Herpes Simplex Encephalitis Research Articles

Takotsubo cardiomyopathy associated with Herpes simplex encephalitis: A case report and literature review

Takotsubo cardiomyopathy (TCM) is a stress-induced cardiomyopathy characterized by transient left ventricular dysfunction. It can be triggered by various central nervous system pathologies including status epilepticus (SE) and N-methyl-d-aspartate receptor (NMDAr) encephalitis. Herpex simplex encephalitis (HSE) is a life-threatening, sporadic, encephalitis associated with focal or global cerebral dysfunction caused by herpes simplex viruses type 1(HSV-1), or less commonly, type 2(HSV-2). While approximately 20% of patients with HSE develop NMDAr antibodies, not all manifest with encephalitis clinically. We present here a 77-year-old woman admitted with HSV-1 encephalitis who presented with acute encephalopathy and seizure-like activity. Continuous EEG monitoring (cEEG) showed periodic lateralized epileptiform discharges (PLEDs) involving the left parietotemporal region but no evidence of electrographic seizures. Her early hospital course was complicated by TCM which subsequently resolved on repeat TTE. She demonstrated initial neurological improvement. However, five weeks later her mental status declined. Again, no seizures were appreciated on cEEG. Unfortunately, repeat studies including lumbar puncture and magnetic resonance imaging (MRI) of the brain were consistent with NMDAr encephalitis. She was treated with immunosuppression and immunomodulation therapies. To our knowledge we report the first case of TCM secondary to HSE without comorbid status epilepticus. However, further studies are needed to better understand the correlation between, and underlying pathophysiology of HSE and TCM, as well as any potential association with this presentation and subsequent development of NMDAr encephalitis.

Outcomes of HSV-1 encephalitis infection in glioblastoma: An integrated systematic analysis

IntroductionHerpes Simplex Virus-1 (HSV-1) is a neurotropic DNA virus with neural latency and stereotypic viral encephalitis. It has been reported to conceal underlying glioblastoma (GBM) due to similar radiographic imaging and clinical presentation. Limited data exist on the co-occurrence of GBM and HSV-1. To better describe the pathophysiology of HSV-1 superinfections in GBM, we performed a comprehensive review of GBM cases with superimposed HSV-1. MethodsA comprehensive literature search of six electronic databases with apriori search criteria was performed to identify eligible cases of GBM with HSV-1. Relevant clinic-radiographic data were collected, Kaplan-Meier estimates, Fisher's exact test, and logistic regression analyses were used. ResultsWe identified 20 cases of HSE in GBM with an overall survival (OS) of 8.0 months. The median age of presentation was 63 years (range: 24–78 years) and the median interval between GBM or HSE diagnosis was 2 months (range: 0.05–25 months). HSE diagnosis before GBM diagnosis was a predictor for improved survival (HR: 0.06; 95% CI: [0.01–0.54]; p < 0.01). There is a significant reduction in OS in patients with concomitant HSE and GBM compared to the cancer genome atlas (TCGA) cohort (median OS: 8 months vs. 14.2 months; p < 0.05). Finally, HSV does not directly infect GBM cells but indirectly activates a local immune response in the tumor microenvironment. ConclusionsSuperimposed HSE in GBM may contribute to a significant reduction in OS compared to uninfected controls, potentially activating proto-oncogenes during active infection and latency. Preoperative HSE may induce an antiviral immune response, which may serve as a positive prognostic factor. Prompt antiviral treatment upon co-occurrence is necessary.

Human inherited complete STAT2 deficiency underlies inflammatory viral diseases.

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

TLR3/TRIF pathway confers protection against herpes simplex encephalitis through NK cell activation mediated by a loop of type I IFN and IL-15 from epithelial and dendritic cells.

Autosomal recessive (AR) and dominant (AD) deficiencies of TLR3 and TRIF are believed to be crucial genetic causes of herpes simplex encephalitis (HSE), which is a fatal disease causing focal or global cerebral dysfunction following infection with herpes simplex virus type 1 (HSV-1). However, few studies have been conducted on the immunopathological networks of HSE in the context of TLR3 and TRIF defects at the cellular and molecular levels. In this work, we deciphered the crosstalk between type I IFN (IFN-I)-producing epithelial layer and IL-15-producing dendritic cells (DC) to activate NK cells for the protective role of TLR3/TRIF pathway in HSE progression after vaginal HSV-1 infection. TLR3- and TRIF-ablated mice showed enhanced susceptibility to HSE progression, along with high HSV-1 burden in vaginal tract, lymphoid tissues and CNS. The increased HSV-1 burden in TLR3- and TRIF-ablated mice did not correlate with increased infiltration of Ly-6C+ monocytes, but it was closely associated with impaired NK cell activation in vaginal tract. Furthermore, using delicate ex vivo experiments and bone marrow transplantation, TRIF deficiency in tissue-resident cells, such as epithelial cells in vaginal tract, was found to cause impaired NK cell activation by means of low IFN-I production, whereas IFN-I receptor in DC was required for NK cell activation via IL-15 production in response to IFN-I produced from epithelial layer. These results provide new information about IFN-I- and IL-15-mediated crosstalk between epithelial cells and DC at the primary infection site, which suppresses HSE progression in a TLR3- and TRIF-dependent manner.

Functional brain networks reorganization in the absence of medial temporal lobe structures: an example of neuroplasticity

AbstractBackgroundMedial temporal lobe structures are particularly vulnerable in age‐related neurodegenerative diseases. Here, we investigated the brain reorganization that allows maintaining relatively normal global cognitive functioning in patients with herpes simplex encephalitis (HSE) – an infectious neurological disease ‐ with marked focal atrophy most pronounced in the medial temporal lobes, particularly the hippocampus. Using rs‐fMRI we (i) characterized the patterns of functional network organization, and (ii) compared the intra‐/interhemispheric functional connectivity (FC) within each patient.MethodA total of nine HSE patients were included (see Table 1), four of them were affected mainly in the left (LH) and five in the right (RH) hemisphere. The rs‐fMRI data were acquired after a long‐term follow‐up (median 16 years) of the disease and were preprocessed using the AFNI software. For each patient, using different brain parcellations, we computed the intra‐ and inter‐FC strength for each hemisphere separately, yielding four measures of intra‐FC LH/RH and inter‐FC LH/RH . We grouped the subjects according to their lesion‐side and their performance (low, high) in a memory task.ResultWe observed, regardless of the lesion side, a highly variable pattern of disrupted FC in each patient. Left‐lesioned patients showed high intra‐FCLH/RH particularly in the precuneus/posterior cingulate (PPC) and the angular gyrus while right‐lesioned patients exhibited a high inter‐FCRH in the medial prefrontal cortex (MPFC) and PPC regions. Both left and right‐lesioned showed decreased intra‐FCLH/RH in ventral medial temporal areas, more pronounced in the left‐lesioned patients (Figure1). Right‐lesioned individuals who showed a pattern of inter‐FC within the right MPF and PPC performed consistently higher on the memory task (percentiles &gt; 50) (Figure2).ConclusionThe substantial HSE‐induced medial temporal lobe lesions induce a global network reorganization. However, the side of the lesion seems to determine a specific pattern of network reorganization that is associated with differential cognitive performance. Left‐lesioned patients exhibited high PPC intra‐ and inter‐FCLH/RH and low memory performance while the right‐lesioned exhibited a high inter‐FCRH on the PPC and MPFC and better memory performance. Left lesions may result in nonadaptive brain reorganizations, however, right lesions, when linked to prefrontal brain reorganizations, may result in cognitive benefits and therefore be adaptive.

Neuroimaging Clinics: Central Nervous System Infections

The recent Covid-19 pandemic highlighted the potential for infectious diseases to cause catastrophe of biblical scale with unprecedented speed. Within months of onset, the pandemic almost brought to their knees the health care systems of some of the most advanced and developed cities on earth, in addition to the eventual millions of mortalities and many millions more morbidities. Of the many lessons learnt and re-learnt, the importance of early diagnosis and intervention is repeatedly emphasized. This is true not just for Covid19 infections, but also for the commonest and most important central nervous system infections such as bacterial meningitis and herpes simplex encephalitis. Automated molecular diagnostic tests may provide rapid microbiologic diagnosis for a broad array of infectious agents, however, imaging modalities remain indispensable as a first line tool not only in the diagnosis of central nervous system infections, but also the detection of complications, and in providing important cues in anatomical, pathophysiological and clinical correlations. The current volume edited by Lim T and Mukherji SK contributed to a significant and timely update on this important yet often under-taught topic of central nervous system infections.

일측 특발성 안면마비를 주소로 내원한 헤르페스 뇌염 환자 1예

Herpes simplex encephalitis (HSE) is a rare, but lethal infectious disease characterized by inflam-mation of the brain parenchyma. The annual incidence rate is reported as one case per 250,000- 500,000 population. Patients present with various non-specific symptoms including headache, fever, decreased consciousness and many other focal neurologic deficits, which often lead to difficult and delayed diagnosis. In the absence of proper management, prognosis is very poor with a mortality rate of about 70%. Here, we discuss about a case of HSE diagnosed after brain magnetic resonance imaging scan, who initially presented with facial paralysis with hearing loss and dizziness.

HSV-1 Encephalitis Presenting with Diplopia: Effects of Infection or Autoimmunity?

This report describes a case in which diplopia was developed as a finding of postinfectious anti- N -methyl- d -aspartate receptor encephalitis. Infectious encephalitis, especially herpes simplex virus, is essential as it is one of the triggers of autoimmune encephalitis. Even if the cases present unexpected clinical findings, we should be vigilant in terms of autoimmune processes, such as diplopia seen in our case.

Herpes Simplex Virus Encephalitis.

Herpes simplex virus (HSV) encephalitis (HSVE), which is caused by HSV-1 or HSV-2, is a rare neurologic disorder associated with focal or global cerebral dysfunction. HSVE is a syndrome of altered mental status, fever, and se.

A case of herpes simplex virus induced peripheral neuropathy and encephalitis with positive GM3 and CASPR2 antibody

BackgroundWe reported on a case involving an older patient with HSV-1 encephalitis who simultaneously experienced the onset of peripheral nerve symptoms associated with the presence of anti-GM3 immunoglobulin G (IgG).Case presentationA 77-year-old male was admitted to hospital with high fever, weakness of both lower limbs, and an unstable gait. A CSF test revealed a strikingly increased protein level (1,002 mg/L, normative values: 150-450 mg/L) and MRI revealed hyper-signal lesions in the right temporal lobe, right hippocampus, right insula, and right cingulate gyrus. The CSF was positive for HSV PCR (HSV-1,17870). In addition, the serum samples were positive for CASPR2 antibodies (antibody titer: 1/10) and anti-GM3 immunoglobulin G (IgG) (+). The patient was diagnosed with HSV-1-induced peripheral nerve symptoms that were associated with encephalitis and the presence of anti-GM3 IgG and anti-CASPR2 antibodies. The patient had received included intravenous immunoglobulin, intravenous acyclovir, and corticosteroids therapy. At the one-year follow-up examination, he had regained the necessary skills associated with daily life.ConclusionsHerpes simplex virus infection often induces encephalitis, and reaction to the virus may trigger an autoimmune response. Early diagnosis and treatment can avoid the progression of the disease to include autoimmune encephalitis.

Contactin-associated protein-2 and anti-aquaporin-4 antibody positive autoimmune encephalitis secondary to herpes simplex encephalitis: A case report.

Recurrent herpes simplex encephalitis (HSE) can easily induce autoimmune encephalitis (AE). However, there are few reports of anti-contactin-associated protein-2 (CASPR2)-related encephalitis, especially with positive anti-aquaporin 4 (AQP4) antibodies. A 14-year-old boy was admitted to the Department of Neurology of the First Affiliated Hospital of Kunming Medical University for "headache, dizziness, and fever for four days" with positive anti-CASPR2 and anti-AQP4 antibodies in the cerebrospinal fluid. Cranial MRI showed lesions in the right hippocampus, amygdala, and insular lobe, with local sulcus enhancement in the right insular, temporal, and frontal lobes. The fluid-attenuated inversion recovery was significantly enhanced. Human herpes virus type I was detected by cerebrospinal fluid metagenomic testing. The patient was diagnosed with AE secondary to HSE, with positive anti-CASPR2 and anti-AQP4 antibodies. After 2 weeks of immunoglobulin and methylprednisolone immunomodulatory therapy, acyclovir antivirus, mannitol dehydration, reducing intracranial pressure, and other symptomatic support therapy. The patient's symptoms significantly improved, with no complaints of discomfort, and he was discharged for observation. The patient was followed up a month after discharge and had no complaints of discomfort. CASPR2 and anti-aquaporin-4 antibody-positive AE have not been reported to be positive. This case will raise awareness of CASPR2 and anti-aquaporin-4 antibody-positive AE secondary to HSE, strengthen diagnostic capacities, and provide advice to treat it.

Clinical Features of Herpes Simplex Encephalitis and Risk Factors for Post-Encephalitic Epilepsy in Children

ObjectiveHerpes simplex encephalitis (HSE) is a common form of sporadic encephalitis and is prone to neurological sequelae such as epilepsy in young children, which can have a significant impact on young children at the time of neurological development. This study aimed to analyze the clinical features of HSE in children and to explore its risk factors for post-encephalitic epilepsy (PE).MethodsThe case data of children who met the HSE diagnostic criteria between January 2013 and June 2021 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed.Results The incidence of PE in children with HSE was 42.2% (19/45cases). The initial symptoms were fever with headache or convulsions. In the acute phase, there were 13 cases (28.9%) with psychiatric behavior disorders, 16 cases (35.6%) with neurological deficit symptoms, and 24 cases (53.3%) with altered consciousness. Univariate analysis of fever duration, fever peak, psychiatric behavior disorders, neurological deficit symptoms, acute phase seizures and seizure frequency, ICU length of stay, admission GCS, and cranial imaging in children with HSE indicated statistically significant mixed involvement (all P < 0.05), and multivariate logistic regression analysis suggested that repetitive seizures (more than 5 seizures) (OR = 1.551;95% CI 1.229–1.958, P < 0.001) in the acute phase was an independent risk factor for the occurrence of PE.Conclusion The main symptoms in children with HSE in the acute phase include seizures, altered consciousness, neurological deficit symptoms, and psychiatric behavioral abnormalities. Children with HSE has a high incidence of PE, especially if they have repetitive seizures (more than 5 seizures) in the acute phase.

HSV encephalitis relapse in the setting of chemotherapy

AbstractPatients who suffer a brain injury trigger are vulnerable to late relapse of herpes simplex encephalitis. We present an immunocompromised patient with late‐life relapse of herpes simplex encephalitis after an ischemic stroke.

Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who is compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impair cellular apoptosis and necroptosis upon TLR3, TLR4 or TNFR1 stimulation, and ZBP1/DAI-mediated necroptotic cell death following HSV-1 infection. The patient's fibroblasts display no detectable RIPK3 expression. Following TNFR1 or TLR3 stimulation, the patient's cells do not undergo apoptosis or necroptosis. Following HSV-1 infection, the cells support excessive viral growth despite normal induction of antiviral IFN-β and interferon-stimulated genes (ISGs). This phenotype is, nevertheless, rescued by the application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons display impaired cell death and enhanced viral growth following HSV-1 infection, as do isogenic RIPK3- knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE, by impairing the cell death-dependent control of HSV-1 in cortical neurons independently of type I IFN immunity.

IFIH1 deficiency causing neonatal herpes simplex virus encephalitis and recurrent retinitis

Homozygous loss-of-function variants in Interferon induced with helicase C domain 1 (IFIH1) leads to immunodeficiency with early onset recurrent and severe viral respiratory infections (Immunodeficiency 95; MIM 619773). Severe respiratory infections with RNA viruses such as rhinovirus and respiratory syncytial virus (RSV) are most characteristic of IFIH1 deficiency. IFIH1 encodes melanoma differentiation-associated protein 5 (MDA5), an intracellular sensor of mainly long double-stranded RNA (ds-RNA), a viral replication intermediate. When activated, MDA5 triggers antiviral pathways including increased transcription of Type 1-interferon. The antiviral role of MDA5 is best described for positive (+) RNA viruses such as Picornavirus family which produce long ds-RNA as a replication intermediate. We present a patient with neonatal herpes simplex virus (HSV) encephalitis and recurrent retinitis with homozygous variant of unknown significance (VUS) in IFIH1, c.2062A>G (p.Lys688Glu).Patient is a 10-year-old male, born of consanguineous parents from the United Arab Emirates. Past medical history is notable for neonatal HSV encephalitis, grade 3 intraventricular hemorrhage, cerebral palsy, epilepsy, optic atrophy and recurrent HSV retinitis. Patient has no additional history of severe or recurrent infections. No family history of recurrent or severe infections, malignancy, autoimmunity or autoinflammation.Immune evaluation demonstrated anemia with elevated mean corpuscular volume and mild elevation of platelets and monocytes. Patient had normal lymphocyte subsets, normal T and B cell subset distributions, protective vaccine titers and normal immunoglobins apart from mildly elevated immunoglobulin G. An Invitae primary immunodeficiency panel demonstrated homozygous VUS in IFIH1, c.2062A>G (p.Lys688Glu). This variant is not found in gnomAD or ClinVar and has a Combined Annotation Dependent Depletion score of 22.6. Functional testing demonstrated decreased interferon induction after stimulation with intracellular RNA, intracellular DNA and agonists of both Toll-like receptor 7 and 9. These findings are consistent with MDA5 deficiency given decreased interferon response with known MDA5 agonists.In summary, we describe a patient with recurrent and severe infections with a DNA virus and no known infections with respiratory RNA viruses. Both DNA and RNA viruses produce long ds-RNA as replication intermediates, an MDA5 agonist. This patient highlights the anti-viral role of MDA5 for both DNA and RNA viruses.

NK cell activation provides protection against herpes simplex encephalitis through TLR3/TRIF-dependent crosstalk between epithelial and dendritic cells

Abstract Herpes simplex encephalitis (HSE), which is a fatal disease causing focal or global cerebral dysfunction following infection with herpes simplex virus type 1 (HSV-1). Previous few studies have been administered on the immunopathological networks of HSE in the context of TLR3 and TRIF defects at the cellular and molecular levels. In this work, we tried to decipher the crosstalk between type I IFN (IFN-I)-producing epithelial layer and IL-15-producing dendritic cells (DC) to activate NK cells for the protective role of TLR3/TRIF pathway in HSE progression after vaginal HSV-1 infection. TLR3- and TRIF-knockout mice showed enhanced susceptibility to HSE progression, with high HSV-1 burden in vaginal tract, lymphoid system, and CNS. The increased HSV-1 burden in TLR3- and TRIF-ablated mice did not correlate with increased infiltration of Ly-6C +monocytes, but it was closely associated with impaired NK cell activation in vaginal tract. In addition, using delicate ex vivo experiments and bone marrow transplantation, TRIF deficiency in tissue-resident cells, such as epithelial cells in vaginal tract, found to cause impaired NK cell activation by means of low IFN-I production, whereas IFN-I receptor in DC play a role in activating NK cells via IL-15 production in response to IFN-I produced from epithelial layer. These results provide new information about IFN-I- and IL-15-mediated crosstalk between epithelial cells and DC at the primary infection site that can suppress HSE progression in a TLR3- and TRIF-dependent manner. This study was supported by the Basic Science Research Program through National Research Foundation of Korea (NRF) grants funded by the Ministry of Education and the Ministry of Science and ICT (MSIT), Republic of Korea (2021R1A2B5B02001578, 2019R1A6A1A03033084 for Seong Kug Eo, 2020R1I1A1A01054533 for Erdenebileg Uyangaa, and 2020R1I1A2055591 for Jin Young Choi, http://www.nrf.re.kr).

HSV-1 and HHV-6 Meningoencephalitis in a Child with STAT1 Mutation

Introduction: STAT1 is a critical signal transducer for both the interferon gamma receptor and IFN-alpha/beta receptors and is required for responses to herpesviruses. STAT1 defects vary in severity and clinical presentation. STAT1 loss of function (LOF) mutations with Mendelian Susceptibility to Mycobacterial Disease (MSMD) and STAT1 gain of function (GOF) mutations have been described with a wide clinical spectrum, including nontuberculous mycobacteria, disseminated fungal, bacterial, and viral infections in addition to immune dysregulation. We present a 10-year-old female with HSV-1 and HHV-6 meningoencephalitis that was found to have a variant in STAT1. MethodsRetrospective chart review was conducted. Laboratory investigations included lymphocyte immunophenotyping by flow cytometry, lymphocyte proliferation to mitogens and antigens, NK cell functional assays, quantitative immunoglobulins, toll like receptor function defects, genetic evaluation by next generation sequencing, and assays for further evaluation for MSMD, T helper IL17, STAT GOF. ResultsA previously healthy 10-year-old Caucasian female presented with fever, headache, and new-onset seizure with status epilepticus. She was diagnosed with HSV-1 and HHV-6 meningoencephalitis, as CSF PCR panel was positive for HSV-1 and HHV-6. Brain MRI showed findings compatible with HSV-1 encephalitis. She was treated with a 14-day course of acyclovir with no noted neurological sequelae. Infection history was unremarkable except for one episode of otitis media as a child and a couple upper respiratory viral illnesses. Denied prior history of HSV infection. No family history of immunodeficiency disorders. Both parents reported remote history of herpetic gingivostomatitis. Laboratory immune evaluation was remarkable for decreased lymphocyte proliferative response to Candida antigen. Next generation sequencing revealed a variant of uncertain significance in STAT1 (c.295A>G; p.Ile99Val) and did not detect TLR3 or UNC93B1 mutations. ConclusionThe clinical phenotype caused by STAT1 mutations is highly diverse, and there is overlap between GOF and LOF phenotypes, making it difficult to clinically diagnose. Although HSV gingivostomatitis has been reported in a patient with STAT1 GOF, invasive disease, such as meningoencephalitis, has not been reported in those with variants in STAT1.

HSV-1 Infection Among COVID-19 Cases with Ocular and Neurological Manifestations

Introduction: SARS-CoV-2 progression depends on multiple factors, including the compromised immune system and underlying diseases. HSV-1 reactivation in SARS-CoV-2 infection, more likely in patients with pneumonia and immunodeficiency, may be potentially life-threatening and implicate the prognosis. Case Presentation: We report two COVID-19 cases presenting ocular and neurological manifestations suspicious for HSV-1 encephalitis. Conclusions: Our study showed HSV-1 ocular manifestation among two COVID-19 cases. So, the recurrence of HSV-1 infection probably is related to immune responses during COVID-19 pathophysiology.

Association between human genetic variants affecting the host NK cell response and the development of herpes simplex virus type 1 encephalitis.

Herpes simplex virus encephalitis (HSE) is a rare complication of herpes simplex virus type 1 (HSV-1) infection or reactivation. It is so far unclear why only few patients develop HSE. As natural killer (NK) cells provide an important defense against HSV-1, we investigated whether there is an association between distinct human genetic variants associated with the host NK cell response and HSE. Forty-nine adult patients with confirmed HSE and 247 matched controls were analyzed for the distribution of the following genotypes: CD16A (FcγRIIIA) V/F and IGHG1 G1m3/17, both influencing antibody-dependent cellular cytotoxicity; HLA-E*0101/*0103, associated with NK cell activation; and SLFN13 rs9916629C/T associated with NK cell response. Homozygous HLA-E*0101:0101 and HLA-E*0103:0103 variants as well as the rs9916629CC genotype were overrepresented in HSE patients compared to controls (p ≤ 0.001). Notably, cooccurrence of the homozygous HLA-E*0101 and rs9916629CC genotypes was present in 19% of patients but totally absent in controls (p ≤ 0.0001). Distribution of CD16A and IGHG1 variants did not differ between patients and controls. Our data show that the rare combination of HLA-E*0101:0101 and rs9916629CC is significantly associated with HSE. Possibly, these genetic variations could be useful as clinical markers predicting HSE prognosis and helping to adapt the treatment of HSE in the individual patient.

Immunocompromise and herpes simplex virus type 1 encephalitis (HSVE): a nationwide cohort and case-control study (S25.009)

<h3>Objective:</h3> We aim to determine whether a relationship exists between immunocompromise as defined by autoimmune disease or immunosuppressive and immunomodulatory medications in patients and incident HSVE. <h3>Background:</h3> Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is commonest. The association between immune status and HSVE is unclear. Using a U.S. Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. <h3>Design/Methods:</h3> We used the U.S. Medicaid Analytic eXtract Database between the years of 2007–2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age- and sex-matched adult cases of HSVE with a sufficient enrolment period to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson comorbidity index, and non-autoimmune comorbidities. <h3>Results:</h3> Incidence of HSVE was ~3.01 per 10⁵ person-years among adults. A total of 951 HSVE cases and 95,100 age- and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong, adjusted OR 2.6 (95% CI [2.2, 3.2]). The association of HSVE and immunomodulating medications had an OR of 2.2 [1.9, 2.6], also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: 2.3 [1.9, 2.7] for autoimmune disease and 2.0 [1.7, 2.3] for immunosuppressive and immunomodulatory medications. <h3>Conclusions:</h3> In a large, national population, HSVE is strongly associated with pre-existing autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date. <b>Disclosure:</b> Dr. Tang has received personal compensation for serving as an employee of Third Rock Ventures. Dr. Bhattacharyya has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion Pharmaceuticals. Dr. Bhattacharyya has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Continuum. The institution of Dr. Bhattacharyya has received research support from Alexion Pharmaceuticals. The institution of Dr. Bhattacharyya has received research support from National Institute of Health. The institution of Dr. Bhattacharyya has received research support from UCB. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Miyawaki has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Family Health, Inc.. Dr. Miyawaki has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Morrison and Mahoney. Dr. Miyawaki has stock in Cincinnati Bengals. Dr. Miyawaki has received publishing royalties from a publication relating to health care. Dr. Miyawaki has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant with US Department of Health and Human Services. Dr. Yoshida has received personal compensation for serving as an employee of OM1, Inc. Dr. Yoshida has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for OM1, Inc. Dr. Wilcox has nothing to disclose. Karen Costenbader has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Karen Costenbader has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Karen Costenbader has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Glaxo Smith Kline. Karen Costenbader has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for AstraZeneca Pharmaceuticals LP. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Arthritis and Rheumatology. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Uptodate. Karen Costenbader has stock in Neutrolis. The institution of Karen Costenbader has received research support from Gilead. The institution of Karen Costenbader has received research support from Exagen. The institution of Karen Costenbader has received research support from Merck. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as a grant reviewer with NIH. Prof. Solomon has nothing to disclose. Mr. Guan has nothing to disclose. Miss Lahey has nothing to disclose.