Herpes Simplex Encephalitis: an Update Gnann, John W.; Whitley, Richard J.
Current infectious disease reports,
03/2017, Letnik:
19, Številka:
3
Journal Article
Recenzirano
Purpose of Review
The goal of this review is to provide an update on current thinking regarding herpes simplex encephalitis (HSE), emphasizing new information about pathogenesis, diagnosis, and ...immune responses. Specific questions to be addressed are the following: (1) Is there a genetic predisposition to HSE? (2) What clinical approaches have the greatest impact on improving the long-term outcomes in patients with HSE? And (3) are there immune-mediated mechanisms that may account for relapsing HSE?
Recent Findings
Toll-like receptor 3 (TLR 3) plays an important role in innate immune responses, including generation of interferons. Multiple single-gene errors in TLR 3 interferon pathways have recently been described in children that result in increased susceptibility to HSE. Conversely, studies in both animal models and humans indicate that both cytolytic viral replication and immune-mediated responses (including cytotoxic T lymphocytes and immune mechanisms mediated by TLR 2) contribute to the pathology of HSV, suggesting possible new therapeutic approaches. In terms of treatment, data clearly indicate that a longer duration between onset of symptoms and initiation of effective antiviral therapy correlates directly with less favorable clinical outcome. Recurrent or relapsing HSE may occasionally occur, but recent observations indicate that many instances of “relapsing HSE”, especially in children, are more often anti-
N
-methyl-
d
-aspartate receptor (NMDAR) encephalitis triggered by the antecedent HSV infection.
Summary
Innate immune responses are critical for defense against HSV; genetic defects in this system may predispose patients to HSE. During acute HSE, exuberant immune responses may contribute to the CNS pathology, suggesting that selective immunosuppressive therapy, coupled with potent antiviral drugs, may eventually play a role in the therapeutic management of HSV. While overall clinical outcomes of HSE remain suboptimal, the initiation of high-dose acyclovir therapy as early as possible in the course of the illness provides the best chance for a patient to survive with minimal neurologic damage. Distinguishing relapsing HSE from autoimmune anti-NMDAR antibody encephalitis is critically important because therapeutic approaches will be very different.
West Nile Virus (WNV) can result in clinically severe neurologic disease. There is no treatment for WNV infection, but administration of anti-WNV polyclonal human antibody has demonstrated efficacy ...in animal models. We compared Omr-IgG-am, an immunoglobulin product with high titers of anti-WNV antibody, with intravenous immunoglobulin (IVIG) and normal saline to assess safety and efficacy in patients with WNV neuroinvasive disease as part of a phase I/II, randomized, double-blind, multicenter study in North America. During 2003-2006, a total of 62 hospitalized patients were randomized to receive Omr-IgG-am, standard IVIG, or normal saline (3:1:1). The primary endpoint was medication safety. Secondary endpoints were morbidity and mortality, measured using 4 standardized assessments of cognitive and functional status. The death rate in the study population was 12.9%. No significant differences were found between groups receiving Omr-IgG-am compared with IVIG or saline for either the safety or efficacy endpoints.
Background. Despite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, ...the mortality rate is approximately 14%–19%. Among survivors, 45%–60% have neuropsychological sequelae at 1 year. Thus, improving therapeutic approaches to HSE remains a high priority. Methods. Following completion of a standard course of intravenous ACV, 87 adult patients with HSE (confirmed by positive polymerase chain reaction PCR for herpes simplex virus DNA in cerebrospinal fluid) were randomized to receive either valacyclovir (VACV) 2 g thrice daily (n = 40) or placebo tablets (n = 47) for 90 days (12 tablets of study medication daily). The primary endpoint was survival with no or mild neuropsychological impairment at 12 months, as measured by the Mattis Dementia Rating Scale (MDRS). Logistic regression was utilized to assess factors related to the primary endpoint. Results. The demographic characteristics of the 2 randomization groups were statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in the MDRS scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group. Conclusions. Following standard treatment with intravenous ACV for PCR-confirmed HSE, an additional 3-month course of oral VACV therapy did not provide added benefit as measured by neuropsychological testing 12 months later in a population of relatively high-functioning survivors. Clinical Trials Registration. NCT00031486.
West Nile Virus (WNV) is a mosquito-borne flavivirus that has caused ongoing seasonal epidemics in the United States since 1999. It is estimated that ≤1% of WNV-infected patients will develop ...neuroinvasive disease (West Nile encephalitis and/or myelitis) that can result in debilitating morbidities and long-term sequelae. It is essential to collect longitudinal information about the recovery process and to characterize predicative factors that may assist in therapeutic decision-making in the future.
We report a longitudinal study of the neurological outcomes (as measured by neurological examination, Glascow Coma Scale, and Modified Mini-Mental State Examination) for 55 subjects with WNV neuroinvasive disease (confirmed by positive CSF IgM) assessed on day 7, at discharge, and on days 14, 30, and 90. The neurological outcome measures were coma (presence and degree), global cognitive status, presence of cranial neuropathy, tremors and/or weakness.
At initial clinical presentation 93% presented with a significant neurological deficit (49% with weakness, 35% with tremor, and 16% with cranial neuropathy). The number of patients with a cognitive deficit fell from 25 at initial evaluation to 9 at their last evaluation. Cranial neuropathy was present in 9 at onset and in only 4 patients at study conclusion. Of the 19 patients who had a tremor at enrollment, 11 continued to exhibit a tremor at follow-up. Seven patients died after initial enrollment in the study, with 5 of those having presented in a coma. The factors that predict either severity or long-term recovery of neurological function include age (older individuals were weaker at follow-up examination), gender (males recovered better from coma), and presentation in a coma with cranial nerve deficits (had a poorer recovery particularly with regard to cognition).
This study represents one of the largest clinical investigations providing prospectively-acquired neurological outcomes data among American patients with WNV central nervous system disease. The findings show that the factors that influence prognosis from the initial presentation include age, gender, and specific neurological deficits at onset.
ClinicalTrials.gov identifier: NCT00138463 and NCT00069316.
Significant advances have been made in our understanding of the natural history and pathogenesis of viral encephalitides. The development of PCR has greatly increased our ability to diagnose viral ...infections of the central nervous system, particularly for herpes and enteroviral infections. Advancing knowledge has led to the recognition that some encephalitides can be reliably prevented by vaccination (eg, Japanese encephalitis and rabies). For other pathogens such as the arboviruses, the focus has been on prevention by vector control. Finally, effective therapy has been established for a very limited number of viral infections (eg, aciclovir for herpes simplex encephalitis). Other potentially useful treatments, such as pleconaril for enteroviral meningoencephalitis are under clinical evaluation. We review current understanding of viral encephalitides with particular reference to emerging viral infections and the availibility of existing treatment regimens.
Polyimides and ionic liquids (ILs) are two classes of materials that have been widely studied as gas separation membranes, each demonstrating respective advantages and limitations. Both polyimides ...and ILs are amenable to modification/functionalization based on selection of the requisite precursors. However, there have been but a handful of reports considering how polyimides and ILs could be integrated to obtain fundamentally new materials with synergistic properties. In this manuscript, we demonstrate a new and versatile way to synthesize polyimides with imidazolium cations directly located within the polymer backbone to form polyimide–ionene hybrids, or “ionic polyimides”. Our strategy for synthesizing ionic polyimides does not require the use of amino-functionalized ILs. Instead, the imidization reaction occurs prior to polymerization in the formation of an imidazole-functionalized diimide monomer. This monomer is then reacted via step-growth (condensation) polymerization with p-dichloroxylene via Menshutkin reactions, simultaneously linking the monomers and creating the ionic components. The resultant ionic polyimide is amenable to thermal processing (e.g., extrusion, melt-pressing) and capable of forming thin films. Upon soaking thin films of the ionic polyimide in a widely used IL, 1-butyl-3-methylimidazolium bistriflimide (C4mimTf2N), a stoichiometric absorption of the IL into the ionic polyimide was observed, forming an ionic polyimide + IL composite. The gas separation performances of ionic polyimide and ionic polyimide + IL composite membranes were studied with respect to CO2, N2, CH4, and H2. The neat ionic polyimide exhibits low permeability to CO2 and H2 (∼0.9 and ∼1.6 barrers, respectively) and very low permeability to N2 and CH4 (∼0.03 barrers for both). For the ionic polyimide + IL composite, the permeabilities of CO2, N2, and CH4 increase by 1800–2700%, while H2 permeability only increased by ∼200%. The large increases in permeability for CO2, N2, and CH4 are due to greatly increased gas diffusivity through the material, with gas solubility essentially unchanged with the IL present. The ionic polyimide and ionic polyimide + IL composite were characterized using a number of techniques. Most interestingly, X-ray diffractometry (XRD) of the films reveals that the ionic polyimide + IL composite displays a sharp peak, indicating that the ionic polyimide may experience supramolecular assembly around the IL. Although the performances of these first ionic polyimide and ionic polyimide + IL composite membranes fall short of Robeson’s Upper Bounds, this work provides a strong foundation on which ionic polyimide materials with more sophisticated structural elements can be developed to understand the structure–property relationships underlying the ionic polyimide platform and ultimately produce high-performance gas separation membranes.
Accurate evaluation of pain plays a critical role in identifying new interventions for the treatment and prevention of herpes zoster and postherpetic neuralgia (PHN). Different types of pain and ...other sensory symptoms are found in patients with herpes zoster, and these vary greatly with respect to their presence, location, duration, intensity, and quality. The results of recent studies of herpes zoster and PHN and the development of new methods for assessing neuropathic pain provide a foundation for diagnosing and assessing the pain associated with herpes zoster. We review the results of recent research to identify the essential components that must be considered in developing an evidence-based description of pain associated with herpes zoster and PHN.
Comprehensive assessments of pain are necessary for clinical research on the epidemiology, natural history, pathophysiologic mechanisms, treatment, and prevention of pain in herpes zoster and PHN.
BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no ...consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics.
We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function.
We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant.
We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.
Due to its attractive mechanical properties and biocompatibility, poly(dimethyl)siloxane (PDMS) is widely used in the fabrication of biomedical materials. On the other hand, PDMS is also prone to ...adsorption of both proteins and bacteria, making PDMS implants susceptible to infection. Herein, we examine the use of durably cross-linked zwitterionic coatings for PDMS surfaces to mitigate bacterial adhesion. Using a single-step photografting technique, poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA) thin films were covalently attached to PDMS substrates. The abilities of these coatings to resist the adhesion of Staphylococcus aureus and Staphylococcus epidermidis were tested in vitro under both wet and droplet conditions, as well as in subcutaneous and transcutaneous implantation models using Sprague-Dawley rats. Zwitterionic thin films effectively reduced bacterial adhesion in both in vitro and in vivo conditions. This was particularly true for pCBMA-coated materials, which exhibited significant reduction in bacterial adhesion and growth with respect to S. aureus and S. epidermidis for all in vitro conditions as well as the ability to resist bacterial growth on PDMS implants. The results of this study suggest that a simple and durable photografting process can be used to produce polymer thin films capable of preventing infection of implantable medical devices.
Abstract Background BK polyomavirus‐associated nephropathy (BKPyVAN) is an important cause of allograft dysfunction and failure in kidney transplant recipients (KTRs) and there are no proven ...effective treatments. Case reports and in vitro data support the potential activity of cidofovir against BK polyomavirus (BKPyV). Methods We report the results of a phase I/II, double‐blind, placebo‐controlled randomized dose‐escalation trial of cidofovir in KTRs with biopsy‐confirmed BKPyVAN and estimated glomerular filtration rate ≥30 mL/min. Intravenous cidofovir (0.25 mg/kg/dose or 0.5 mg/kg/dose) or placebo was administered on days 0, 7, 21, and 35, with final follow‐up through day 49. Results The trial was prematurely discontinued due to slow accrual after 22 KTRs had completed the study. Cidofovir was safe and tolerated at the doses and duration studied. The proportion of subjects with any adverse event (AE) was similar between groups (9/14 64% in the combined cidofovir dose groups and 6/8 75% in the placebo group); 84% of AEs were mild. BKPyV DNAemia reduction by day 49 was similar between groups (>1 log 10 reduction in (2/9 22.2% of 0.25 mg/kg group, 1/5 20% of 0.5 mg/kg group, and 2/8 25% of placebo group). Conclusions These preliminary results indicate that low‐dose cidofovir was safe and tolerated but had no significant BKPyV‐specific antiviral effect in KTRs with BKPyVAN. image
PDF
