Cytokine release syndrome-associated encephalopathy in patients with COVID-19.

BACKGROUND AND PURPOSE: Neurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS. METHODS: In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit. RESULTS: Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF. CONCLUSIONS: Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

Torquetenovirus viremia for early prediction of graft rejection after kidney transplantation.

OBJECTIVES: New biomarkers reflecting the degree of immunosuppression in transplant recipients are needed to provide an optimal personalized balance between rejection and infection risks. METHODS: For this purpose, we investigated TTV viremia dynamics in 66 kidney transplant recipients followed up for two years after transplantation, in relation to BK virus infection and graft rejection. RESULTS: After transplantation, TTV viremia rose by ≥2 log10 copies/mL from baseline to month 3, then declined by ≥1 log10 copies/mL thereafter. Higher TTV viremia was associated with recipients of a deceased donor, a lower count of CD8+ T cells and a higher BKV viremia. Importantly, TTV loads were significantly lower in KTR who would later display graft rejection; indeed, patients with TTV viremia lower than 3.4 log10 copies/mL at transplantation or lower than 4.2 log10 copies/mL at month 1 had a higher risk of developing graft rejection in the two following years (hazard ratio (HR) at D0 = 7.30, p = 0.0007 and HR at M1 = 6.16, p = 0.001). CONCLUSIONS: TTV viremia measurement at early times post transplantation predicts graft rejection and would represent a useful tool to improve kidney transplant monitoring.

Performance of genotypic algorithms for predicting tropism for HIV-1 CRF01_AE recombinant.

OBJECTIVES: There is no consensus about the performances of genotypic rules for predicting HIV-1 non-B subtype tropism. Three genotypic methods were compared for CRF01_AE HIV-1 tropism determination. METHODS: The V3 env region of 207 HIV-1 CRF01_AE and 178 B subtypes from 17 centers in France and 1 center in Switzerland was sequenced. Tropism was determined by Geno2Pheno algorithm with false positive rate (FPR) 5% or 10%, the 11/25 rule or the combined criteria of the 11/25, net charge rule and NXT/S mutations. RESULTS: Overall, 72.5%, 59.4%, 86.0%, 90.8% of the 207 HIV-1 CRF01_AE were R5-tropic viruses determined by Geno2pheno FPR5%, Geno2pheno FPR10%, the combined criteria and the 11/25 rule, respectively. A concordance of 82.6% was observed between Geno2pheno FPR5% and the combined criteria for CRF01_AE. The results were nearly similar for the comparison between Geno2pheno FPR5% and the 11/25 rule. More mismatches were observed when Geno2pheno was used with the FPR10%. Neither HIV viral load, nor current or nadir CD4 was associated with the discordance rate between the different algorithms. CONCLUSION: Geno2pheno predicted more X4-tropic viruses for this set of CRF01_AE sequences than the combined criteria or the 11/25 rule alone. For a conservative approach, Geno2pheno FPR5% seems to be a good compromise to predict CRF01_AE tropism.

Parsonage-Turner syndrome due to autochthonous acute genotype 3f hepatitis E virus infection in a nonimmunocompromised 55-year-old patient.

Hepatitis E virus (HEV) infection is an emerging autochthonous disease in industrialized countries. Extra-hepatic manifestations, in particular neurologic manifestations, have been reported in HEV infection. Only a few cases of hepatitis E-associated Parsonage-Turner syndrome have been reported, and HEV genotypes were rarely determined. Here, we report the case of a Parsonage-Turner syndrome associated with an acute autochthonous HEV infection in a 55-year-old immunocompetent patient. HEV genomic RNA was detected in serum and cerebrospinal fluid samples (CSF), and molecular phylogenetic analysis of HEV was performed. The interest of this case lies in its detailed description notably the molecular analysis of HEV RNA isolated from serum and CSF. HEV infection should be considered in diagnostic investigations of neurologic manifestations associated with liver function perturbations.

Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL: a 2014 French nationwide study.

Background: Surveillance of HIV-1 resistance in treated patients with a detectable viral load (VL) is important to monitor, in order to assess the risk of spread of resistant viruses and to determine the proportion of patients who need new antiretroviral drugs with minimal cross-resistance. Methods: The HIV-1 protease and reverse transcriptase (RT) and integrase genes were sequenced in plasma samples from 782 consecutive patients on failing antiretroviral regimens, seen in 37 specialized centres in 2014. The genotyping results were interpreted using the ANRS v24 algorithm. Prevalence rates were compared with those obtained during a similar survey conducted in 2009. Results: The protease and RT sequences were obtained in 566 patients, and the integrase sequence in 382 patients. Sequencing was successful in 60%, 78%, 78% and 87% of patients with VLs of 51-200, 201-500, 501-1000 and >1000 copies/mL, respectively. Resistance to at least one antiretroviral drug was detected in 56.3% of samples. Respectively, 3.9%, 8.7%, 1.5% and 3.4% of patients harboured viruses that were resistant to any NRTI, NNRTI, PI and integrase inhibitor (INI). Resistance rates were lower in 2014 than in 2009. Resistance was detected in 48.5% of samples from patients with a VL between 51 and 200 copies/mL. Conclusion: In France in 2014, 90.0% of patients in AIDS care centres were receiving antiretroviral drugs and 12.0% of them had VLs >50 copies/mL. Therefore, this study suggests that 6.7% of treated patients in France might transmit resistant strains. Resistance testing may be warranted in all treated patients with VL > 50 copies/mL.

[Tick-borne encephalitis in a child in a nonendemic country: A case report]. / Méningo-encéphalite à tiques chez l'enfant en France : à propos d'un cas.

Tick-borne encephalitis (TBE) is an arbovirus induced by tick-borne encephalitis virus (TBEV) transmitted by tick bite. The disease is rare in France (two to three cases per year) but endemic zones extend from Western Europe to the east coast of Asia (10,000-15,000 cases per year). An 8-year-old boy was admitted to our pediatric ward in Strasbourg (France) for febrile headache with diplopia. Four days after a tick bite, he declared a febrile headache together with maculopapular rash on the elbows, knees, and cheeks. Fourteen days after the outbreak of symptoms, he showed confusion, drowsiness, and binocular diplopia. Brain MRI was normal and the electroencephalogram found diffuse slow activity with no discharge. Lumbar puncture found meningitis with 92 cells (60% neutrophils, 40% lymphocytes). The diagnosis was made with specific IgM and IgG antibody isolation in the serum (Elisa). Lyme serology was negative. The evolution was slowly favorable and the child remained hospitalized for 8 days. The neurological control examination 2 weeks later was normal except for a moderate left deviation during tandem walk and left Romberg manoeuver. Meningitis or meningoencephalitis in a child must raise the diagnosis of TBE in children, even in nonendemic countries, given the recent increased incidence of TBE and the development of tourism. Recent travel in endemic areas, a history of tick bite, and a clinical course in two phases must be sought. The diagnosis is serologic and prevention is based on vaccination.

Clinical relevance of herpes simplex virus viremia in Intensive Care Unit patients.

OBJECTIVES: To determine the clinical relevance of herpes simplex virus (HSV) viremia episodes in critically ill adult patients. METHODS: 1556 blood samples obtained for HSV PCR analysis in Intensive Care Unit (ICU) patients over 4 years were retrospectively analyzed, focusing on the comprehensive analysis of 88 HSV-viremic patients. RESULTS: HSV DNA was detected in 11.8% of samples from the ICU. HSV viral loads remained below 5×10(2) copies/ml in 68.2% of patients and exceeded 10(4) copies/ml in 7.9%. Episodes of HSV-viremia correlated with immunosuppressed status and mechanical ventilation in 79.5% and 65.9% of patients, respectively. Only a subset of patients exhibited HSV-related organ damage, including pneumonia and hepatitis (10.2% and 2.3%, respectively). The mortality rate in HSV-viremic patients was not significantly increased compared to the overall mortality rate in the ICU (27.3% vs. 22.9%, p = 0.33). Only patients with high HSV viral loads tended to have a higher, though non-significant, death rate (57.1%, p = 0.14). CONCLUSIONS: Our results suggest HSV viremia is common in ICU patients, potentially favored by immunocompromised status and mechanical ventilation. The global impact of HSV-viremia on mortality in the ICU was low. Quantifying HSV DNA may help identifying patients at-risk of severe HSV-induced symptoms.

Switching to emtricitabine, tenofovir and rilpivirine as single tablet regimen in virologically suppressed HIV-1-infected patients: a cohort study.

OBJECTIVES: Emtricitabine/tenofovir/rilpivirine as a single-tablet regimen (STR) is widely used without licence in treatment-experienced patients. The purpose of this retrospective observational study was to assess viral suppression of ART-experienced patients switching to STR. METHODS: We assessed 131 pretreated patients switching to STR with HIV RNA <400 HIV-1 RNA copies/mL. The primary outcome measure was the proportion of patients at week 24 with HIV RNA <40 copies/mL. RESULTS: By week 24, eight patients had stopped STR: four because of adverse events and four for other reasons. Three virological failures were observed; among these, at least one patient developed cross-resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), in particular with the E138K pattern. In intent-to-treat analysis, 92% of participants (120 of 131) achieved HIV RNA <40 copies/mL. Only grade 1 to 2 adverse events were observed, mainly consisting of increased liver enzymes (n=33). Systemic exposure to rilpivirine was above the usually observed steady-state levels for the 18 measurements assessed. CONCLUSIONS: Efficacy and tolerability are similar to those in treatment-naïve patients.

High incidence but low burden of coronaviruses and preferential associations between respiratory viruses.

Respiratory viruses are the leading cause of acute infections in humans. However, the burden of certain respiratory viruses, such as coronaviruses, and the relevance of viral coinfections remain unclear. In this study, we investigated the distribution and seasonal occurrences of respiratory viruses detected by multiplex molecular assay in 6,014 samples from 2008 to 2011 in a French hospital. We assessed the detection frequencies of 14 respiratory viruses and their clinical impact in immunosuppressed and nonimmunosuppressed patients. Furthermore, we explored the preferential association patterns between respiratory viruses in multiple infections. Our results indicated that human rhinovirus/enterovirus (HRV/EV) and coronavirus (HCoV) were frequently detected in respiratory samples (48.81% and 11.74% of infected samples, respectively), and the detection frequencies of these viruses were further increased in immunosuppressed patients. The most common subtypes of HCoV were HCoV-229E (33.80%) and HCoV-HKU1 (32.39%). A sharp increase in the detection frequencies of HCoV-229E and HCoV-HKU1 over several months suggested that these subtypes were epidemic in our population. In immunosuppressed patients, HCoV contributed to upper respiratory tract infections (52%). Evidence did not support lower respiratory tract infections exclusive to a unique HCoV infection. In multiply infected individuals, determined in 6.3% of samples, HRV/EV and HCoV were detected in 33.29% and 22.90% of samples, respectively. Interestingly, nearly 50% of HCoV infections were detected in association with another virus. Since the distributions of respiratory viruses in multiply infected patients were subject to preferential association patterns between viruses, we propose complex interactions between different respiratory viruses and host factors.

[Study of hepatitis C virus leukotropism by characterization of viral quasispecies in the liver transplantation setting]. / Etude du leucotropisme du virus de l'hépatite C par analyse des quasi-espèces virales dans le contexte de la transplantation hépatique.

Besides hepatocytes, representing the main replication site of hepatitis C virus, peripheral blood mononuclear cells also represent a crucial target for viral infection. Hepatitis C virus compartmentalization (i.e., non-random distribution) of viral variants between plasma and peripheral blood mononuclear cells, more frequently observed in liver transplant patients compared to non-transplanted patients, makes liver transplantation an interesting model for the analysis of hepatitis C leukotropism. This article aims to present, firstly, in clinical and biological features arguing favour of hepatitis C virus infection leukotropism and, secondly, to review current knowledge about compartmentalization between plasma and peripheral blood mononuclear cells, especially in the liver transplantation setting.

[Neutralizing antibodies in hepatitis C virus infection]. / Anticorps neutralisants dirigés contre le virus de l'hépatite C.

Hepatitis C virus (HCV) results in persistent infection in more than 70% of infected individuals despite the development of humoral and cellular immune responses. Following infection, although antibodies targeting epitopes of both structural and non structural proteins are elicited, the virus evades antibody-mediated neutralization. Studies of host neutralizing responses against HCV have been limited by the lack of a convenient tissue culture system for HCV infection. In the past five years in vitro models have been developed to characterize interaction of HCV glycoproteins with host cell entry factors and detect antibodies interfering with HCV entry and infection. These models have been used to characterize targets of neutralizing responses and better understand their impact on the pathogenesis of infection.

[New lights on infectious mononucleosis]. / La mononucléose infectieuse (MNI) « revisitée ¼.

This review focuses on recent studies that shed new lights on infectious mononucleosis (IM). The major transmission of Epstein-Barr virus (EBV) via saliva is opposed to the possibility of sexual transmission of EBV in developed countries. Multiple infections with different LMP-1 EBV genotypes are frequently observed during IM but with unclear significance. The strict lymphotropism of the virus during primary EBV infection is questioned. Prolonged high EBV-load in saliva is clearly demonstrated during IM and could be explained by a different immune response in tonsil versus blood. Benign and severe IM are also explained by the variability of the immune response. Correlations between severity of IM and high viral load in blood are controversial. A relationship between IM and Hodgkin's disease is suggested by several epidemiological studies. Despite potential new antiviral targets and preliminary human vaccine trials, the lack of curative or preventive treatment against IM is pointed out.

[Recurrence of hepatitis C virus (HCV) infection after liver transplantation for HCV-related disease: host factors and viral factors implicated in the occurrence and the severity of HCV recurrence]. / Récurrence de l'infection par le virus de l'hépatite C (VHC) après transplantation du foie pour hépatopathie due au VHC: facteurs liés à l'hôte et facteurs viraux impliqués dans la survenue et la gravité de la récurrence de l'hépatite virale C.

Cirrhosis due to chronic infection by hepatitis C virus (HCV), associated or not to a primary hepatocarcinoma, has become the first indication of liver transplantation. Graft reinfection by HCV is considered to be systematic while its prognosis is variable from one patient to another. A better knowledge of factors implicated in the occurrence and severity of hepatitis C recurrence is crucial in order to make optimal patients' monitoring. This article aims to present available data in this field, clarifying the role of viral factors (viral load, genotype, evolution of viral quasispecies) and host-related factors (immune response) which could take part in the development of hepatitis C recurrence.

Comparison of serum hepatitis C virus (HCV) RNA and core antigen levels in patients coinfected with human immunodeficiency virus and HCV and treated with interferon plus ribavirin.

Trak-C (Ortho-Clinical Diagnostics) is an enzyme-linked immunosorbent assay-based method capable of quantifying hepatitis C virus (HCV) core antigen (CA) in serum and could be an alternative to molecular detection and quantification of HCV RNA. We have evaluated the Trak-C assay in comparison with an HCV RNA quantitative assay (Versant HCV v3.0; Bayer Diagnostics) in the follow-up of 348 treated, human immunodeficiency virus (HIV)/HCV-coinfected patients included in the ANRS HC02 RIBAVIC trial. ANRS HC02 RIBAVIC is a therapeutic, multicenter, randomized protocol comparing the efficacy of alpha interferon 2b (IFN-alpha2b) (3 million units three times a week)-ribavirin (800 mg/day) to that of pegylated IFN-alpha2b (1.5 mug/kg of body weight/week)-ribavirin (800 mg/day) during 48 weeks of treatment of HIV/HCV-coinfected patients naïve to HCV treatment. Patients were assessed for virological analysis at day 0 and weeks 4, 12, 24, 48, and 72. Correlation of HCV RNA and HCV CA at the initiation of treatment was excellent (r = 0.92). HCV RNA and CA kinetics were similar during follow-up of HCV treatment from day 0 to week 72 whatever the group of response and genotype. The positive and negative predictive values of response to the treatment at week 4 were 59 and 94%, respectively, for HCV RNA load reduction of >2 log and 54 and 94%, respectively, for HCV CA below the threshold value (4.18 log(10) pg/ml . 10(4)). Trak-C, a new assay able to quantify CA in HIV/HCV-coinfected patients, correlates well with quantitative HCV RNA assays and is cheaper and easier to perform than molecular technology. HCV CA could be a valuable alternative test for therapeutic follow-up of coinfected patients treated with IFN plus ribavirin in developing countries.