Valproic acid as adjuvant treatment for convulsive status epilepticus: a randomised clinical trial.

BACKGROUND: Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20-40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE. METHODS: This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90. RESULTS: A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) versus placebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89-1.19); p = 0.58]. There were no between-group differences for secondary outcomes. CONCLUSIONS: VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15. TRIAL REGISTRATION NO: NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.

Mouse and Human Liver Contain Immunoglobulin A-Secreting Cells Originating From Peyer's Patches and Directed Against Intestinal Antigens.

BACKGROUND & AIMS: The liver receives blood from the gastrointestinal tract through the portal vein, and thereby is exposed continuously to dietary antigens and commensal bacteria. Alcoholic liver disease (ALD) is associated with intestinal dysbiosis, increased intestinal permeability, release of microbes into the portal circulation, and increased serum levels and liver deposits of IgA. We characterized B-cell production of IgA in livers of mice at homeostasis, after oral immunization, in a mouse model of ALD and in human liver samples. METHODS: We performed studies with Balb/c and C57BL/6-Ly5.1 mice, as well as transgenic mice (quasimonoclonal, activation-induced [cytidine] deaminase-Cre-tamoxifen-dependent estrogen receptor 2 [ERT2], Blimp-1-green fluorescent protein [GFP]). C57BL/6-Ly5.1 mice were fed chronic plus binge ethanol to create a model of ALD. Some mice also were given repeated injections of FTY720, which prevents egress of IgA-secreting cells from Peyer's patches. We obtained nontumor liver tissues from patients with colorectal carcinoma undergoing surgery for liver metastases or hepatocellular carcinoma. B cells were isolated from mouse and human liver tissues and analyzed by flow cytometry and enzyme-linked ImmunoSpot (ELISpot). In wild-type and transgenic mice, we traced newly generated IgA-secreting cells at steady state and after oral immunization with 4-hydroxy-3-nitrophenylacetyl (NP)-Ficoll or cholera toxin. IgA responses were also evaluated in our model of ALD. RESULTS: Livers of control mice contained proliferative plasmablasts that originated from Peyer's patches and produced IgAs reactive to commensal bacteria. After oral immunization with cholera toxin or a thymus-independent antigen, a substantial number of antigen-specific IgA-secreting cells was found in the liver. Mice fed ethanol had features of hepatitis and increased numbers of IgA-secreting cells in liver, compared with mice given control diets, as well as higher levels of serum IgA and IgA deposits in liver sinusoids. Injection of FTY720 during ethanol feeding reduced liver and serum levels of IgA and IgA deposits in liver and prevented liver injury. Human liver tissues contained a significant proportion of IgA-producing plasma cells that shared phenotypic and functional attributes with those from mouse liver, including reactivity to commensal bacteria. CONCLUSIONS: Based on studies of mice and human liver tissues, we found the liver to be a site of IgA production by B cells, derived from gut-associated lymphoid tissues. These IgAs react with commensal bacteria and oral antigens. Livers from mice with ethanol-induced injury contain increased numbers of IgA-secreting cells and have IgA deposits in sinusoids. IgAs in the liver could mediate clearance of gut-derived antigens that arrive through portal circulation at homeostasis and protect these organs from pathogens.

Plasmacytoid dendritic cells are dispensable for noninfectious intestinal IgA responses in vivo.

Intestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T-cell responses and inducing anti-inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti-viral immunity and T-cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T-cell-independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short-term nor long-term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T-cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T-cell-dependent or T-cell-independent Ags, and are not required for proliferation and IgA switch of Ag-specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA responses.

Severe varicella-zoster virus pneumonia: a multicenter cohort study.

BACKGROUND: Pneumonia is a dreaded complication of varicella-zoster virus (VZV) infection in adults; however, the data are limited. Our objective was to investigate the clinical features, management, and outcomes of critically ill patients with VZV-related community-acquired pneumonia (VZV-CAP). METHODS: This was an observational study of patients with VZV-CAP admitted to 29 intensive care units (ICUs) from January 1996 to January 2015. RESULTS: One hundred and two patients with VZV-CAP were included. Patients were young (age 39 years (interquartile range 32-51)) and 53 (52%) were immunocompromised. Time since respiratory symptom onset was 2 (1-3) days. There was a seasonal distribution of the disease, with more cases during spring and winter time. All but four patients presented with typical skin rash on ICU admission. Half the patients received mechanical ventilation within 1 (1-2) day following ICU admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) = 150 (80-284), 80% with acute respiratory distress syndrome (ARDS)). Sequential Organ Failure Assessment (SOFA) score on day 1 (odds ratio (OR) 1.90 (1.33-2.70); p < 0.001), oxygen flow at ICU admission (OR 1.25 (1.08-1.45); p = 0.004), and early bacterial co-infection (OR 14.94 (2.00-111.8); p = 0.009) were independently associated with the need for mechanical ventilation. Duration of mechanical ventilation was 14 (7-21) days. ICU and hospital mortality rates were 17% and 24%, respectively. All patients were treated with aciclovir and 10 received adjunctive therapy with steroids. Compared to 60 matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, ICU length of stay, and a similar hospital mortality, but experienced more ICU-acquired infections. CONCLUSIONS: Severe VZV-CAP is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. Steroid therapy did not influence mortality, but increased the risk of superinfection.

B Cells Loaded with Synthetic Particulate Antigens: A Versatile Platform To Generate Antigen-Specific Helper T Cells for Cell Therapy.

Adoptive cell therapy represents a promising approach for several chronic diseases. This study describes an innovative strategy for biofunctionalization of nanoparticles, allowing the generation of synthetic particulate antigens (SPAg). SPAg activate polyclonal B cells and vectorize noncognate proteins into their endosomes, generating highly efficient stimulators for ex vivo expansion of antigen-specific CD4+ T cells. This method also allows harnessing the ability of B cells to polarize CD4+ T cells into effectors or regulators.

Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest: A Randomized, Controlled Study.

BACKGROUND: Targeted temperature management is recommended after out-of-hospital cardiac arrest. Whether advanced internal cooling is superior to basic external cooling remains unknown. The aim of this multicenter, controlled trial was to evaluate the benefit of endovascular versus basic surface cooling. METHODS AND RESULTS: Inclusion criteria were the following: age of 18 to 79 years, out-of-hospital cardiac arrest related to a presumed cardiac cause, time to return of spontaneous circulation <60 minutes, delay between return of spontaneous circulation and inclusion <240 minutes, and unconscious patient after return of spontaneous circulation and before the start of cooling. Exclusion criteria were terminal disease, pregnancy, known coagulopathy, uncontrolled bleeding, temperature on admission <30°C, in-hospital cardiac arrest, immediate need for extracorporeal life support or hemodialysis. Patients were randomized between 2 cooling strategies: endovascular femoral devices (Icy catheter, Coolgard, Zoll, formerly Alsius; n=203) or basic external cooling using fans, a homemade tent, and ice packs (n=197). The primary end point, that is, favorable outcome evaluated by survival without major neurological damage (Cerebral Performance Categories 1-2) at day 28, was not significantly different between groups (odds ratio, 1.41; 95% confidence interval, 0.93-2.16; P=0.107). Improvement in favorable outcome at day 90 in favor of the endovascular group did not reach significance (odds ratio, 1.51; 95% confidence interval, 0.96-2.35; P=0.07). Time to target temperature (33°C) was significantly shorter and target hypothermia was more strictly maintained in the endovascular than in the surface group (P<0.001). Minor side effects directly related to the cooling method were observed more frequently in the endovascular group (P=0.009). CONCLUSION: Despite better hypothermia induction and maintenance, endovascular cooling was not significantly superior to basic external cooling in terms of favorable outcome. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00392639.

A novel whole blood assay to quantify the release of T cell associated cytokines in response to Bordetella pertussis antigens.

BACKGROUND: Bordetella pertussis continues to cause whooping cough globally even in countries with high immunisation coverage. Booster vaccinations with acellular pertussis vaccines are thus used in children, adolescents, and adults. T cell immunity is crucial for orchestrating the immune response after vaccination. However, T cell assays can be expensive and difficult to implement in large clinical trials. In this study, a whole blood (WB) stimulation assay was developed to identify secreted T cell associated cytokines in different age groups after acellular pertussis booster vaccination. MATERIAL AND METHODS: Longitudinal WB samples were collected from a small set of subjects (n = 38) aged 7-70 years participating in a larger ongoing clinical trial. For assay development, samples were diluted and incubated with purified inactivated pertussis toxin (PT), filamentous haemagglutinin (FHA), inactivated B. pertussis lysate, and complete medium (M) as stimulating conditions, with anti-CD28 and anti-CD49d as co-stimulants. Different timepoints around the vaccination (D0, D7, D14, D28), WB dilution factor (1:2, 1:4) and incubation time (24 h, 48 h, 72 h) were compared. Responses to 15 cytokines were tested with Luminex/multiplex immunoassay. RESULTS: The optimized assay consisted of WB incubation with M, PT, and FHA (including the two co-stimulants). After 48 h incubation, supernatants were collected for measurement of seven selected T cell associated cytokines (IL-2, IL-5, IL-10, IL-13, IL-17 A, IL-17F, and IFN-y) from samples before and 28 days after vaccination. PT stimulation showed a trend for upregulation of IL-2, IL-13, and IL-17 A/F for adult subjects, whereas the responses of all cytokines were downregulated for the paediatric subjects. Furthermore, PT and FHA-stimulated WB showed diverse cytokine producing profiles. CONCLUSIONS: The developed WB-based cytokine assay was shown to be less costly, easy to perform, and functional in differently aged individuals. Further, it requires only a small amount of fresh blood, which is beneficial especially for studies including infants. Our results support the use of this assay for other immunological studies in the future.

Digital health technologies and Alzheimer's disease clinical trials: might decentralized clinical trials increase participation by people with cognitive impairment?

BACKGROUND: Therapeutic trials in Alzheimer's disease (AD) face many obstacles-particularly with regard to screening and recruitment. DISCUSSION: Decentralized clinical trials (DCTs) are being developed in other diseases and appear to be of value for overcoming these difficulties. The use of remote visits offers hope of broader recruitment and thus a reduction in inequalities due to age, geography, and ethnicity. Furthermore, it might be easier to involve primary care providers and caregivers in DCTs. However, further studies are needed to determine the feasibility of DCTs in AD. A mixed-model DCT might constitute the first step towards completely remote trials in AD and should be assessed first.

The role of bactericidal and opsonic activity in immunity against Bordetella pertussis.

INTRODUCTION: Pertussis vaccines have drastically reduced the disease burden in humans since their implementation. Despite their success, pertussis remains an important global public health challenge. Bordetella pertussis resurgence could be a result of greater surveillance combined with improved diagnosis methods, changes in Bordetella pertussis biology, vaccine schedules, and/or coverage. Additionally, mechanisms of protection conferred by acellular pertussis (aP) and whole-cell pertussis (wP) vaccines differ qualitatively. There are no clear immune correlates of protection for pertussis vaccines. Pertussis antigens can induce toxin neutralizing antibodies, block adherence or engage complement mediated phagocytic/bactericidal killing. AREAS COVERED: We reviewed the existing evidence on antibody-mediated serum bactericidal and opsonophagocytic activity and discussed the relevance of these functional antibodies in the development of next-generation pertussis vaccines. EXPERT OPINION: Current paradigm proposes that wP vaccines may confer greater herd protection than aP vaccines due to their enhanced clearance of bacteria from the nasopharynx in animal models. Functional antibodies may contribute to the reduction of nasal colonization, which differentiates aP and wP vaccines. Understanding the intrinsic differences in protective immune responses elicited by each class of vaccines will help to identify biomarkers that can be used as immunological end points in clinical trials.

The whole-cell pertussis vaccine imposes a broad effector B cell response in mouse heterologous prime-boost settings.

ÍSince the introduction of new generation pertussis vaccines, resurgence of pertussis has been observed in many developed countries. Former whole-cell pertussis (wP) vaccines are able to protect against disease and transmission but have been replaced in several industrialized countries because of their reactogenicity and adverse effects. Current acellular pertussis (aP) vaccines, made of purified proteins of Bordetella pertussis, are efficient at preventing disease but fail to induce long-term protection from infection. While the systemic and mucosal T cell immunity induced by the 2 types of vaccines has been well described, much less is known concerning B cell responses. Taking advantage of an inducible activation-induced cytidine deaminase fate-mapping mouse model, we compared effector and memory B cells induced by the 2 classes of vaccines and showed that a stronger and broader memory B cell and plasma cell response was achieved by a wP prime. We also observed that homologous or heterologous vaccine combinations that include at least 1 wP administration, even as a booster dose, were sufficient to induce this broad effector response, thus highlighting its dominant imprint on the B cell profile. Finally, we describe the settlement of memory B cell populations in the lung following subcutaneous wP prime vaccination.

Mature IgM-expressing plasma cells sense antigen and develop competence for cytokine production upon antigenic challenge.

Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells. Fully mature IgM-expressing plasma cells resident in the bone marrow retain expression of a functional BCR, whereas their IgG+ counterparts do not. Antigen boost modifies the gene expression profile of IgM+ plasma cells and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing plasma cells can sense antigen and acquire competence for cytokine production upon antigenic challenge.

Frequency of adverse drug reactions in children: a prospective study.

AIMS: To assess the frequency of adverse drug reactions (ADRs) in children in France. METHODS: In a prospective study over a period of 1 week, we evaluated the incidence of ADRs (1) as a cause of admission to a regional children's hospital; (2) occurring during hospitalization in a regional children's hospital; and (3) as a cause of consultation with private paediatricians. RESULTS: Four out of 260 children were admitted to the regional children's hospital for ADRs (1.53% [0.42, 3.89]) and six developed ADRs during hospitalization (2.64% [0.97, 5.66]), 4/428 attended the Accident and Emergency Department for ADRs (0.93% [0.25, 2.37]) and 8/1192 consulted a private paediatrician for ADRs (0.67% [0.29, 1.31]). CONCLUSIONS: Our results are in agreement with the incidence of ADRs in children found in others countries.