Latent human herpesvirus 6 is reactivated in CAR T cells.

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.

Encephalitis in HIV-negative immunodeficient patients: a prospective multicentre study, France, 2016 to 2019.

BackgroundData on infectious encephalitis in immunodeficient (ID) individuals are scarce. This population may present with atypical clinical symptoms, be infected by uncommon pathogens and develop poor outcomes.AimWe aimed to describe the epidemiology of infectious encephalitis among HIV-negative ID patients.MethodsPatients from the ENCEIF (Etude Nationale de Cohorte des Encéphalites Infectieuses en France) prospective cohort meeting criteria for infectious encephalitis between January 2016 and December 2019 were included. We compared clinical presentation, magnetic resonance imaging (MRI) results, biological results, infection causes and outcome of ID patients with immunocompetent (IC) patients using Pearson's chi-squared test and Student's t-test. We carried out logistic regression to assess the role of immunodeficiency as risk factor for poor outcome.ResultsID patients (n = 58) were older (mean 72 vs 59 years), had higher prevalence of diabetes (26% vs 12%), pre-existing neurological disorders (12% vs 5%) and higher case-fatality rate (23.6% vs 5.6%) compared to IC patients (n = 436). Varicella zoster virus was the primary cause of encephalitis in ID patients (this aetiology was more frequent in ID (25.9%) than in IC patients (11.5%)), with herpes simplex virus second (22.4% in ID patients vs 27.3% in IC patients). Immunodeficiency was an independent risk factor for death or major sequelae (odds ratio: 3.41, 95%CI: 1.70-6.85).ConclusionsVaricella zoster virus is the most frequent cause of infectious encephalitis in ID patients. Immunodeficiency is a major risk factor for poor outcome. ID encephalitis patients should benefit from stringent investigation of cause and early empiric treatment.

Infectious encephalitis in elderly patients: a prospective multicentre observational study in France 2016-2019.

PURPOSE: Data on encephalitis in elderly patients are scarce. We aimed to describe the characteristics, aetiologies, management, and outcome of encephalitis in patients older than 65 years. METHODS: We performed an ancillary study of ENCEIF, a prospective cohort that enrolled all cases of encephalitis managed in 46 clinical sites in France during years 2016-2019. Cases were categorized in three age groups: (1) 18-64; (2) 65-79; (3) ≥ 80 years. RESULTS: Of the 494 adults with encephalitis enrolled, 258 (52%) were ≥ 65 years, including 74 (15%) ≥ 80 years. Patients ≥ 65 years were more likely to present with coma, impaired consciousness, confusion, aphasia, and rash, but less likely to present with fever, and headache (P < 0.05 for each). Median cerebrospinal fluid (CSF) white cells count was 61/mm3[13-220] in 65-79 years, 62 [17-180] in ≥ 80 years, vs. 114 [34-302] in < 65 years (P = 0.01). The proportion of cases due to Listeria monocytogenes and VZV increased after 65 years (P < 0.001), while the proportion of tick-borne encephalitis and Mycobacterium tuberculosis decreased with age (P < 0.05 for each). In-hospital mortality was 6/234 (3%) in < 65 years, 18/183 (10%) in 65-79 years, and 13/73 (18%) in ≥ 80 years (P < 0.001). Age ≥ 80 years, coma on admission, CSF protein ≥ 0.8 g/L and viral encephalitis were independently predictive of 6 month mortality. CONCLUSION: Elderly patients represent > 50% of adults with encephalitis in France, with higher proportion of L. monocytogenes and VZV encephalitis, increased risk of death, and sequels. The empirical treatment currently recommended, aciclovir and amoxicillin, is appropriate for this age group.

Sequential infection of Epstein-Barr virus and cryptococcal encephalitis after umbilical cord blood transplantation in a child with X-linked adrenoleukodystrophy.

Dual infection with two pathogens can be found in few cases of encephalitis. Cases of sequential infection with EBV and cryptococcal encephalitis in post-transplant patients are rare. We describe a 5-year-old boy with X-linked adrenoleukodystrophy who presented sequential infection with EBV and cryptococcal encephalitis after umbilical cord blood transplant. The patient showed fever, vomiting and emotional agitation with EBV DNA detected in CSF on day 100. The child underwent 3 doses of intravenous rituximab with a good response. However, the child presented with right facial paralysis, headache, and fever on day 130 after 2 weeks of clinical stability. Brain MRI demonstrated chronic granuloma formed with ring enhancement. FilmArray ME PCR confirmed the existence of Cryptococcus neoformans/gattii in the CSF. The child underwent sequential treatment with amphotericin liposome B and flucytosine. Maintenance treatment with fluconazole was administered for 1 year. Facial paralysis was on longer present on day 260. Cryptococcus neoformans/gattii was not detected on day 310. The biochemistry and cell count of the CSF were completely normal on day 520. Follow-up 2.5 years after presentation, brain MRI changes showed near complete resolution of the lesions. The child survived for 3 years to the last following-up. Invasive cryptococcal encephalitis is rare and life-threatening complication of transplantation. It is important to recognize dual infections, and perform treatment quickly to improve the prognosis of encephalitis after transplantation.

From Severe Herpes Zoster to Rare Suid Herpesvirus Encephalitis: A New Twist of the Varicellovirus Genus Infection in Patients with Kidney Diseases.

Both the herpes zoster virus and suid herpesvirus type 1 (SuHV-1) belong to the Varicellovirus genus of the α-herpesviridae subfamily. They may cause opportunistic infections especially in patients with kidney diseases, varying from latent illness to overt lethality. Under these circumstances, impaired renal function is both the culprit for and victim of the infection. However, fulminant eruption of severe skin herpes zoster in lupus nephritis (LN) patients under prolonged immunosuppressive therapy is rare and even more rarely seen is the SuHV-1 encephalitis in human. Facing the evolution of these rare infections, we hence chose to review the clinical pathogenicity of these two viruses which were cognate in origin but distinct in virulence. As such, we began with the first of the two above viral diseases and proceeded with peculiar renal involvement, unique clinical symptoms and pertinent lethal risk. Of importance, LN was used to exemplify the reciprocally detrimental interactions between impaired renal function and suppressed immune response. Then in a manner similar to the gradient overlay, SuHV-1 encephalitis was discussed focusing on its neurotropic features, specific MRI findings and exclusive test of high throughput sequencing. Our report highlighted novel presentations of the Varicellovirus genus infection by providing a productive multidisciplinary communication with pointed disclosure of the renal involvement. It may therefore be of great medical relevance and educational value for clinicians, especially the unseasoned ones, to foresee and manage similar cases in susceptible patients.

Immune-mediated encephalitis for the infectious disease specialist.

PURPOSE OF REVIEW: Autoimmune encephalitis is increasingly recognized and must be distinguished from infectious forms of encephalitis. Moreover, physicians should be aware of infectious triggers of autoimmune encephalitis and of infectious complications associated with treatment. RECENT FINDINGS: Recent epidemiological studies suggest that the incidence of autoimmune encephalitis may rival that of infectious encephalitis. Although distinguishing autoimmune from infectious forms of encephalitis on clinical grounds can be challenging, recently proposed diagnostic criteria can provide some assistance. There has been an explosion in our knowledge of autoimmune encephalitis associated with antibodies to neuronal cell surface antigens, and two of the most common forms, anti-NMDA receptor encephalitis and anti-LGI1 encephalitis, are typically associated with distinctive clinical features. Although tumors have long been known to trigger autoimmune encephalitis, it has been recently recognized that herpes simplex encephalitis may trigger the generation of antineuronal autoantibodies resulting in an autoimmune neurologic relapse. Both first and second-line therapies for autoimmune encephalitis are associated with infectious complications, whereas emerging treatments, including anakinra and tocilizumab, may also result in increased susceptibility to certain infections. SUMMARY: The diagnosis and management of autoimmune encephalitis is complex, and awareness of diagnostic criteria and modalities, typical clinical syndromes, infectious triggers of disease, and infectious complications of therapies is critical in optimizing care for affected patients.

Into Darkness and Silence: What Caused Helen Keller's Deafblindness?

In 1882, at 19 months of age, Helen Keller developed a febrile illness that left her both deaf and blind. Historical biographies attribute the illness to rubella, scarlet fever, encephalitis, or meningitis. This analysis of her illness suggests she likely had bacterial meningitis, caused by Neisseria meningitidis or possibly Haemophilus influenzae.

Neuroendoscopy for post-infective hydrocephalus in children.

The treatment of hydrocephalus has changed in recent years with better imaging and introduction of endoscopic procedures as well as enhanced shunts. Indications of endoscopic third ventriculostomy (ETV) are now more refined with better quantification of outcome. This article reviews the current state of neuroendoscopy for infective hydrocephalus in children. The roles of third ventriculostomy as a primary procedure or after shunt malfunction, endoscopic interventions in multiloculated hydrocephalus and introduction of intraventricular lavage to salvage severely infected children are evaluated.

Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults.

BACKGROUND: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. METHODS: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. RESULTS: All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. CONCLUSIONS: These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.

Febrile infection-related epilepsy syndrome treated with anakinra.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939-945.

Heme dampens T-cell sequestration by modulating glial cell responses during rodent cerebral malaria.

Cerebral malaria is the deadliest complication of Plasmodium falciparum infection. Its pathophysiology is associated with a strong pro-inflammatory reaction and the activation of glial cells. Among modulators released during the infection, heme seems to play a controversial role in the pathophysiology of malaria. Herein, we first investigated the phenotype of glial cells during cerebral malaria in C57BL/6 mice infected with P. berghei ANKA. Given the fact that high levels of heme were associated with cerebral malaria, we then investigated its impact on microglial, astrocyte, and T cell responses to further clarify its contribution in the neuropathophysiology. Surprisingly, we found that administration of heme twice a day from day three of infection induced the expression of the Heme oxygenase-1 (Hmox1) gene and prevented brain damages. More specifically, heme inhibited the M1 phenotype of microglia, hampered the activation of astrocytes, and decreased the cerebral expression of Ifng, Tnfa and Ip10. Heme might that way alter the migration of pathogenic CD4 and CD8 T lymphocytes within the brain observed during cerebral malaria. Taking into account that cerebral malaria results from a complex interplay between host- and parasite-derived factors, it is possible that genetic polymorphisms of Hmox1, which could be associated with the control of systemic levels of heme during P. falciparum infection, might explain its dual role and its contribution to the resistance to cerebral malaria.

Long-term outcomes of infective encephalitis in children: a systematic review and meta-analysis.

AIM: The long-term outcomes of childhood infective encephalitis are variable and not well quantified. We aimed to systematically review the literature and undertake meta-analyses on predetermined outcomes to address this knowledge gap and identify areas for future research. METHOD: We searched electronic databases, performed complementary reviews of references of fully extracted articles, and made contact with experts on infective encephalitis. Articles published up until April 2016 were selected for screening. RESULTS: We evaluated sequelae of 1018 survivors of childhood infective encephalitis (934 with complete follow-up) from 16 studies. Mean age during acute encephalitis episodes was 5 years 3.6 months (range 1.2mo-17y), 57.6% were male (500/868), and mean follow-up period was 4 years 1.2 months (range 1-12y). Incomplete recovery was reported in 312 children (42.0%; 95% confidence interval [CI] 31.6-53.1% in pooled estimate). Among the other sequelae, developmental delay, abnormal behaviour, motor impairment, and seizures were reported among 35.0% (95% CI 10.0-65.0%), 18.0% (95% CI 8.0-31.0%), 17.0% (95% CI 10.0-26.0%), and 10.0% (95% CI 6.0-14.0%) respectively. INTERPRETATION: Almost half of childhood infective encephalitis survivors report incomplete recovery in the long-term; most commonly developmental delay, behavioural abnormality, and neurological impairments (i.e. seizure). Well designed, large-scale prospective studies are needed to better quantify neurodevelopmental sequelae among childhood encephalitis survivors.

Unusual Necrotizing Encephalitis in Raccoons and Skunks Concurrently Infected With Canine Distemper Virus and Sarcocystis sp.

Canine distemper virus commonly infects free-ranging, terrestrial mesopredators throughout the United States. Due to the immunosuppressive effects of the virus, concurrent opportunistic infections are also common. Among these, secondary systemic protozoal infections have been described in a number of species. We report an unusual presentation of necrotizing encephalitis associated withSarcocystissp in four raccoons and one skunk concurrently infected with canine distemper virus. Lesions were characterized by variably sized necrotizing cavitations composed of abundant mineral admixed with inflammatory cells and protozoa.Sarcocystissp was confirmed via immunohistochemistry using a monoclonal antibody toSarcocystis neurona The pathologic changes are similar to lesions in human AIDS patients infected withToxoplasma gondii.

Successful treatment of toxoplasmic encephalitis diagnosed early by polymerase chain reaction after allogeneic hematopoietic stem cell transplantation: two case reports and review of the literature.

Toxoplasmic encephalitis represents a rare, but often fatal infection after allogeneic hematopoietic stem cell transplantation. Polymerase chain reaction (PCR)-based preemptive therapy is considered promising for this disease, but is not routinely applied, especially in low seroprevalence countries including Japan. We encountered 2 cases of toxoplasmic encephalitis after transplantation that were successfully treated. The diagnosis of toxoplasmic encephalitis in these cases was confirmed by PCR testing when neurological symptoms were observed. Both patients received pyrimethamine and sulfadiazine treatments within 2 weeks of the development of neurological symptoms, and remained free of recurrence for 32 and 12 months. These results emphasized the importance of the PCR test and immediate treatment after diagnosis for the management of toxoplasmic encephalitis.

Paroxysmal Sympathetic Hyperactivity in Critically Ill Children with Encephalitis and Meningoencephalitis.

BACKGROUND: Autonomic dysfunction in pediatric patients with acquired brain injury is often encountered and greatly understudied. We sought to identify the incidence of Paroxysmal Sympathetic Hyperactivity (PSH) in critically ill pediatric patients with meningoencephalitis and encephalitis, associated risk factors and influence on outcome. METHODS: Children admitted to the pediatric intensive care unit (PICU) with a diagnosis of meningoencephalitis and/or encephalitis were identified from a single institution Neurocritical Care database. The patients were stratified as having a bacterial or non-bacterial cause of their meningoencephalitis/encephalitis. Data from their hospitalization was supplemented with a retrospective review of the electronic medical record. PSH was defined as episodic lability in heart rate and/or blood pressure, hyperthermia, diaphoresis, dystonic posturing, tachypnea and/or agitation without any other cause. Statistical analysis was performed using t-test and chi-squared to compare outcomes and risk factors between patients with PSH and without. RESULTS: PSH was found in 41 % of children studied. Subgroup analysis revealed patients with non-bacterial encephalitis were more likely to experience PSH (51 %) as compared to those with bacterial causes (27 %). Fever and/or seizures on presentation and female gender were associated with higher occurrence of PSH but only in the non-bacterial etiology group. There were trends toward increased length of PICU and overall hospital stay for patients with PSH. CONCLUSIONS: PSH was found in a high percentage of our patients with significant variation in risk factors and outcome noted between patients with bacterial and nonbacterial causes of their meningoencephalitis/encephalitis.

Adrenal Crisis Presenting as Recurrent Encephalopathy Mimicking Autoimmune, Infectious Encephalitis, and Common Variable Immune Deficiency: A Case Report.

INTRODUCTION: Adrenal crisis can present with life-threatening complications and mimic autoimmune or infectious encephalitis, and common variable immune deficiency (CVID). The literature regarding the neurological complications of adrenal crisis is limited and focuses on patients who present with hypotension and electrolyte abnormalities. CASE REPORT: A 30-year-old man presented 3 times to our hospital with encephalopathy, fever, and left sided weakness with a history of multiple autoimmune diseases and prior hospitalizations for encephalopathy. During his first 2 admissions, he was normotensive and without electrolyte abnormalities. Extensive workup for infectious, paraneoplastic, seizure, metabolic, toxic, and vascular etiologies, and autoimmune encephalitis was negative. His exam returned to baseline with empiric steroid treatment, and he was discharged. He re-presented 2 months later with encephalopathy for a third admission. During this subsequent presentation, he had hyponatremia, low serum osmolality, elevated urine sodium, undetectable morning cortisol, and 21-α hydroxylase autoantibodies. A diagnosis of autoimmune adrenal insufficiency was established, he was treated with physiological doses of hydrocortisone and fludrocortisone, and improved rapidly to near baseline function. He has remained relapse-free at 4-year follow up. During all admissions, he was also found to have low immunoglobulin G levels and met criteria for CVID; however, his immunoglobin levels recovered with steroid replacement. CONCLUSION: The reported patient demonstrated some of the neurological complications of adrenal crisis which can mimic other autoimmune conditions such as CVID. The neurologist should be aware that recurrent encephalopathy from adrenal insufficiency can occur regardless of hemodynamic or electrolyte changes on typical hospital metabolic panels.

Pediatric Autoimmune Encephalitis and Its Relationship With Infection.

Autoimmune encephalitis (AE) is an increasingly recognized inflammatory disorder of the central nervous system and is most often characterized by antibodies against intracellular and neuronal surface antigens. AE is a devastating disease that may result in developmental delay or regression in children. However, the pathogenesis of AE is not clear, and immune system disorders after infection likely play an important role in AE. Many studies have reported that patients with herpes simplex virus encephalitis develop anti-N-methyl-d-aspartate receptor encephalitis after antiviral treatment. It is critical to recognize pediatric AE early and to distinguish it from infectious forms because AE is treatable and responsive to immunotherapies. In this review, we discuss the clinical features of pediatric AE and focus on the relationship between AE and postinfection status. In addition, we review the probable mechanisms underlying infection-triggered AE, which include molecular mimicry, bystander activation, epitope spreading, immune system disorder, and genetic susceptibility.

Clinical significance of Epstein-Barr virus in the cerebrospinal fluid of immunocompetent patients.

INTRODUCTION: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.