Characteristics, management and outcome of Herpes Simplex and Varicella-Zoster virus encephalitis: a multicentre prospective cohort study.

OBJECTIVE: To characterize differences between Herpes Simplex virus encephalitis and Varicella-Zoster virus encephalitis (HSVE and VZVE) and other aetiologies of infectious encephalitis (IE), and to investigate the impact of time-to-aciclovir (ACV) start, ACV dose and duration on outcome. METHODS: We compared 132 HSVE, 65 VZVE and 297 other IE enrolled in a prospective cohort (ENCEIF). We estimated associations between time-to-ACV start, dose or duration and outcome through adjusted odds ratio (aOR) using logistic regression analysis. RESULTS: Prevalence of immunodepression differed among aetiologies: 15/65 (23%) for VZVE, 13/132 (10%) for HSVE and 30/297 (10%) for other IE (p <0.05), as was presence of seizure at admission: 27/132 (20%) for HSVE, 4/65 (6%) for VZVE and 43/297 (14%) for other IE (p <0.05). Poor outcome at hospital discharge (Glasgow outcome scale ≤3) differed among the three groups: 40/127 (31%) for HSVE, 12/65 (18%) for VZVE and 38/290 (13%) for other IE (p <0.05). Time-to-ACV start was associated with outcome in HSVE (aOR 3.61 [1.25-10.40]), but not in VZVE (aOR 0.84 [0.18-3.85]). Increased ACV dose was not associated with outcome among HSVE (aOR 1.25 [0.44-3.64]) nor VZVE (aOR 1.16 [0.24-5.73]). DISCUSSION: HSVE and VZVE are distinct in clinical presentation, outcome and prognostic factors. The impact of early ACV initiation was more apparent for HSVE than for VZVE; however, this could be because of VZVE's smaller sample size and lower outcome rate leading to low statistical power or because of potential distinct IE pathophysiology.

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.

Outcome and Sequelae of Autoimmune Encephalitis.

Autoimmune etiologies are a common cause for encephalitis. The clinical syndromes consistent with autoimmune encephalitis are both distinct and increasingly recognized, but less is known about persisting sequelae or outcomes. We searched PubMed for reports on outcomes after autoimmune encephalitis. Studies assessing validated, quantitative outcomes were included. We performed a narrative review of the published literature of outcomes after autoimmune encephalitis. We found 146 studies that produced outcomes data. The mortality rates were 6%-19% and the relapse risks were 10%-62%. Most patients achieved a good outcome based on a score on the modified Rankin Scale (mRS) of ≤2. Forty-nine studies evaluated outcomes beyond mRS; these studies investigated cognitive outcome, psychiatric sequelae, neurological deficits, global function, and quality-of-life/patient-reported outcomes using various tools at varying time points after the index hospital discharge. These more-detailed assessments revealed that most patients had persistent impairments, with frequent deficits in cognitive function, especially memory and attention. Depression and anxiety were also common. Many of these sequelae continued to improve over months or even years after the acute illness. While we found that lasting impairments were common among survivors of autoimmune encephalitis, additional research is needed to better understand the nature and impact of these sequelae. Standardized evaluation protocols are needed to improve the ability to compare outcomes across studies, guide rehabilitation strategies, and inform outcomes of interest in treatment trials as the field advances.

Outcome and Sequelae of Infectious Encephalitis.

Acute infectious encephalitis is a widely studied clinical syndrome. Although identified almost 100 years ago, its immediate and delayed consequences are still neglected despite their high frequency and possible severity. We reviewed the available data on sequelae and persisting symptoms following infectious encephalitis with the aim of characterizing the clinical picture of these patients at months to years after hospitalization. We searched PubMed for case series involving sequelae after infectious encephalitis. We carried out a narrative review of the literature on encephalitis caused by members of the Herpesviridae family (herpes simplex virus, varicella zoster virus, and human herpesvirus-6), members of the Flaviviridae family (West Nile virus, tick-borne encephalitis virus, and Japanese encephalitis virus), alphaviruses, and Nipah virus. We retrieved 41 studies that yielded original data involving 3,072 adult patients evaluated after infectious encephalitis. At least one of the five domains of cognitive outcome, psychiatric disorders, neurological deficits, global functioning, and quality of life was investigated in the reviewed studies. Various tests were used in the 41 studies and the investigation took place at different times after hospital discharge. The results showed that most patients are discharged with impairments, with frequent deficits in cognitive function such as memory loss or attention disorders. Sequelae tend to improve within several years following flavivirus or Nipah virus infection, but long-term data are scarce for other pathogens. Further research is needed to better understand the extent of sequelae after infectious encephalitis, and to propose a standardized assessment method and assess the rehabilitation efficacy in these patients.

Characteristics, management, and outcomes of patients with infectious encephalitis requiring intensive care: A prospective multicentre observational study.

PURPOSE: Infectious encephalitis (IE) is a severe disease which requires intensive care unit (ICU) admission in up to 50% of cases. We aimed to describe characteristics, management and outcomes of IE patients who required ICU admission. MATERIALS AND METHODS: Ancillary study focusing on patients with ICU admission within the ENCEIF cohort, a French prospective observational multicentre study. The primary criteria for outcome was the functional status at hospital discharge, categorized using the Glasgow outcome scale (GOS). Logistic regression model was used to identify risk factors for poor outcome, defined as a GOS ≤ 3. RESULTS: We enrolled 198 ICU patients with IE. HSV was the primary cause (n = 72, 36% of all IE, 53% of IE with microbiological documentation). Fifty-two patients (26%) had poor outcome at hospital discharge, including 22 deaths (11%). Immunodeficiency, supratentorial focal signs on admission, lower cerebrospinal fluid (CSF) white cells count (<75/mm3), abnormal brain imaging, and time from symptoms onset to acyclovir start >2 days were independent predictors of poor outcome. CONCLUSION: HSV is the primary cause of IE requiring ICU admission. IE patients admitted in ICU have a poor prognosis with 11% of in-hospital mortality and 15% of severe disabilities in survivors at discharge.

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.

Encephalitis in travellers: a prospective multicentre study.

BACKGROUND: As the epidemiology of encephalitis varies from one country to another, international travel may be an important clue for the diagnostic workout of this puzzling disease. METHODS: We performed an ancillary study using the ENCEIF prospective cohort conducted in 62 clinical sites in France from 2016 to 2019. All cases of encephalitis in adults that fulfilled a case definition derived from the International Encephalitis Consortium were included. Travellers were defined as patients who spent at least one night in a foreign country within the last six months. RESULTS: Of the 494 encephalitis patients enrolled, 69 (14%) were travellers. As compared to non-travellers, they were younger (median age, 48 years [interquartile range, 36-69] vs 66 [49-76], P < 0.001), less likely to be immunocompromised: 2/69 (3%) vs 56/425 (13%), P = 0.02, and reported more arthralgia: 7/69 (10%) vs 11/425 (3%), P = 0.007. The risk of poor outcome at hospital discharge (Glasgow outcome scale ≤3), was similar for travellers and for non-travellers after adjustment (aOR 0.80 [0.36-1.80], P = 0.594). Arboviruses were the main causes of encephalitis in travellers: 15/69 (22%) vs 20/425 (5%) in non-travellers, P < 0.001, and Herpes simplex virus (HSV) was the second (9/69, 13%). Of note, in 19% (13/69) of cases, the risk of encephalitis in travellers may have been decreased with a vaccine. CONCLUSION: The two primary causes of encephalitis in travellers are arboviruses and HSV. Empirical treatment of encephalitis in travellers must include acyclovir. Pre-travel advice and vaccination may decrease the risk of encephalitis in travellers.

ESCMID rapid guidelines for assessment and management of long COVID.

SCOPE: The aim of these guidelines is to provide evidence-based recommendations for the assessment and management of individuals with persistent symptoms after acute COVID-19 infection and to provide a definition for this entity, termed 'long COVID'. METHODS: We performed a search of the literature on studies addressing epidemiology, symptoms, assessment, and treatment of long COVID. The recommendations were grouped by these headings and by organ systems for assessment and treatment. An expert opinion definition of long COVID is provided. Symptoms were reviewed by a search of the available literature. For assessment recommendations, we aimed to perform a diagnostic meta-analysis, but no studies provided relevant results. For treatment recommendations we performed a systematic review of the literature in accordance with the PRISMA statement. We aimed to evaluate patient-related outcomes, including quality of life, return to baseline physical activity, and return to work. Quality assessment of studies included in the systematic review is provided according to study design. RECOMMENDATIONS: Evidence was insufficient to provide any recommendation other than conditional guidance. The panel recommends considering routine blood tests, chest imaging, and pulmonary functions tests for patients with persistent respiratory symptoms at 3 months. Other tests should be performed mainly to exclude other conditions according to symptoms. For management, no evidence-based recommendations could be provided. Physical and respiratory rehabilitation should be considered. On the basis of limited evidence, the panel suggests designing high-quality prospective clinical studies/trials, including a control group, to further evaluate the assessment and management of individuals with persistent symptoms of COVID-19.

Training in infectious diseases across Europe in 2021 - a survey on training delivery, content and assessment.

OBJECTIVES: To define the status of infectious diseases (ID) as an approved specialty in Europe; to enumerate the number of specialists (in general and in relation to the overall population) and specialist trainees and describe the content, delivery and evaluation of postgraduate training in ID in different countries. METHODS: Structured web-based questionnaire surveys in March 2021 of responsible national authorities, specialist societies and individual country representatives to the Section of Infectious Diseases of the European Union for Medical Specialties. Descriptive analysis of quantitative and qualitative responses. RESULTS: In responses received from 33/35 (94.3%) countries, ID is recognized as a specialty in 24 and as a subspecialty of general internal medicine (GIM) in eight, but it is not recognized in Spain. The number of ID specialists per country varies from <5 per million inhabitants to 78 per million inhabitants. Median length of training is 5 years (interquartile range 4.0-6.0 years) with variable amounts of preceding and/or concurrent GIM. Only 21.2% of countries (7/33) provide the minimum recommended training of 6 months in microbiology and 30% cover competencies such as palliative care, team working and leadership, audit, and quality control. Training is monitored by personal logbook or e-portfolio in 75.8% (25/33) and assessed by final examinations in 69.7% (23/33) of countries, but yearly reviews with trainees only occur in 54.5% (18/33) of countries. CONCLUSIONS: There are substantial gaps in modernization of ID training in many countries to match current European training requirements. Joint training with clinical microbiology (CM) and in multidisciplinary team working should be extended. Training/monitoring trainers should find greater focus, together with regular feedback to trainees within many national training programmes.

Training and assessment of medical specialists in clinical microbiology and infectious diseases in Europe.

BACKGROUND: There is wide variation in the availability and training of specialists in the diagnosis and management of infections across Europe. OBJECTIVES: To describe and reflect on the current objectives, structure and content of European curricula and examinations for the training and assessment of medical specialists in Clinical (Medical) Microbiology (CM/MM) and Infectious Diseases (ID). SOURCES: Narrative review of developments over the past two decades and related policy documents and scientific literature. CONTENT: Responsibility for curricula and examinations lies with the European Union of Medical Specialists (UEMS). The ID Section of UEMS was inaugurated in 1997 and the MM Section separated from Laboratory Medicine in 2008. The sections collaborate closely with each other and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Updated European Training Requirements (ETR) were approved for MM in 2017 and ID in 2018. These comprehensive curricula outline the framework for delivery of specialist training and quality control for trainers and training programmes, emphasizing the need for documented, regular formative reviews of progress of trainees. Competencies to be achieved include both specialty-related and generic knowledge, skills and professional behaviours. The indicative length of training is typically 5 years; a year of clinical training is mandated for CM/MM trainees and 6 months of microbiology laboratory training for ID trainees. Each Section is developing examinations using multiple choice questions to test the knowledge base defined in their ETR, to be delivered in 2022 following pilot examinations in 2021. IMPLICATIONS: The revised ETRs and European examinations for medical specialists in CM/MM and ID provide benchmarks for national authorities to adapt or adopt locally. Through harmonization of postgraduate training and assessment, they support the promotion and recognition of high standards of clinical practice and hence improved care for patients throughout Europe, and improved mobility of trainees and specialists.

A Prospective Cohort Study to Identify Clinical, Biological, and Imaging Features That Predict the Etiology of Acute Encephalitis.

BACKGROUND: New diagnostic tools have been developed to improve the diagnosis of infectious encephalitis. Using a prospective cohort of encephalitis patients, our objective was to identify possible clusters of patients with similar patterns among encephalitis of unknown cause (EUC) and to describe to what extent a patient's initial presentation may be predictive of encephalitis etiology, particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV). METHODS: The National Cohort of Infectious Encephalitis in France is an ongoing prospective cohort study implemented in France in 2016. Patients who present with documented or suspected acute infectious encephalitis were included. Focusing on the variables that describe the initial presentation, we performed a factor analysis of mixed data (FAMD) to investigate a pattern of association between the initial presentation of a patient and the etiologic pathogen. RESULTS: As of 1 August 2018, data from 349 patients were analyzed. The most frequent pathogens were HSV (25%), VZV (11%), tick-borne encephalitis virus (6%), Listeria (5%), influenza virus (3%), and EUC (34%). Using the FAMD, it was not possible to identify a specific pattern related to the group of EUC. Age, temporal or hemorrhagic lesions, and cerebral spinal fluid lymphocytosis were significantly associated with HSV/VZV encephalitis. CONCLUSIONS: No initial clinical/imaging/biology pattern was identified at admission among EUC, despite the improvement in diagnostic tools. In this context, the recommendation for a universal, early, probabilistic, initial treatment against HSV and VZV is still relevant, regardless of the initial clinical presentation of the encephalitis.

The COVID-19 pandemic should not jeopardize dengue control.

The concurrent circulation of dengue and coronavirus disease 2019 (COVID-19) may produce many unfavourable outcomes-such as co-infections; delays in diagnosis, treatment, and mitigation measures; overwhelming of the healthcare system; underreporting of cases; deterioration in surveillance and control interventions; and exacerbation of social inequalities. Indeed, lockdown is greatly compromising the effectiveness of vector control, especially social mobilization campaigns and preventive insecticide spraying in private spaces (indoor and peridomestic spraying). Thus, failure to appropriately implement the full range of vector control interventions can lead to a reduction in their overall effectiveness and an increasing risk of vector-borne diseases circulating. Consequently, the health community and policy makers should develop proactive policies and allocate adequate resources to prevent and manage the resurgence of dengue and other vector-borne diseases in the new era of COVID-19.

Anterior Thalamic Stimulation Induced Relapsing Encephalitis.

Deep brain stimulation of the anterior thalamic nucleus is one of the promising therapeutic options for epilepsy. Several studies are still under way to further strengthen and clarify the mechanism, efficacy, and complications. Contrary to hardware-related and operation-related events, the stimulation-related adverse effect is mild, target-dependent, and adjustable. We present a case of relapsing herpes simplex encephalitis (HSE) as a newly reported and potentially fatal stimulation-related adverse effect following stimulation of the anterior thalamic nucleus (ANT-DBS) accompanied by fever, confusion, and cognitive impairment in a 32-year-old epileptic patient with a history of herpes meningoencephalitis 31 years earlier. The T2-weighted/FLAIR high-signal intensity in the temporal lobe developed at a "distance" from the stimulation target. The positive polymerase chain reaction of herpes virus deoxyribonucleic acid in the cerebrospinal fluid confirmed the diagnosis. The condition improved partially on acyclovir and stimulation stopped. Seizures disappeared and then returned after few months. The unique case report presents a rationale for considering history of herpes encephalitis as a relative contraindication for ANT-DBS, and HSE relapse should be suspected in patients with post-stimulation fever and/or altered consciousness.

Herpes simplex virus encephalitis update.

PURPOSE OF REVIEW: HSV is the most frequently identified cause of infectious encephalitis, in Western countries. This article is an update on the topic based on a review of recent studies from 2017 to 2018. RECENT FINDINGS: Acyclovir is still the first line treatment, and no new drugs are currently available for clinical use. The major considerations for HSV encephalitis are as follows: point one, clinical evaluation remains the most important factor, as though CSF HSV PCR has a good sensitivity, in a small proportion of patients the initial testing might be negative. MRI brain is the first line imaging test, and mesial temporal lobe involvement and other typical findings are important for diagnosis; point 2, there should be emphasis on sequela, short-term, and long-term outcomes, and not just case fatality rated in future studies and clinical management. Auto-immune encephalitis can be triggered by HSV, and should be considered in patients who are not responding to treatment; point 3, future studies should be on better management of sequela, and better treatment regimens including those targeting the immune response. SUMMARY: Autoimmune encephalitis is a clearly identified complication of HSV encephalitis. Inflammatory mechanisms are linked to the clinical presentation as well as severity and poor outcome. Initial corticosteroid therapy has to be evaluated in order to prevent complications.

Serodiagnosis of Extraintestinal Amebiasis: Retrospective Evaluation of the Diagnostic Performance of the Bordier® ELISA Kit.

Soluble antigens from an axenic culture of Entamoeba histolytica were used to develop a commercial ELISA kit to quantify anti-E. histolytica antibodies in sera of patients with extraintestinal amebiasis in non-endemic settings. The diagnostic specificity and sensitivity of the test were assessed retrospectively using 131 human serum samples with amoebic serologic status available. They were selected according to their results in immunofluorescence (IFAT) and were separated in 2 sample categories: 64 sera with positive results by IFAT and 67 with negative results by IFAT. The sensitivity and specificity of the ELISA kit were assessed at 95.0% and 94.0% compared to the IFAT. The test can be useful to exclude a potential diagnosis of amebiasis and could be used as a screening method since ELISA is an automated technique.

Inline Coupling of Electrokinetic Preconcentration Method to Taylor Dispersion Analysis for Size-Based Characterization of Low-UV-Absorbing Nanoparticles.

The inline coupling of the field-amplified sample injection (FASI) to Taylor dispersion analysis (TDA) was used to characterize low-UV absorbing carboxylated silica nanoparticles (cNPs). The hydrodynamic diameters (Dh) were measured by using a commercial capillary electrophoresis instrument. The proposed methodology did not require any complicated instruments or chromophoric dye to increase the detection sensitivity. A practical method based on a half-Gaussian fitting was proposed for the data processing. The results obtained by this method were compared with those derived from dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. From these results, it appeared that the size derived by TDA is in excellent agreement with those measured by DLS and TEM, as demonstrated by stable nanoparticles with narrow size distributions. Intermediate precision relative standard deviations less than 5% were obtained by FASI-TDA. The effect of the FASI-induced cNP peak dispersion on the reliability of the results was discussed in detail.

Neurological Presentation of Zika Virus Infection Beyond the Perinatal Period.

PURPOSE OF REVIEW: Our purpose was to summarize the current knowledge about the neurological presentation of Zika virus infection after the perinatal period. Other Flaviviruses infections, such as West Nile virus (WNV) or Japanese encephalitis virus (JEV), can result in neuro-invasive disease such as myelitis, encephalitis, or meningitis. We aimed at describing the specificities of ZV neurological infection. RECENT FINDINGS: The recent outbreaks demonstrated clearly the neurotropism of ZV. However, by contrast with other Flaviviruses, the most frequent neurological presentation of ZV infection beyond the perinatal period was Guillain-Barré syndrome, especially the demyelination form of GBS. Encephalitis and myelitis seem to occur less frequently after ZV infection than after WNV or JEV infection. The pathophysiology of neurological ZV infections is still poorly understood and no specific treatment is available. Moreover, no data is available about long-term persisting symptoms and possible impairment of patients after the acute clinical episode.

Herpes simplex type 2 encephalitis and methotrexate medication: a fortuitous or causative association in a patient with spondyloarthritis?

It is unclear whether immunosuppression is a risk factor for herpes encephalitis. Herein, we describe a rare case of herpes simplex virus type 2 encephalitis in a patient treated with low-dose methotrexate for HLA-B27-associated spondyloarthritis. The patient was successfully treated with acyclovir but presented sequelae of encephalitis. Here we discuss the possible role of low-dose methotrexate therapy as a risk factor of neurological herpes reactivation and severe disease. The host-related and viral risk factors are also addressed.

Waning immunity against mumps in vaccinated young adults, France 2013.

In 2013, 15 clusters of mumps were notified in France; 72% (82/114) of the cases had been vaccinated twice with measles-mumps-rubella vaccine. To determine whether the risk of mumps increased with time since the last vaccination, we conducted a case-control study among clusters in universities and military barracks. A confirmed case had an inflammation of a salivary gland plus laboratory confirmation in 2013. A probable case presented with inflammation of a salivary gland in 2013 either lasting for > 2 days or with epidemiological link to a confirmed case. Controls had no mumps symptoms and attended the same university course, student party or military barracks. We collected clinical and vaccination data via web questionnaire and medical records. We calculated adjusted odds ratios (aOR) using logistic regression. 59% (50/85) of cases and 62% (199/321) of controls had been vaccinated twice. The odds of mumps increased for twice-vaccinated individuals by 10% for every year that had passed since the second dose (aOR 1.10; 95% confidence interval (CI): 1.02-1.19; p = 0.02). Mumps immunity waned with increasing time since vaccination. Our findings contributed to the French High Council of Public Health's decision to recommend a third MMR dose during outbreaks for individuals whose second dose dates > 10 years.