Including Varicella Zoster Virus Research Articles

Immunogenicity and Safety of the Recombinant Adjuvanted Herpes Zoster Vaccine in Patients with Chronic Lymphocytic Leukemia and Multiple Myeloma

Background/objectives: Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are susceptible to viral infections, including varicella-zoster virus (VZV) reactivation due to both disease-related and treatment-induced immunosuppression. The recombinant adjuvanted herpes zoster vaccine (RZV) has shown high efficacy in immunocompetent adults, but immunogenicity data in CLL and MM patients are limited. This study evaluates the immunogenicity and safety of RZV in this population. Methods: Patients with CLL and MM vaccinated with RZV (administered in two doses at least one month apart) were included in the study. Pre- and post-vaccination anti-VZV IgM and IgG antibody levels were measured to assess immunogenicity, and adverse events (AEs) were captured for safety evaluation. Results: Seventy-eight patients received both vaccine doses, and 71 had post-vaccination samples. Most of the patients were IgM seronegative and IgG seropositive before vaccination. Pre-vaccination IgG levels were higher in CLL patients compared to MM patients (p = 0.001), while post-vaccination IgG levels significantly increased in both CLL (p < 0.0001) and MM (p < 0.0001) patients. In actively treated CLL patients, pre-vaccination IgG levels were significantly lower than in not actively treated patients (p = 0.002). Post-vaccination IgG levels were lower in MM patients receiving antiviral prophylaxis concurrently with the vaccination (p = 0.013). AEs were reported in 49.4% of patients after the first dose and 48.7% after the second dose, mostly mild (local or low-grade systemic). One case of immune thrombocytopenia was noted. Conclusions: RZV demonstrated strong immunogenicity and acceptable safety in CLL and MM patients, significantly boosting IgG levels, even in actively treated or heavily pretreated patients.

Differential diagnosis of exanthematous viruses during the 2022 Mpox outbreak in Minas Gerais, Brazil.

Brazil ranks second in the number of cases during the global monkeypox epidemic. The study, conducted in Minas Gerais, the second most populous state in Brazil with over 20 million inhabitants, utilized differential diagnostics, revealing a significant number of positive cases for other exanthematous viruses and emphasizing the need for accurate diagnoses. During the study, we were able to assess the co-circulation of other viruses alongside monkeypox, including varicella-zoster virus, molluscum contagiosum virus, and other orthopoxviruses. The significance of the research is underscored by the concentration of positive cases in populous areas, highlighting the challenges posed by emerging infectious diseases. This demographic context further amplifies the importance of the research in guiding public health policies and medical interventions, given the substantial population at risk. The study not only addresses a global concern but also holds critical implications for a state with such a large population and geographic expanse within Brazil. Overall, the study emphasizes the pivotal role of surveillance and precise diagnosis in guiding effective public health responses and ensuring appropriate medical interventions.

Immunopathogenesis of Orthopoxviridae: insights into immunology from smallpox to monkeypox (mpox)

Since 2019, notable global viral outbreaks have occurred necessitating further research and healthcare system investigations. Following the coronavirus disease 2019 (COVID-19) pandemic, in 2022, whilst severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains evolved, monkeypox virus (MPXV) infections became more evident. MPXV is of the Orthopoxviridae genus, belonging to the family Poxviridae. Zoonotic transmission (animal-to-human transmission) may occur. The Orthopoxviridae genus includes other orthopoxviruses (OPXVs) present in animal host reservoirs that include cowpox viruses (CPXVs), vaccinia virus (VACV), and variola virus (VARV), with the latter being a causal agent of smallpox and excessive mortality. This review aims to present facts about MPXV-specific pathogenesis, epidemiology, and immunology alongside historical perspectives. MPXV was rarely reported outside Africa before April 2000. Early research since 1796 contributed towards the eradication of VARV leading to immunisation strategies. The World Health Organisation (WHO) announcement that VARV had been eradicated was confirmed in 1980. On the 23rd of July 2022, the WHO announced MPXV as a health emergency. Therefore, concern due to the propagation of MPXV causing monkeypox (mpox) disease requires clarity. Infected hosts display symptoms like extensive cellular-initiated rashes and lesions. Infection with MPXV makes it difficult to differentiate from other diseases or skin conditions. Antiviral therapeutic drugs were typically prescribed for smallpox and mpox disease; however, the molecular and immunological mechanisms with cellular changes remain of interest. Furthermore, no official authorized treatment exists for mpox disease. Some humans across the globe may be considered at risk. Historically, presenting symptoms of mpox resemble other viral diseases. Symptoms include rashes or lesions like Streptococcus, but also human herpes viruses (HHVs), including Varicella zoster virus (VZV).

Transverse myelitis following bivalent COVID‐19 booster vaccine and quadrivalent seasonal influenza vaccine

Transverse myelitis following bivalent <scp>COVID</scp>‐19 booster vaccine and quadrivalent seasonal influenza vaccine

Development of a Novel Loop-Mediated Isothermal Amplification Method for the Rapid Detection of Monkeypox Virus Infections.

A recent outbreak of monkeypox virus (mpox) has prompted researchers to explore diagnostics as a means of impeding transmission and further spread. Rapid, sensitive, and specific methods are crucial for accurately diagnosing mpox infections. Here, we developed a loop-mediated isothermal amplification (LAMP) assay for the specific detection of mpox. The primer sets were designed to target regions in and around the N4R gene, and results showed a detection limit of 2 × 100 DNA copies, which is comparable to the gold-standard qPCR method currently used to detect mpox. Particularly, the assay provides results visible to the naked eye within 30 min. This test specifically detects mpox DNA with no cross-reactivity to related DNA viruses including Varicella Zoster Virus (VZV), Hepatitis B virus (HBV), Vaccinia virus (VACV), Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV-2), Human papillomavirus-16 (HPV-16) and Human papillomavirus-18 (HPV-18). Furthermore, the LAMP assay has been evaluated using clinical samples from laboratory-confirmed mpox patients and found to be consistent with the qPCR results. Our results show that this single-tube LAMP method can contribute to diagnosis of suspected mpox infections in the field and clinic, especially in regions with limited laboratory resources.

Characterization of Varicella-Zoster (VZV) Specific T Cell Response in Healthy Subjects and Transplanted Patients by Using Enzyme Linked Immunospot (ELISpot) Assays.

Solid organ transplant recipients, due to the administration of post-transplant immunosuppressive therapies, are at greater risk of viral reactivation episodes, mainly from herpes viruses, including varicella-zoster virus (VZV). The aim of this pilot study was to develop functional immunological assays (VZV-ELISpot) for the quantification and characterization of the VZV-specific effector-memory and central-memory responses in healthy subjects and transplanted patients. Glycoprotein gE and immediate-early 63 (IE-63) were used as antigens for in vitro stimulation. VZV-seropositive healthy subjects showed higher responses in respect to seronegative subjects. Even if differences were observed between VZV-seropositive healthy subjects and transplanted subjects at pre-transplant, the VZV-specific T-cell response was reduced at 60 days after transplant, mainly for the high level of immunosuppression. Phenotypical characterization revealed that response against VZV was mainly mediated by CD4 T cells. The results obtained in this study might be useful for the definition of personalized follow-up of the transplanted patients, providing useful information on the status of the patient potentially at risk of viral reactivation or other opportunistic infections.

Alphaherpesvirus Vaccines.

Prophylactic and therapeutic vaccines for the alphaherpesviruses including varicella zoster virus (VZV) and herpes simplex virus types 1 and 2 have been the focus of enormous preclinical and clinical research. A live viral vaccine for prevention of chickenpox and a subunit therapeutic vaccine to prevent zoster are highly successful. In contrast, progress towards the development of effective prophylactic or therapeutic vaccines against HSV-1 and HSV-2 has met with limited success. This review provides an overview of the successes and failures, the different types of immune responses elicited by various vaccine modalities, and the need to reconsider the preclinical models and immune correlates of protection against HSV.

Calcineurin phosphatase activity regulates Varicella-Zoster Virus induced cell-cell fusion.

Cell-cell fusion (abbreviated as cell fusion) is a characteristic pathology of medically important viruses, including varicella-zoster virus (VZV), the causative agent of chickenpox and shingles. Cell fusion is mediated by a complex of VZV glycoproteins, gB and gH-gL, and must be tightly regulated to enable skin pathogenesis based on studies with gB and gH hyperfusogenic VZV mutants. Although the function of gB and gH-gL in the regulation of cell fusion has been explored, whether host factors are directly involved in this regulation process is unknown. Here, we discovered host factors that modulated VZV gB/gH-gL mediated cell fusion via high-throughput screening of bioactive compounds with known cellular targets. Two structurally related non-antibiotic macrolides, tacrolimus and pimecrolimus, both significantly increased VZV gB/gH-gL mediated cell fusion. These compounds form a drug-protein complex with FKBP1A, which binds to calcineurin and specifically inhibits calcineurin phosphatase activity. Inhibition of calcineurin phosphatase activity also enhanced both herpes simplex virus-1 fusion complex and syncytin-1 mediated cell fusion, indicating a broad role of calcineurin in modulating this process. To characterize the role of calcineurin phosphatase activity in VZV gB/gH-gL mediated fusion, a series of biochemical, biological and infectivity assays was performed. Pimecrolimus-induced, enhanced cell fusion was significantly reduced by shRNA knockdown of FKBP1A, further supporting the role of calcineurin phosphatase activity in fusion regulation. Importantly, inhibition of calcineurin phosphatase activity during VZV infection caused exaggerated syncytia formation and suppressed virus propagation, which was consistent with the previously reported phenotypes of gB and gH hyperfusogenic VZV mutants. Seven host cell proteins that remained uniquely phosphorylated when calcineurin phosphatase activity was inhibited were identified as potential downstream factors involved in fusion regulation. These findings demonstrate that calcineurin is a critical host cell factor pivotal in the regulation of VZV induced cell fusion, which is essential for VZV pathogenesis.

Advances in the Diagnosis and Management of Acute Retinal Necrosis.

Acute retinal necrosis (ARN) is a devastating syndrome characterized by panuveitis, retinal necrosis, and a high rate of retinal detachment that may result in poor visual outcomes if not promptly diagnosed and treated. ARN is most commonly caused by viruses with the herpesvirus family. Etiologies include varicella-zoster virus, herpes simplex virus, and cytomegalovirus, and may be promptly diagnosed by polymerase chain reaction testing of aqueous or vitreous fluid. The true incidence of ARN is not known due to its rarity; as a result, clinical treatment is often guided by retrospective case series, case reports, and expert opinion. Standard of care has evolved over time but currently includes a combination of systemic and intravitreal antiviral in conjunction with topical or oral steroids and surgical therapy as needed. Combination therapy may reduce the rate of severe vision loss and increase the rate of visual acuity gain, although further studies are needed in this area. In particular for patients with mild to moderate disease, combination therapy may reduce the rate of retinal detachment. Adjunctive therapies including oral corticosteroid and prophylactic laser barricade are incompletely studied, but corticosteroid in particular, may reduce inflammation, which also is involved in the severe disease pathogenesis observed in ARN. This review discusses the advances in diagnosis and treatment of ARN, including management with combination antiviral medication and surgical interventions.

Zoster patients on earth and astronauts in space share similar immunologic profiles

BackgroundOn long-duration spaceflight, most astronauts experience persistent immune dysregulation and the reactivation of latent herpesviruses, including varicella zoster virus (VZV). To understand the clinical risk of these perturbations to astronauts, we paralleled the immunology and virology work-up of astronauts to otherwise healthy terrestrial persons with acute herpes zoster. MethodsBlood samples from 42 zoster patients – confirmed positive by PCR for VZV DNA in saliva (range from 100 to >285 million copies/mL) were analyzed for peripheral leukocyte distribution, T cell function, and plasma cytokine profiles via multi-parametric flow cytometry and multiplex bead-based immune-array assays. Patient findings were compared to normal value ranges specific for each assay that were defined in-house previously from healthy adult test subjects. ResultsCompared to the healthy adult ranges, the zoster patients possess (1) a higher proportion of constitutively activated T-cells, (2) a T-cell population skewed towards a more experienced maturation state, (3) depressed general T-cell function, and (4) a higher concentration of 20 of 22 measured plasma cytokines. DiscussionThe pattern of immune dysregulation in zoster patients is similar to that of astronauts during spaceflight who shed VZV DNA in their saliva. Because future deep space exploration missions will be of an unprecedented duration, prolonged immune depression and chronic viral reactivation threaten to manifest overt disease in exploration class astronauts.

Long-segment transverse myelitis in an immunocompetent patient due to varicella zoster virus reactivation

Transverse myelitis is a segmental, full-thickness inflammation of the spinal cord with various etiologies including varicella zoster virus infection. Symptoms can manifest as sensory deficits, severe lower back pain radiating down the legs, bowel/bladder incontinence, and extremity weakness. This case report is unique in that it highlights a patient who developed long-segment transverse myelitis after a varicella zoster virus infection which has not been previously reported in the literature.

Investigating the Association of Giant Cell Arteritis with Varicella Zoster Virus in Temporal Artery Biopsies or Ascending Aortic Resections.

A variety of infectious agents, including varicella zoster virus (VZV), have been hypothesized to play a role in the pathogenesis of giant cell arteritis (GCA). The detectability of the virus in patients with GCA is debatable. To further investigate an association between GCA and VZV infection, 10 years of GCA cases were evaluated for VZV by immunohistochemistry (IHC). All temporal artery biopsies and ascending aortic resections positive for GCA from 2007 to 2017 at Brigham and Women's Hospital were immunostained using a VZV antibody cocktail (SG1-1, SG1-SG4, NCP-1, and IE-62). Forty-one temporal artery biopsies and 47 ascending aortic resections positive for GCA were identified, all of which were found to be negative for VZV by IHC. Twelve temporal artery biopsies in this cohort were previously analyzed by unbiased metagenomics sequencing and were negative for VZV DNA. These results argue against a clinically relevant association between VZV infection and GCA, and support neither routine testing for VZV nor treatment with antiviral drugs.

Altered CD4+ T cell immunity in nurses occupationally exposed to viral pathogens

Pathogen exposure, including but not limited to herpesviruses, moulds the shape of the immune system, both at a basal state and in response to immune challenge. However, little is known about the impact of high exposure to other viruses on baseline immune signatures and how the immune system copes with repetitive exposures to maintain a balanced functionality. Here we investigated baseline immune signatures, including detailed T cell phenotyping, antigen-specific CD4+ and CD8+ T cell responses and cytokine profile in paediatric (PED) nurses, who have high occupational exposure to viral pathogens including varicella zoster virus (VZV) and respiratory viruses, and in neonatal intensive care unit (NICU) nurses, as a control group with infrequent occupational exposure. Our results show a lower CD4+ T cell response to two VZV proteins (IE62 and gE) and to tetanus toxoid (TT) in PED nurses who are cytomegalovirus (CMV)-seronegative, compared to CMV-seronegative NICU nurses, and that the decline might be more pronounced the more sustained the exposure. This decline might be due to an attrition of VZV- and TT-specific T cells as a result of the continuous pressure on the CD4+ T cell compartment. Moreover, our data suggest that the distinct T cell phenotypes known to be associated with CMV-seropositivity might be less prominent in PED nurses compared to NICU nurses, implying a plausible attenuating effect of occupational exposure on CMV-associated immunosenescence. Overall, this pilot study reveals an impact of occupational exposure to viral pathogens on CD4+ T cell immunity and supports further investigation in a larger cohort.

The Association between Viral Infections, Maternal and Fetal Mortality/Morbidity

Viral infections in pregnancy are a major cause of maternal and fetal mortality/morbidity. The viral infections of concern during pregnancy are caused by cytomegalovirus (CMV) rubella virus and herpes simplex virus (HSV). Other viruses now known to cause congenital infections include varicella-zoster virus (VZS), West Nile virus, measles virus, enterovirus, HIV and Zika virus. Also, hepatitis E is important because of its high mortality rate associated with infection during pregnancy. Mortality and morbidity from Cytomegalovirus and varicella –zoster virus are discussed.

Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study.

Epidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS. We enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (≤3 weeks after stroke/trauma); cases had convalescent samples (7-28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1-14.3) years for cases and 10.7 (6.9-13.2) years for controls (P=0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2-4.0; P=0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic. Herpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship.

Standard Duration of Varicella Zoster Virus Prophylaxis May be Inadequate to Prevent Viral Reactivation in Patients with Chronic Lymphocytic Leukemia Treated with Front-Line Bendamustine Plus Rituximab

Abstract Background: Bendamustine plus rituximab (BR) is an effective front-line treatment for chronic lymphocytic leukemia (CLL). Immunosuppression induced from disease- and/or treatment-related factors can frequently result in infectious complications, including varicella zoster virus (VZV) reactivation. Antiviral prophylaxis is not universally prescribed for these patients and the duration of treatment is not well defined. We therefore retrospectively reviewed the incidence of VZV reactivation and the impact of antiviral prophylaxis on this complication in CLL patients treated with front-line BR. Methods: We reviewed charts of 82 consecutive CLL patients with adequate clinical follow-up who were treated a median of 5 cycles with front-line BR at the Cleveland Clinic and University Hospitals of Cleveland from December 2005 to February 2015. Patients were grouped as having received antiviral prophylaxis or not. Baseline characteristics were compared between groups using the Chi-square test or Wilcoxon rank sum test. VZV reactivation from the start of front-line therapy was estimated using the cumulative incidence method and compared using the Gray test. Univariable prognostic factors for VZV reactivation were identified with Fine and Gray regression. The number of patients who reactivated was too small for multivariable analysis. All analyses were done using SAS software (SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided and P &lt; 0.05 was used to indicate statistical significance. Results: The median age of patients at the time of BR treatment was 69 years (range 44-93 years). 71% were male. Median follow-up was 1.5 years. 23 patients (28%) received antiviral prophylaxis, 20 acyclovir and 3 valacyclovir. The median duration of antiviral prophylaxis was 8.8 months. Patients who received antiviral prophylaxis were more likely to have had a history of VZV than those who did not receive prophylaxis (17% vs. 0%, P = 0.001). Additionally, patients who received antiviral prophylaxis were more likely to have received prior Zostavax compared to those who did not receive prophylaxis (22% vs. 5%, P = 0.022). All other baseline demographics including age, gender, ECOG PS, Rai stage, and cytogenetics were similar between the groups. 7 patients (8.5%) reactivated VZV following front-line BR therapy. Of the 7, 4 received antiviral prophylaxis with acyclovir and 3 did not receive prophylaxis (P = 0.20). Only one patient who reactivated VZV did so after receiving second line therapy. None of the patients who reactivated had a prior history of zoster activation. Notably, patients who received antiviral prophylaxis and reactivated VZV did so more than 6 months from the time of BR initiation, with reactivation occurring greater than 3 years after the start of front-line BR. [Figure 1] Conclusions: CLL patients who receive front-line BR are at risk for VZV reactivation regardless of antiviral prophylaxis. History of VZV did not predict the likelihood of viral reactivation. Patients who received prophylaxis and experienced VZV reactivation did so more than 6 months from treatment initiation. These data suggest that when given to CLL patients receiving front-line BR, a standard 6-8 month regimen of VZV prophylaxis is insufficient. Rather, prolonged prophylaxis extending years after treatment completion may be more appropriate to prevent VZV reactivation. Further prospective studies are required to further explore this benefit. Figure 1. Incidence of VZV reactivation over time in CLL patients treated with front-line BR who received antiviral prophylaxis. Figure 1. Incidence of VZV reactivation over time in CLL patients treated with front-line BR who received antiviral prophylaxis. Disclosures Smith: celegene, spectrum, genentech: Honoraria. Hill:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Is Treatment with Bortezomib for Multiple Myeloma or Amyloidosis Associated with Cytomegalovirus Reactivation?

BackgroundBortezomib (Velcade®) is an inhibitor of the 26S proteasome used as a first line therapy for multiple myeloma, for retreatment of relapsed multiple myeloma and for treatment of AL amyloidosis. An increased incidence of reactivation of herpesviruses including varicella zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) has been reported following administration of bortezomib (Oakervee et al 2005) In addition one study has described an increased incidence of cytomegalovirus (CMV) reactivation in myeloma patients post autografting treated previously with bortezomib when compared to other regimens (Marchesi et al 2014). We noted several cases of CMV viraemia with one case of likely end organ involvement (colitis) among patients given bortezomib. To determine how frequently this association occurs, we introduced a clinical protocol to monitor our patients on bortezomib for CMV infection.MethodsAll patients with myeloma or amyloidosis due their first dose of bortezomib were tested for CMV by polymerase chain reaction (PCR) on whole blood at baseline prior to treatment and then tested every 2 weeks after their initial dose or whenever they re-attended for clinic appointments, regardless of symptoms. Where possible, data on pre- treatment CMV serostatus was also recorded.We applied a protocol for pre-emptive therapy that we use for transplant patients (Atabani et al 2012). Whereas transplant patients with a viral load greater than 3000 genomes/ml (2520 IU/ml) whole blood are treated, bortezomib patients who had CMV levels in excess of 7500 copies/ml were given treatment (either oral valganciclovir or IV ganciclovir) until 2 consecutive blood samples showed undetectable levels.Results60 new bortezomib starters were tested with 43 being tested by CMV PCR at baseline i.e pre-treatment. The characteristics of these patients are shown in table 1 Table 1Patient characteristicsCharacteristicSexMale = 35 Female = 25AgeMedian 63.5 (range 33-89)Underlying diseaseAmyloidosis =39 Multiple myeloma= 21Pre-treatment CMV serostatusIgG positive = 35 IgG negative =17 Unknown= 8CMV viraemia was detected in 14/60 (23%) patients (10 myeloma and 4 amyloidosis) of whom 13 were known to be seropositive showing that the majority of the viraemias seen were reactivations/reinfections rather than primary infections. No CMV viraemia was seen in the seronegative group. Of those who had a true baseline none were positive prior to starting treatment. Of those without a true baseline, 5 had a detectable viraemia on their first blood sample. The course of the viraemia in these 14 patients is shown in figure 1. Five patients (all myeloma) reached the threshold for treatment and all responded to therapy including one patient who had 2 separate CMV reactivations. There were no cases of CMV end-organ disease.SummaryIn our cohort, 14/60 (23%) patients developed a CMV viraemia after starting bortezomib, corresponding to 13/35 (37%) who were initially CMV seropositive. Although we cannot exclude CMV reinfection from an exogenous source, we suggest that most of these were reactivations of latent CMV. Clinically, the majority of these episodes were self limiting although, because we elected to treat those patients who reached a pre-defined threshold of 7500 copies/ml, the true course of viraemia and the risk of subsequent end organ disease is unclear. Further investigation of the incidence of CMV reactivation and its clinical significance is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High-resolution MRI vessel wall imaging in varicella zoster virus vasculopathy

Contrast-enhanced vessel wall imaging high-resolution MRI (HRMR) has revealed vessel wall thickening and enhancement in multiple intracranial vasculopathies, including varicella zoster virus (VZV) vasculopathy. We retrospectively reviewed a database of patients with virologically-verified VZV vasculopathy, who underwent initial and follow-up HRMR between April 2011 and May 2014. Six patients were identified. Baseline demographic and clinical characteristics were collected, including stroke risk factors, history of VZV-related disorders, neurological presentation, course and antiviral treatment. Initial HRMR in patients with VZV vasculopathy demonstrated various patterns of stenosis, vessel wall thickening and enhancement, predominantly in terminal internal carotid artery segments and the M1 segment of the middle cerebral arteries. Follow-up HRMR showed improvement of stenosis, with reduced vessel wall thickening and enhancement at multiple times after treatment. HRMR has the potential to assist in diagnosis and treatment of VZV vasculopathy.

Use of Staged Molecular Analysis to Determine Causes of Unexplained Central Nervous System Infections

No agent is implicated in most central nervous system (CNS) infections. To investigate cerebrospinal fluid samples from patients with CNS infections of unknown cause in 1 hospital in Taiwan, we used a staged molecular approach, incorporating techniques including multiplex MassTag PCR, 16S rRNA PCR, DNA microarray, and high-throughput pyrosequencing. We determined the infectious agent for 31 (24%) of 131 previously negative samples. Candidate pathogens were identified for 25 (27%) of 94 unexplained meningitis cases and 6 (16%) of 37 unexplained encephalitis cases. Epstein-Barr virus (18 infections) accounted for most of the identified agents in unexplained meningitis cases, followed by Escherichia coli (5), enterovirus (2), human herpesvirus 2 (1), and Mycobacterium tuberculosis. Herpesviruses were identified in samples from patients with unexplained encephalitis cases, including varicella-zoster virus (3 infections), human herpesvirus 1 (2), and cytomegalovirus (1). Our study confirms the power of multiplex MassTag PCR as a rapid diagnostic tool for identifying pathogens causing unexplained CNS infections.

Human antimicrobial peptides LL-37 and human β-defensin-2 reduce viral replication in keratinocytes infected with varicella zoster virus.

There is mounting evidence that antimicrobial peptides have an important role in cutaneous defence, but the expression of these antimicrobial peptides in atopic eczema (AE) is still unclear. There are several families of antimicrobial peptides, including cathelicidins and human β-defensins. Patients with AE are more susceptible to severe cutaneous viral infections, including varicella zoster virus (VZV). To characterize the functional activity of the antimicrobial peptides LL-37 (human cathelicidin) and human β-defensin (hBD)-2 keratinocytes were infected with VZV, in a skin-infection model. Flow-cytometry analysis was used to investigate LL-37 expression in normal human keratinocytes, and quantitative PCR was used to determine viral loads in infected HaCaT keratinocytes and B cells, with and without exogenous LL-37 and hBD-2. LL-37 expression was present in keratinocytes, and both exogenous LL-37 and hBD-2 significantly reduced VZV load in infected keratinocytes and B cells. Specific antibodies blocked the antiviral action exhibited by these antimicrobial peptides. Pre-incubation of VZV with LL-37, but not hBD-2, further reduced VZV load. Both LL-37 and hBD-2 have an antiviral effect on VZV replication in the keratinocyte HaCaT cell line and in B cells, but their mechanism of action is different. Evidence of the relationship between antimicrobial peptide expression and higher susceptibility to infections in AE skin is still emerging. Developing novel antiviral therapies based on antimicrobial peptides may provide improved treatment options for patients with AE.