Primary Varicella Zoster Virus Research Articles

Disseminated cryptococcosis in a patient with multiple sclerosis treated with fingolimod

Multiple sclerosis (MS), a leading nontraumatic cause of neurologic disability,1 is an inflammatory disorder involving autoreactive T cells attacking myelin sheaths in the CNS, resulting in demyelination and axonal loss. The development of disease-modifying therapies (DMTs) for MS has been remarkable in recent years. Many approved DMTs for MS are parenteral. Oral fingolimod2,3 (Gilenya, Novartis, Basel, Switzerland) was approved by the US Food and Drug Administration (FDA) in 2010. Immunomodulation including sequestration of lymphocytes in the secondary lymphoid organs is the main proposed mechanism of action. In a phase 3 trial, rare but fatal viral infections were observed.2 One patient with MS developed disseminated primary varicella-zoster virus infection. Another patient had herpes simplex encephalitis. Both patients received fingolimod 1.25 mg once daily, a dose that is higher than the currently FDA-approved dose. Although fingolimod at 0.5 mg once daily did not show increased infection incidence in individual trials that led to FDA approval, a recent analysis of pooled trial data demonstrated a relatively higher rate of varicella-zoster virus infections in patients treated with fingolimod 0.5 mg daily than in placebo recipients.4 Disseminated cryptococcosis is a rare opportunistic infection reported in immunocompromised individuals such as patients with AIDS.5 In this report, we describe a patient with MS who received fingolimod therapy and subsequently developed disseminated cryptococcal infection. Acknowledgment: The author thanks Dr. F. Yan for collecting histology, MRI data, and editing.

Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections.

Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promising vaccine approaches are being explored in pre-clinical investigations with few progressing to early phase clinical trials. Consensus research findings suggest that robust humoral and cellular immune responses may partially control the frequency of reactivation episodes and reduce clinical symptoms. Live-attenuated viral vaccines have long been considered as a viable option for generating robust and protective immune responses against viral pathogens. Varicella zoster virus (VZV) belongs to the same alphaherpesvirus subfamily with herpes simplex viruses. A live-attenuated VZV vaccine has been extensively used in a prophylactic and therapeutic approach to combat primary and recurrent VZV infection indicating that a similar vaccine approach may be feasible for HSVs. In this review, we summarize pre-clinical approaches to HSV vaccine development and current efforts to test certain vaccine approaches in human clinical trials. Also, we discuss the potential advantages of using a safe, live-attenuated HSV-1 vaccine strain to protect against both HSV-1 and HSV-2 infections.

Herpes zoster em crianças saudáveis: o rosto inocente da controvérsia

Introduction: Herpes zoster (HZ) emerges sporadically by reactivation of the varicella zoster virus (VZV). It lies latent within the dorsal root of sensory ganglia or cranial nerves after primary infection, which manifests clinically as varicella. Its incidence increases with age and is rare in childhood. Case report: We describe the case of a 9-year-old previously healthy male, brought to medical consultation for pain and vesicular exanthema in the T1 dermatome, compatible with HZ. He was treated with acyclovir and improved clinically after three weeks. Discussion: In healthy children, HZ is rare. The main risk factor for childhood onset of HZ is primary VZV infection during gestation or the first year of life. It is not necessary to exclude underlying immunodeficiency, except in cases of recurrence. Due to its characteristics, childhood HZ is a disease that raises questions at diagnosis and regarding appropriate treatment.

A Case of Concurrent Acute Viral Myocarditis and Intussusceptions in a 3-Year-Old Child

Varicella-zoster virus (VZV) is a herpesvirus that causes two clinically distinct forms of disease, varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection results in characteristic diffuse vesicular rash of chickenpox. Although vaccination substantially attenuates disease manifestations, significant complications such as secondary soft tissue infection, encephalitis, and pneumonia can occur. The specific types of complications among patients with chickenpox also tend to vary by age. However, the most frequent chickenpox-related complications in children

High Incidence of Herpes Zoster After Lung Transplantation.

Primary varicella zoster virus (VZV) infection causes varicella and subsequently lifelong latent infection in ganglia from which it may reactivate leading to herpes zoster (HZ). Recently, we reported that VZV-reactive memory T-cells are significantly lower in transplant recipients than controls. In addition, the VZV-specific IgG titres after transplantation were significantly lower than before transplantation. Data on the incidence and timing of VZV reactivation after lung transplantation is limited. Therefore, we investigated the incidence of HZ after lung transplantation. Additionally, we questioned whether the VZV-specific T-cell and B-cell memory responses are recovered after VZV reactivation. The records of 101 patients (median age: 54 years) who underwent lung transplantation between April 2002 and April 2013 were analysed for VZV-PCR DNA till October 2013. VZV infection was clinically diagnosed and confirmed by PCR in 15 patients. One patient who was VZV IgG negative before transplantation, developed primary VZV infection 1.2 years after transplantation. Fifteen patients developed HZ: one patient had systemic dissemination, one patient developed disseminated vesicular rash in C2-C5 and died 6 days later, and 13 patients had uncomplicated cutaneous HZ involving 1-3 dermatomes. The median time to HZ was 1.4 years after transplantation. The overall incidence rate of HZ after transplantation (38 cases/1000 PY) was significantly higher than the age-matched healthy population (7-8 cases/1000 PY). The VZV-specific B and T-cell memory responses of 5 patients before and after HZ were compared with 5 patients without HZ. In 4 out of 5 patients the number of VZV-specific IgG producing B-cells increased after HZ to higher frequencies than those without HZ (p=0.06). The percentage of VZV-reactive CD4 and CD8 central and effector memory T-cells increased in all patients after HZ to significantly higher frequencies compared to those without HZ (p=0.03).In conclusion, HZ is a frequent complication after lung transplantation and increases VZV-specific T- and B-cell memory responses. Boosting the VZV adaptive immune response by prophylactic VZV vaccination before transplantation may limit the incidence of HZ after transplantation.

Gastro-intestinal Involvement of Primary Varicella Zoster Virus Infection in a Renal Transplant Recipient

Biopsy proven gastro-intestinal involvement of Varicella Zoster Virus (VZV) infection is rare and has not previously been reported in renal transplant recipients. This case report concerns a 65 year old, VZV seronegative, renal transplant recipient who presented with a non-vesicular rash and abdominal pain. Endoscopy revealed gastro-duodenal ulceration and in gastric biopsies VZV-DNA was detected by polymerase chain reaction assay. We conclude that abdominal pain in the absence of vesicular skin lesions may be the presenting symptom of visceral VZV infection, a potentially life threatening disease. To diminish the risk of VZV infection, patients on the waiting list for transplantation who are VZV seronegative or have non-protective VZV-IgG antibody titers, it is advised to vaccinate for VZV prior to transplantation.

Varicella complicated by group A beta-hemolytic streptococcal sepsis and disseminating intravascular coagulation associated with osteonecrosis of the mandible in a 2 year old patient

We would like to report a case of a child with primary varicella zoster virus (VZV) infection complicated by group A beta-hemolytic streptococcal (GABHS) septicaemia and disseminating intravascular coagulation (DIC) with osteonecrosis of the mandible. A review of the literature suggests that this is the first reported association of mandibular osteonecrosis and VZV, GABHS and DIC.

Progressive varicella syndrome with Varicella gangrenosa in an immune-competent infant

Varicella is common and highly contagious and affects nearly all susceptible children before adolescence. Progressive varicella syndrome is a severe complication of primary Varicella Zoster Virus (VZV) infection, with visceral organ involvement, coagulopathy, severe hemorrhage, and continued vesicular lesion development. We report a rare case of progressive varicella syndrome with varicella gangrenosa in a previously well female child of ten months. She presented with history of recurrent vesiculo-bullous skin lesions involving the chest, back and extremities since two months with dry gangrene of 1st, 3rd and right great toe. VZV Polymerase Chain Reaction (PCR) of vesicle fluid was positive. Workup for immunodeficiency state was negative. She responded dramatically to intravenous acyclovir.

Age and Immune Status of Rhesus Macaques Impact Simian Varicella Virus Gene Expression in Sensory Ganglia

Simian varicella virus (SVV) infection of rhesus macaques (RMs) recapitulates the hallmarks of varicella-zoster virus (VZV) infection of humans, including the establishment of latency within the sensory ganglia. Various factors, including age and immune fitness, influence the outcome of primary VZV infection, as well as reactivation resulting in herpes zoster (HZ). To increase our understanding of the role of lymphocyte subsets in the establishment of viral latency, we analyzed the latent SVV transcriptome in juvenile RMs depleted of CD4 T, CD8 T, or CD20 B lymphocytes during acute infection. We have previously shown that SVV latency in sensory ganglia of nondepleted juvenile RMs is associated with a limited transcriptional profile. In contrast, CD4 depletion during primary infection resulted in the failure to establish a characteristic latent viral transcription profile in sensory ganglia, where we detected 68 out of 69 SVV-encoded open reading frames (ORFs). CD-depleted RMs displayed a latent transcriptional profile that included additional viral transcripts within the core region of the genome not detected in control RMs. The latent transcriptome of CD20-depleted RMs was comparable to the latent transcription in the sensory ganglia of control RMs. Lastly, we investigated the impact of age on the establishment of SVV latency. SVV gene expression was more active in ganglia from two aged RMs than in ganglia from juvenile RMs, with 25 of 69 SVV transcripts detected. Therefore, immune fitness at the time of infection modulates the establishment and/or maintenance of SVV latency.

T-Cell Tropism of Simian Varicella Virus during Primary Infection

Varicella-zoster virus (VZV) causes varicella, establishes a life-long latent infection of ganglia and reactivates to cause herpes zoster. The cell types that transport VZV from the respiratory tract to skin and ganglia during primary infection are unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of non-human primates parallel those of primary VZV infection in humans. To identify the host cell types involved in virus dissemination and pathology, we infected African green monkeys intratracheally with recombinant SVV expressing enhanced green fluorescent protein (SVV-EGFP) and with wild-type SVV (SVV-wt) as a control. The SVV-infected cell types and virus kinetics were determined by flow cytometry and immunohistochemistry, and virus culture and SVV-specific real-time PCR, respectively. All monkeys developed fever and skin rash. Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt. In lungs, SVV infected alveolar myeloid cells and T-cells. During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. In early non-vesicular stages of varicella, SVV was seen mainly in perivascular skin infiltrates composed of macrophages, dendritic cells, dendrocytes and memory T-cells, implicating hematogenous spread. In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons. In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host.

Infections in Children Treated With Biological Agents

Infections in Children Treated With Biological Agents

Ramsay Hunt Syndrome in 2 Patients With Acquired Immunodeficiency Syndrome

Varicella zoster virus (VZV) is a herpes virus that can infect humans. After primary infection, it can reactivate with advancing age in immunocompetent hosts, causing the disease herpes zoster. It can occur earlier in life owing to decreased specific VZV humoral or cell-mediated immunity as seen in patients infected with the human immunodeficiency virus (HIV). Patients infected with HIV are at risk for severe illness either from primary VZV infection or reactivation. Herpes zoster may occur at any stage of HIV infection, and it is clinically recognizable by the presence of vesicles in a single dermatome, multiple contiguous dermatomes, or disseminated outside dermatomal pattern. Reactivation of VZV in the geniculate ganglion and seventh cranial nerve leads to Ramsay Hunt syndrome (RHS), which has been described in patients with HIV infection. We report 2 cases of VZV-associated RHS in HIV-infected patients. One patient had controlled HIV infection on antiretrovirals with undetectable HIV viral load, and the other patient had history of acquired immunodeficiency syndrome, very low CD4+ T-cell count, and prior use of steroids. Both developed seventh cranial nerve palsy and were treated with intravenous antiviral therapy and systemic steroids. Both patients have persistent facial asymmetry long after treatment for RHS. Our aim was to increase awareness of this rare syndrome in health care providers who care for individuals with HIV/acquired immunodeficiency syndrome.

Cerebral Venous Sinus Thrombosis: Association with Primary Varicella Zoster Virus Infection

Varicella zoster virus (VZV) has been known to cause cerebral arterial vasculopathy and an acquired antibody-mediated coagulopathy associated with purpura fulminans and generalized thromboembolism. There are no published reports of cerebral venous sinus thrombosis (CVST) associated with primary VZV infection. We report 2 cases that highlight an unusual presentation of VZV infection: CVST with primary varicella infection. One patient had extensive CVST with coexistent middle cerebral artery involvement. Primary VZV infection can be associated with thrombosis of cerebral arteries and venous sinuses.

Herpes zoster infection: A case report

Herpes zoster (HZ) or ‘shingles’ results from reactivation of the Varicella zoster virus (VZV). Primary VZV infections in sero negative individuals are known as varicella or chicken pox. Secondary or reactivated disease is known as shingles or herpes zoster. Early diagnosis and use of antiviral agents should be the mainstay of its management. This paper presents a case report of such an infection and its management.

Safety and Efficacy of Etanercept in a Cohort of Patients with Juvenile Idiopathic Arthritis Under 4 Years of Age

To evaluate safety, tolerability, and efficacy of etanercept in a cohort of patients with juvenile idiopathic arthritis (JIA) under 4 years of age. Data were collected at every visit during treatment with etanercept in 25 children who began treatment at a mean age of 3 years (range 18-48 months). Safety endpoints included the incidence of any adverse events. Efficacy endpoints included the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 criteria for improvement. Data from 25 patients with JIA treated with etanercept for a mean period of 23 months were analyzed. All patients received concomitant medications: 24 methotrexate, 3 cyclosporin A, and 10 corticosteroids. After the first 6 months of treatment, 15 (71.4%) patients achieved an ACR Pedi30 response and at the last observation 20 (80%) achieved ACR Pedi30. ACR Pedi50 and 70 responses were, respectively, 62% and 43% at 6 months and 72% and 64% at the last followup. Five patients (20%) discontinued etanercept for lack of efficacy. Two (8%) developed adverse events, both primary varicella zoster virus (VZV) infections (both not vaccinated). One was hospitalized because of a necrotizing fasciitis secondary to VZV infection. No cases of tuberculosis, opportunistic infections, or malignancies were reported. In our cohort of patients etanercept proved to be safe and efficacious in the majority of children. The response in toddlers was similar to that in older children. We observed only 1 case of severe infection that required hospitalization and stopped treatment temporarily.

Fetal varicella syndrome: a diagnostic dilemma

IntroductionPrimary varicella zoster virus (VZV) infection is common childhood disease. Over 90% of the antenatal population in the UK are seropositive for VZV. For this reason primary VZV infection is...

Varicella zoster virus infection in inflammatory bowel disease

The risk of viral infection is increased in immunosuppressed inflammatory bowel disease (IBD) patients. Varicella zoster virus (VZV) is of particular interest in IBD because of a number of reports of severe, disseminated, and occasionally fatal varicella infection in immunosuppressed IBD patients. We reviewed publications describing VZV infection in IBD patients and combined these data with a review of the current literature relating to both primary and secondary varicella in IBD. Twenty cases of primary varicella infection and 32 cases of herpes zoster infection have been reported in IBD. Additional cases are reported in clinical trials. The risk of VZV infection is increased with all immunosuppressants used in IBD, but corticosteroids and combination immunosuppression appear to be a particular risk. Healthcare providers need to be aware of the various manifestations of primary and secondary VZV infection in immunosuppressed IBD patients. Patients should be screened for VZV immunity and vaccinated prior to commencing immunosuppression.

Varicella-Zoster Virus Expression in the Cerebral Arteries of Diabetic Subjects

Primary varicella-zoster virus (VZV) infection causes varicella (chickenpox), after which VZV becomes latent in ganglionic neurons along the entire neuraxis. A decline in cell-mediated immunity to VZV in elderly and immunocompromised individuals results in zoster (shingles). Within the first year after herpes zoster, there is a 30% increased risk of stroke.1–2 Approximately one-third of patients with VZV vasculopathy do not have zoster rash and diabetic patients are at greater risk for both zoster3 and stroke; therefore, we examined the cerebral arteries of 4 diabetic subjects for the presence of VZV DNA and antigen.

Herpes zoster infection

Herpes zoster (HZ) or 'shingles' results from reactivation of the varicella-zoster virus (VZV). Developmental anomalies, osteonecrosis of jaw bones, and facial scarring are the other complications associated with it. Primary VZV infections in sero-negative individuals are known as varicella or chicken pox. Secondary or reactivated disease is known as shingles or herpes zoster. Early diagnosis and prompt treatment of the disease in the prodromal phase by the use of antiviral agents should be the mainstay of its management. This paper presents a case report of such an infection and its management.

CD4 T Cell Immunity Is Critical for the Control of Simian Varicella Virus Infection in a Nonhuman Primate Model of VZV Infection

Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses.