZV vaccination after allo‐HCT.Aims:We conducted a single‐center, single‐arm, prospective study to evaluate safety and efficacy of live attenuated varicella vaccine for preventing VZV disease in adult patients who underwent allo‐HCT.Methods:Patients without active chronic GVHD, relapse and ongoing immunosuppressive therapy at 2 years after allo‐HCT were eligible for this study. We administered a single dose of live attenuated varicella vaccine (Biken, Osaka, Japan) to the enrolled patients. The primary endpoint was cumulative incidence of VZV disease after vaccination. Secondary endpoints were adverse effect of vaccine, and evaluation of VZV antibody titer and VZV specific T‐cells before and after vaccination. Immunoglobulin G (IgG) antibody titers against VZV were measured by enzyme immunoassay (EIA) using patient plasma. IgG index value of equal to or greater than 4 was considered positive. This study was approved by the institutional review boards of Jichi Medical University. Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki. The study was registered at UMIN Clinical Trials Registry (UMIN000013799).Results:A total of 25 adult patients were enrolled in this study. The cumulative incidences of VZV disease at 1 and 2 years after vaccination were both 20.0% (95% confidence interval (CI), 2.7–34.2%). Six patients developed VZV disease (zoster) at a median of 224 days (range 89–874) after vaccination. No adverse events associated with varicella vaccine were observed. The median VZV IgG titers were 3.8 (range &lt;2 ‐ 82.2) before vaccination and 5.2 (range &lt;2 ‐ 56.9) at 1 month after vaccination. To predict the development of VZV disease after vaccination, we defined some cut off values of lymphocyte and IgG using the receiver‐operating characteristics curve. The lower CD4+ T‐cell count (≤468/μL) and CD4/CD8 T‐cell ratio (≤0.53) at the time of vaccination groups significantly experienced VZV disease at 2 years after vaccination (28.6% vs 0%, p = 0.036, and 44.4% vs 0%, p = 0.0020, respectively). In addition, the lower VZV IgG (≤8.1) at 1month after vaccination was also associated with higher incidence of VZV disease (29.4% vs 0% at 2 years, p = 0.062).Summary/Conclusion:The current study indicated that a single dose of live attenuated varicella vaccine was safe and effective for preventing VZV disease in adult allo‐HCT patients. However, the effect was insufficient for some patients. Therefore, additional strategies, such as the administration of at least 2 dose of varicella vaccine, may be necessary to eradicate VZV disease.