Epidemiology of herpes zoster. The herpes zoster patient as a source of infection with chickenpox

The authors analyse the inpatient findings accumulated from 2,179 observations on herpes zoster cases for 10 years. The clinico-epidemiological characterization of herpes zoster patients as the potential source of chickenpox infection is presented. The clinical data speak for the droplet transfer of the agent (varicella zoster virus) in this infection, which has permitted the formulation of exact practical recommendations of quarantine and isolation measures in the focus of herpes zoster.     

Herpesvirus-Associated Central Nervous System Diseases after Allogeneic Hematopoietic Stem Cell Transplantation

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ±1.9% and 4.1% ±1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19⁺CD20⁺ B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.     

Varicella-like herpesvirus infections of nonhuman primates

At least three distinct herpesviruses cause varicella like exanthematous diseases among nonhuman primates. Spontaneous epizootics have resulted in high morbidity and mortality rates among Cercopithecus aethiops, Erythrocebus patas and Macaca species in research colonies. Mild infections have been observed in infant chimpanzees and a gorilla. This group of diseases is of interest not only because they are a threat to primate colonies, but also because their pathologic similarity to progressive human varicella makes them a potentially valuable animal model of this disease. The nonhuman primate varicella-like exanthematous diseases are reviewed and compared to varicella in man.     

Simian Varicella in Old World Monkeys

Simian varicella virus (SVV) causes a natural erythematous disease in Old World monkeys and is responsible for simian varicella epizootics that occur sporadically in facilities housing nonhuman primates. This review summarizes the biology of SVV and simian varicella as a veterinary disease of nonhuman primates. SVV is closely related to varicella–zoster virus, the causative agent of human varicella and herpes zoster. Clinical signs of simian varicella include fever, vesicular skin rash, and hepatitis. Simian varicella may range from a mild infection to a severe and life-threatening disease, and epizootics may have high morbidity and mortality rates. SVV establishes a lifelong latent infection in neural ganglia of animals in which the primary disease resolves, and the virus may reactivate later in life to cause a secondary disease corresponding to herpes zoster. Prompt diagnosis is important for control and prevention of epizootics. Antiviral treatment for simian varicella may be effective if administered early in the course of infection.Abbreviations: FEAU, 1-(2′-deoxy-2′-flouro-β-D-arabinofuranosyl)-5-iodouracil, IE, immediate early, ORF, open reading frame, PBL, peripheral blood lymphocyte, SVV, simian varicella virus, VZV, varicella–zoster virusSimian varicella is a natural erythematous disease of Old World primates (Superfamily Cercopithecoidea, Subfamily Cercopithecinae), involving particularly patas (Erythrocebus patas), African green or vervet (Chlorocebus aethiops), and various species of macaque (Macaca spp.) monkeys. Epizootics of simian varicella occur sporadically in facilities housing nonhuman primates. These outbreaks are sometimes associated with high morbidity and mortality and the loss of valuable research animals. Simian varicella virus (SVV; Cercopithecine herpesvirus 9), a primate herpesvirus, is the etiologic agent of the disease. SVV is antigenically and genetically related to varicella–zoster virus (VZV; Human herpesvirus 3), the cause of human varicella (chickenpox) and herpes zoster (shingles). The clinical similarities between simian and human varicella and the relatedness of SVV and VZV, indicate that SVV infection of nonhuman primates is a useful model for study of varicella pathogenesis and development of antiviral therapies. A previous comprehensive review emphasized simian varicella as an experimental model for VZV infections.²² This review focuses on simian varicella as a veterinary disease of nonhuman primates. Simian varicella outbreaks and their epidemiology are considered, and the etiologic agent, clinical manifestations, pathogenesis, diagnosis, treatment, and control of the disease are discussed.     

Molecular and therapeutic aspects of varicella-zoster virus infection

Varicella-zoster virus (VZV) is a highly species-specific member of the Herpesviridae family. The virus exhibits multiple cell tropisms, infecting peripheral blood mononuclear cells and skin cells before establishing latency in sensory neurons. Such tropisms are essential both for primary infection, which manifests itself as chickenpox (varicella), and subsequent reactivation to cause herpes zoster (shingles). The highly cell-associated nature of the virus, coupled with its narrow host range, has resulted in the lack of an animal model that mimics its diseases in humans, thereby greatly hindering the study of events in VZV pathogenesis. Despite this, extensive studies both in vitro and in vivo in small-animal models have provided a fascinating insight into molecular events that govern VZV diseases. In addition, VZV has become the first human herpes virus for which a live attenuated vaccine has been developed.     

Herpes Simplex Encephalitis: Two Fatal Cases

The clinical and pathological features of the first two reported cases of herpes simplex encephalitis occurring in Saskatchewan are presented. The clinical history of an acute onset, an early organic mental syndrome followed by coma, neurologic disturbances, rapid progression and death suggests the diagnosis. The acute, diffuse, inflammatory process with predominant involvement of the temporal lobes of the cerebral hemispheres and the presence of intranuclear inclusions in nerve and glial cells are illustrated. The viral particles were found in electron micrographs from the brain tissue of both patients. The definitive diagnosis was established by the isolation, from postmortem brain tissue, of the herpes simplex virus, which was grown in tissue culture and shown to be pathogenic in suckling mice.     

Isolation of varicella-zoster virus from pharyngeal and nasal swabs in varicella patients

Thirteen children aged 5 months to 4 years were observed during a varicella epidemic in an Infants' Hospital; except for two normal individuals, the children had various forms of congenital defects. Eleven of the children developed varicella. During the first 3 days of exanthem, a total of 17 VZ virus strains were isolated: 12 from vesicular fluid, 3 from 23 nasal and 2 from 22 pharyngeal swabs. No strain was isolated during the incubation period despite 57 and 56 swabs having been collected from the throat and nose, respectively; nor was VZ virus isolated from 6 pharyngeal and 7 nasal swabs taken on the first day of exanthem. Isolation attempts performed from vesicular fluid to control quality of the isolation conditions gave a positivity rate of 100%. Under these optimal isolation conditions VZ virus was found in the nose or throat alongside skin vesicles in four of the 11 ill children. Besides VZ virus, the pharyngeal and nasal swabs yielded, respectively, four and four cytomegalovirus strains. The cytomegalovirus infections were inapparent.     

Detection of herpes simplex and varicella zoster viruses in clinical specimens using direct immunofluorescence and cell culture assays

Patients (33 in toto) with a clinical diagnosis of herpes infections (simplex, zoster or chickenpox) were investigated for the presence of herpes simplex virus (HSV) and varicella zoster virus (VZV) in skin samples, using direct immunofluorescence and cell culture assays. Five patients with nonherpetic vesiculobullous disorders were included as negative controls. Of the 33 patients, nineteen (57.6%) were positive for HSV or VZV and fourteen (42.4%) were negative. Five controls were all negative for HSV or VZV. Of the nineteen positive patients, HSV was isolated from eight (42.1%) patients, by both direct immunofluorescence and cell culture assays. VZV was isolated from eleven (57.9%) patients, eleven (100%) by direct immunofluorescence assay, and six (54.5%) by cell culture assays. HSV was isolated from one patient clinically diagnosed as chickenpox (VZV), but otherwise the positive laboratory results were concordant with the clinical diagnosis. For epidemiological studies, atypical cases and immunocompromised patients the clinical diagnosis should be confirmed in the laboratory.     

Pediatric cataracts

Congenital and acquired pediatric cataracts are recognized by many as being among the visually devastating pathologies of children. They remain one of the leading causes of legal blindness for children in under developed countries world wide. Diagnosed in approximately 400–500 patients per year in the United States alone, their presence requires agressive management with concurrent amblyopia therapy. Although most pediatric opacities are idiopathic, systemic etiologies which include genetic inheritance (Fabry's disease, Lowe's syndrome, Conradi's syndrome) metabolic disturbances (Galactosemia, Hypocalcemia, hypoglycemia, retinitis pigmentosa), infectious diseases (maternal syphilis, varicella virus, herpes virus, cytomegalovirus), toxic substances and trauma must be investigated. We reviewed the literature for pertinent information on the differential diagnosis of congenital and acquired cataracts in the pediatric population. The modalities and techniques of the pediatric examination are presented along with a discussion of the maladies, most recent advances in surgical intervention, optical or contact lens correction and amblyopia therapy associated with pediatric cataracts.     

Avian pox infection in a Canada goose (Branta canadensis)

Lesions suggestive of Avian Pox were found on a debilitated Canada goose (Branta canadensis). These were demonstrated histologically to be characteristic poxvirus lesions and poxvirus particles were seen using electron microscopy. The virus was successfully transmitted to domestic geese but not to leghorn chickens or to domestic ducks.     

Scanning electron microscopic studies of virus-infected cells. I. Cytopathic effects and maturation of vesicular stomatitis virus in L2 cells.

L2 cells infected with vesicular stomatitis virus under single-cycle conditions have been studied by scanning electron microscopy after preparation by the critical point drying technique. Three dimensional images of intact cells show bullet-shaped vesicular stomatitis virus virions budding singly and in radiating clusters both from the plasma membrane between cellular microvilli and from the sides of microvilli. Virus-induced cytopathic effects observed by scanning electron microscopy include intermeshing of microvilli, loss of filipodia which attach cells to the substrate, and rounding up and detachment of infected cells from the substrate.     

Identification of Novel Cetacean Poxviruses in Cetaceans Stranded in South West England

Poxvirus infections in marine mammals have been mainly reported through their clinical lesions and electron microscopy (EM). Poxvirus particles in association with such lesions have been demonstrated by EM and were previously classified as two new viruses, cetacean poxvirus 1 (CePV-1) and cetacean poxvirus 2 (CePV-2). In this study, epidermal pox lesions in cetaceans stranded in South West England (Cornwall) between 2008 and 2012 were investigated by electron microscopy and molecular analysis. PCR and sequencing of a highly conserved region within the viral DNA polymerase gene ruled out both parapox- and orthopoxviruses. Moreover, phylogenetic analysis of the PCR product clustered the sequences with those previously described as cetacean poxviruses. However, taking the close genetic distance of this gene fragment across the family of poxviridae into account, it is reasonable to postulate further, novel cetacean poxvirus species. The nucleotide similarity within each cluster (tentative species) detected ranged from 98.6% to 100%, whilst the similarity between the clusters was no more than 95%. The detection of several species of poxvirus in different cetacean species confirms the likelihood of a heterogeneous cetacean poxvirus genus, comparable to the heterogeneity observed in other poxvirus genera.     

The enantiomers of carbocyclic 5'-norguanosine: activity towards Epstein-Barr virus

(-)-5'-noraristeromycin (1) has shown antiviral activity towards, particularly cytomegalovirus, vaccinia virus and measles while its (+)-enantiomer (2) is effective towards hepatitis B virus. To determine if the antiviral characteristics of 1 and 2 extended to the guanine analogues (3 and 4), these enantiomers were prepared and evaluated against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6), human herpes virus type 8 (HHV-8), vaccinia virus (VV), cowpox virus (CV), vesicular stomatitis virus (VSV), respiratory syncytial virus (RSV), hepatitis B virus (HBV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The only activity found for 3 was for Epstein-Barr virus in VCA Elisa (EC50 0.78 microg/mL), immunofluorescence assay for VCA or gp 350/250 (1.8-4.0 microg/mL) and DNA hybridization (EC50 0.82 microg/mL) assays with no accompanying toxicity seen in the host Daudi cells. No activity was noted for 4.     

Cellular Viraemia in Babies Infected with Rubella Virus before Birth

Chronic viraemia has been detected in 10 out of 12 rubella syndrome babies at periods ranging from 1 to 196 days. The virus was found to be associated with leucocytes, and it is assumed that removal of neutralizing antibody is the most likely explanation for the high success rate in detecting viraemia. The findings are discussed in relation to diagnosis by virus isolation, to pathogenesis, and to the possible significance in explaining the failure of the foetus to develop a tolerance to rubella virus. Several published reports of viraemia in the acute exanthematous disease are contrasted with the less frequent reports of viraemia in the chronic disease of early postnatal life.     

Acute viral infection of the central nervous system in children: an 8-year review.

Reliable information on acute viral infections of the central nervous system (CNS) in Canadian children has not been available. To investigation this disease in Halifax the medical records of 180 patients with presumed or definite acute viral CNS infection diagnosed at the Izaak Walton Killam Hospital for Children over an 8-year period were reviewed. The yearly incidence was estimated at 19.5/100 000 for children up to 16 years of age, and the peak incidence was in July, August and September. The cause was determined in 64 (36%) of the 180 patients; it was most commonly a known infectious disease -- mumps (in 24 patients) or varicella (in 9 patients). An enterovirus was responsible in nine cases, herpes simplex virus in eight and measles virus in six. The clinical manifestations were variable and included apnea in three infants who would otherwise have been considered to have nearly suffered the sudden infant death syndrome. Localizing features were present on the electroencephalograms of nine patients, including six with herpes simplex infection. Serologic study of paired serum samples obtained during the acute phase of the illness and during convalescence was the most useful laboratory method of establishing the diagnosis. As medical therapy for specific causes of acute viral CNS infection advances, greater attention should be placed on establishing the correct diagnosis.     

Herpesvirus simiae infection in Macaca radiata

Forty of 79 bonnet macaques (Macaca radiata) housed in an outdoor structure became infected with a respiratory disease, and 16 died. The most conspicuous lesions were those of hemorrhagic interstitial lobar pneumonia and focal hepatic necrosis with monocytic infiltration and eosinophilic intranuclear inclusions. A virus, in high titer, was obtained from the lung and liver of two fatal cases (10⁷ TCID₅₀ × gram of tissue) by inoculating tissue homogenates in primary vervet monkey kidney, BSC-1, and MA104 cell cultures. The cytopathic effect was identical with that induced by Herpesvirus simiae in the same cell cultures. Similar cellular changes were seen in LLC-MK2 cell cultures. Infected cells contained eosinophilic intranuclear inclusions, and intranuclear herpes-like virus particles were seen by electron microscopy. The virus could not be passed serially in mice by the intracerebral route of inoculation. Bonnet monkeys (herpes antibody-free), inoculated intravenously with the virus, developed vesicular lesions on the arms, face, hands, and soles of the feet; and the virus was recovered from the vesicular fluid. All lesions disappeared within three weeks after inoculation, and the animals later recovered. On the basis of host range, cytopathic effect, electron microscopy, mouse susceptibility, and the results of neutralization tests in tissue cultures, the virus was identified as Herpesvirus simiae.     

Susceptibility of mink to certain viral animal diseases foreign to the United States.

Mink (Mustela vison) were inoculated with viruses: African horse sickness (AHS), African swine fever (ASF), bovine herpes virus II (BHV2), foot-and-mouth disease (FMD), goat pox (GP), hog cholera (HC), peste des petits ruminants (PPR), rinderpest (RP), swine vesicular disease (SVD), vesicular exanthema of swine (VES) and vesicular stomatitis (VS). Their susceptibility was measured by development of clinical signs, virus isolation and detection of precipitin and/or virus neutralizing antibodies. SVD virus produced a lesion in one mink. Virus was isolated from mink inoculated with SVD, FMD and BHV2. Neutralizing and/or precipitin antibodies were detected in mink inoculated with ASF, FMD, GP, RP, SVD and VS viruses. Mink were not susceptible to AHS, HC, PPR and VES viruses.     

Varicella zoster virus vaccines: potential complications and possible improvements

Varicella zoster virus(VZV) is the causative agent of varicella(chicken pox) and herpes zoster(shingles). After primary infection, the virus remains latent in sensory ganglia, and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine(v-Oka) is highly attenuated in the skin, yet retains its neurovirulence and may reactivate and damage sensory neurons. The reactivation is sometimes associated with postherpetic neuralgia(PHN), a severe pain along the affected sensory nerves that can linger for years, even after the herpetic rash resolves. In addition to the older population that develops a secondary infection resulting in herpes zoster, childhood breakthrough herpes zoster affects a small population of vaccinated children. There is a great need for a neuro-attenuated vaccine that would prevent not only the varicella manifestation, but, more importantly, any establishment of latency, and therefore herpes zoster. The development of a genetically-defined live-attenuated VZV vaccine that prevents neuronal and latent infection, in addition to primary varicella, is imperative for eventual eradication of VZV, and, if fully understood, has vast implications for many related herpesviruses and other viruses with similar pathogenic mechanisms.     

Detection limit of negative staining electron microscopy for the diagnosis of bioterrorism‐related micro‐organisms

Aims: To determine the detection limit of diagnostic negative staining electron microscopy for the diagnosis of pathogens that could be used for bioterrorism. Methods and Results: Suspensions of vaccinia poxvirus and endospores of Bacillus subtilis were used at defined concentrations as a model for poxviruses and spores of anthrax (Bacillus anthracis), both of which are pathogens that could be used for bioterrorist attacks. Negative staining electron microscopy was performed directly or after sedimentation of these suspensions on to the sample supports using airfuge ultracentrifugation. For both virus and spores, the detection limit using direct adsorption of a 10‐μl sample volume onto the sample support was 10⁶ particles per ml. Using airfuge ultracentrifugation with a sample volume of 80 μl, the detection limit could be reduced to 10⁵ particles per ml for spores and to 5 × 10⁴ particles per ml for poxviruses. The influence on particle detection of incubation time, washing and adsorption procedures was investigated. Conclusions: The reproducibility and sensitivity of the method were acceptable, particularly considering the small sample volume and low particle number applied onto the sample support. Significance and Impact of the Study: Diagnostic negative staining electron microscopy is used for the diagnosis of pathogens in emergency situations because it allows a rapid examination of all particulate matter down to the nanometre scale. This study provides precise detection limit for the method, an important factor for the validation and improvement of the technique.     

Viral Aetiology of Central Nervous System Infections in Adults Admitted to a Tertiary Referral Hospital in Southern Vietnam over 12 Years

Background

Central nervous system (CNS) infections are important diseases in both children and adults worldwide. The spectrum of infections is broad, encompassing bacterial/aseptic meningitis and encephalitis. Viruses are regarded as the most common causes of encephalitis and aseptic meningitis. Better understanding of the viral causes of the diseases is of public health importance, in order to better inform immunization policy, and may influence clinical management.

Methodology/Principal Findings

Study was conducted at the Hospital for Tropical Diseases in Ho Chi Minh City, a primary, secondary, and tertiary referral hospital for all southern provinces of Vietnam. Between December 1996 and May 2008, patients with CNS infections of presumed viral origin were enrolled. Laboratory diagnostics consisted of molecular and serological tests targeted at 14 meningitis/encephalitis-associated viruses.Of 291 enrolled patients, fatal outcome and neurological sequelae were recorded in 10% (28/291) and 27% (78/291), respectively. Mortality was especially high (9/19, 47%) amongst those with confirmed herpes simplex encephalitis which is attributed to the limited availability of intravenous acyclovir/valacyclovir. Japanese encephalitis virus, dengue virus, herpes simplex virus, and enteroviruses were the most common viruses detected, responsible for 36 (12%), 19 (6.5%), 19 (6.5%) and 8 (2.7%) respectively, followed by rubella virus (6, 2%), varicella zoster virus (5, 1.7%), mumps virus (2, 0.7%), cytomegalovirus (1, 0.3%), and rabies virus (1, 0.3%).

Conclusions/Significance

Viral infections of the CNS in adults in Vietnam are associated with high morbidity and mortality. Despite extensive laboratory testing, 68% of the patients remain undiagnosed. Together with our previous reports, the data confirm that Japanese encephalitis virus, dengue virus, herpes simplex virus, and enteroviruses are the leading identified causes of CNS viral infections in Vietnam, suggest that the majority of morbidity/mortality amongst patients with a confirmed/probable diagnosis is preventable by adequate vaccination/treatment, and are therefore of public health significance.