T cell migration and effector function differences in familial adenomatous polyposis patients with APC gene mutations.

Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the Adenomatous polyposis coli (APC) gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. APC is therefore considered a tumor suppressor gene. While the role of APC in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. Our recent work indicates that the APC protein is involved in various phases of both CD4 and CD8 T cells responses. This prompted us to investigate an array of immune cell features in FAP subjects carrying APC mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. We characterized the immune cell repertoire in peripheral blood and the capacity of immune cells to respond ex vivo to different stimuli either in whole blood or in purified T cells. A variety of experimental approaches were used, including, pultiparamater flow cytometry, NanosString gene expression profiling, Multiplex and regular ELISA, confocal microscopy and computer-based image analyis methods. We found that the percentage of several T and natural killer (NK) cell populations, the expression of several genes induced upon innate or adaptive immune stimulation and the production of several cytokines and chemokines was different. Moreover, the capacity of T cells to migrate in response to chemokine was consistently altered. Finally, immunological synapses between FAP cytotoxic T cells and tumor target cells were more poorly structured. Our findings of this pilot study suggest that mild but multiple immune cell dysfunctions, together with intestinal epithelial dysplasia in FAP subjects, may facilitate the long-term polyposis and colorectal tumor development. Although at an initial discovery phase due to the limited sample size of this rare disease cohort, our findings open new perspectives to consider immune cell abnormalities into polyposis pathology.

Use and persistence of single and multiple inhaler triple therapy prescribed for patients with COPD in France: a retrospective study on THIN database (OPTI study).

INTRODUCTION: From 2018 single inhaler triple therapy (SITT) became available in France to treat moderate-to-severe chronic obstructive pulmonary disease (COPD). Given its simplified inhaler use compared with multiple inhaler triple therapy (MITT), this therapeutic option has the potential to offer benefit in terms of improved persistence and adherence. Given the lack of real-world evidence of the effectiveness of triple therapy, this study was designed to evaluate the use of MITT and SITT in France and compare persistence. METHODS: A retrospective cohort study was performed. Patients with COPD who initiated triple therapy between 1 July 2017 and 31 December 2019 were included from The Health Improvement Network, a large electronic medical database in France, which includes pharmacy data. A 60-day treatment gap defined discontinuation and thereby persistence. RESULTS: A total of 3134 patients initiated triple therapy for COPD in the study period, among them 485 with SITT. In 2019, the rate of use of SITT was 28.2%. The mean age (67.3 years) and sex (44.2% female) of patients initiating triple therapy was similar between MITT and SITT, and most patients had escalated from dual therapy (84.1%). However, SITT was more frequently initiated by a pulmonologist (59.8%) and a higher prevalence of comorbid asthma was observed for SITT (47.0% vs 37.9%). Persistence was assessed among patients who did not discontinue after a single dispensation of triple therapy (n=1674). Median persistence was 181 days for SITT and 135 days for MITT, and the covariate-adjusted HR for persistence was 1.47 (p<0.001) and the estimated persistence at 1 year was 33% for SITT compared with 18% for MITT. DISCUSSION: This study suggests that persistence was higher for the patients treated with SITT compared with MITT in France. Moreover, most patients initiated with triple therapy were previously treated with dual therapy and had exacerbations in the previous year.

The tumor suppressor adenomatous polyposis coli regulates T lymphocyte migration.

Adenomatous polyposis coli (APC) is a tumor suppressor whose mutations underlie familial adenomatous polyposis (FAP) and colorectal cancer. Although its role in intestinal epithelial cells is well characterized, APC importance in T cell biology is ill defined. APC regulates cytoskeleton organization, cell polarity, and migration in various cell types. Here, we address whether APC plays a role in T lymphocyte migration. Using a series of cell biology tools, we unveiled that T cells from FAP patients carrying APC mutations display impaired adhesion and motility in constrained environments. We further dissected the cellular mechanisms underpinning these defects in APC-depleted CEM T cell line that recapitulate the phenotype observed in FAP T cells. We found that APC affects T cell motility by modulating integrin-dependent adhesion and cytoskeleton reorganization. Hence, APC mutations in FAP patients not only drive intestinal neoplasms but also impair T cell migration, potentially contributing to inefficient antitumor immunity.

Characteristics Associated with Olfactory and Taste Disorders in COVID-19.

INTRODUCTION: Olfactory and taste disorders (OTDs) have been reported in COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the mechanisms of which remain unclear. We conducted a detailed analysis of OTDs as part of 2 seroepidemiological investigations of COVID-19 outbreaks. METHODS: Two retrospective cohort studies were conducted in a high school and primary schools of Northern France following a COVID-19 epidemic in February-March 2020. Students, their relatives, and school staff were included. Anti-SARS-CoV-2 antibodies were identified using a flow-cytometry-based assay detecting anti-S IgG. RESULTS: Among 2,004 participants (median [IQR] age: 31 [11-43] years), 303 (15.2%) tested positive for SARS-CoV-2 antibodies. OTDs were present in 91 (30.0%) and 92 (30.3%) of them, respectively, and had 85.1 and 78.0% positive predictive values for SARS-CoV-2 infection, respectively. In seropositive participants, OTDs were independently associated with an age above 18 years, female gender, fatigue, and headache. CONCLUSION: This study confirms the higher frequency of OTDs in females than males and adults than children. Their high predictive value for the diagnosis of COVID-19 suggests that they should be systematically searched for in patients with respiratory symptoms, fever, or headache. The association of OTDs with headache, not previously reported, suggests that they share a common mechanism, which deserves further investigation.

SARS-CoV-2 infection in schools in a northern French city: a retrospective serological cohort study in an area of high transmission, France, January to April 2020.

BackgroundChildren's role in SARS-CoV-2 epidemiology remains unclear. We investigated an initially unnoticed SARS-CoV-2 outbreak linked to schools in northern France, beginning as early as mid-January 2020.AimsThis retrospective observational study documents the extent of SARS-CoV-2 transmission, linked to an affected high school (n = 664 participants) and primary schools (n = 1,340 study participants), in the context of unsuspected SARS-CoV-2 circulation and limited control measures.MethodsBetween 30 March and 30 April 2020, all school staff, as well as pupils and their parents and relatives were invited for SARS-CoV-2 antibody testing and to complete a questionnaire covering symptom history since 13 January 2020.ResultsIn the high school, infection attack rates were 38.1% (91/239), 43.4% (23/53), and 59.3% (16/27), in pupils, teachers, and non-teaching staff respectively vs 10.1% (23/228) and 12.0% (14/117) in the pupils' parents and relatives (p < 0.001). Among the six primary schools, three children attending separate schools at the outbreak start, while symptomatic, might have introduced SARS-CoV-2 there, but symptomatic secondary cases related to them could not be definitely identified. In the primary schools overall, antibody prevalence in pupils sharing classes with symptomatic cases was higher than in pupils from other classes: 15/65 (23.1%) vs 30/445 (6.7%) (p < 0.001). Among 46 SARS-CoV-2 seropositive pupils < 12 years old, 20 were asymptomatic. Whether past HKU1 and OC43 seasonal coronavirus infection protected against SARS-CoV-2 infection in 6-11 year olds could not be inferred.ConclusionsViral circulation can occur in high and primary schools so keeping them open requires consideration of appropriate control measures and enhanced surveillance.

Serologic responses to SARS-CoV-2 infection among hospital staff with mild disease in eastern France.

BACKGROUND: The serologic response of individuals with mild forms of SARS-CoV-2 infection is poorly characterized. METHODS: Hospital staff who had recovered from mild forms of PCR-confirmed SARS-CoV-2 infection were tested for anti-SARS-CoV-2 antibodies using two assays: a rapid immunodiagnostic test (99.4% specificity) and the S-Flow assay (~99% specificity). The neutralizing activity of the sera was tested with a pseudovirus-based assay. FINDINGS: Of 162 hospital staff who participated in the investigation, 160 reported SARS-CoV-2 infection that had not required hospital admission and were included in these analyses. The median time from symptom onset to blood sample collection was 24 days (IQR: 21-28, range 13-39). The rapid immunodiagnostic test detected antibodies in 153 (95.6%) of the samples and the S-Flow assay in 159 (99.4%), failing to detect antibodies in one sample collected 18 days after symptom onset (the rapid test did not detect antibodies in that patient). Neutralizing antibodies (NAbs) were detected in 79%, 92% and 98% of samples collected 13-20, 21-27 and 28-41 days after symptom onset, respectively (P = 0.02). INTERPRETATION: Antibodies against SARS-CoV-2 were detected in virtually all hospital staff sampled from 13 days after the onset of COVID-19 symptoms. This finding supports the use of serologic testing for the diagnosis of individuals who have recovered from SARS-CoV-2 infection. The neutralizing activity of the antibodies increased overtime. Future studies will help assess the persistence of the humoral response and its associated neutralization capacity in recovered patients. FUNDINGS: The funders had no role in study design, data collection, interpretation, or the decision to submit the work for publication.

Outbreak of Salmonella enterica serotype Poona in infants linked to persistent Salmonella contamination in an infant formula manufacturing facility, France, August 2018 to February 2019.

We describe a Salmonella Poona outbreak involving 31 infant cases in France. Following outbreak detection on 18 January 2019, consumption of rice-based infant formula manufactured at a facility in Spain was identified as the probable cause, leading to a recall on 24 January. Whole genome sequencing analysis linked present outbreak isolates to a 2010-11 S. Poona outbreak in Spain associated with formula manufactured in the same facility, indicating a persistent source of contamination.

Ongoing nationwide outbreak of Salmonella Agona associated with internationally distributed infant milk products, France, December 2017.

On 1 December 2017, an outbreak of Salmonella Agona infections among infants was identified in France. To date, 37 cases (median age: 4 months) and two further international cases have been confirmed. Five different infant milk products manufactured at one facility were implicated. On 2 and 10 December, the company recalled the implicated products; on 22 December, all products processed at the facility since February 2017. Trace-forward investigations indicated product distribution to 66 countries.

Predisposing factors and outcome of uncommon yeast species-related fungaemia based on an exhaustive surveillance programme (2002-14).

Objectives: Using registry data to compare fungaemia caused by uncommon yeast species (UYS; i.e. other than Candida albicans , Candida glabrata , Candida parapsilosis , Candida tropicalis and Candida krusei ) and C. albicans -related fungaemia can reveal specific predisposing factors of UYS with potential impact on treatment strategies. Methods: We analysed 338 episodes of UYS fungaemia prospectively collected from 27 hospitals (Paris, France; 1 October 2002-31 December 2014) and compared these with 1998 single episodes of C. albicans fungaemia using univariate and multivariate analyses. Results: The proportion of UYS fungaemia was stable over time. Thirty-five different species were identified (27 ascomycetes, 8 basidiomycetes), 11 had caspofungin MIC 50 >0.25 mg/L and 15 fluconazole MIC 50 >4 mg/L. Haematological malignancies [OR=2.39 (95% CI 1.79-3.18)] and prior exposure to antifungal drugs [OR=1.87 (1.30-2.69)] were independent predisposing factors for UYS infections upon multivariate analysis. However, when considering the genus/species complex level, only infections due to Candida kefyr -related species [OR=4.01 (2.42-6.64)] and to Trichosporon spp. [OR=5.38 (1.72-16.81)] remained associated with haematological malignancies, those due to the GEOTRICHUM group with acute leukaemia [OR=61.29 (19.23-195.36)], and infections with Trichosporon spp. or the GEOTRICHUM group with prior exposure to caspofungin [OR=15.67 (3.62-67.80) and OR=13.17 (3.33-52.03), respectively] but not to fluconazole. The global mortality at day 30 for UYS was similar to that for C. albicans (35.4%, and 39.9%, respectively), but very divergent results were observed according to the specific UYS. Conclusions: UYS encompass a high diversity of species, each with its own behaviour and predisposing factors for human infections. This variety makes it important to rapidly identify an isolate to the species level in order to optimize antifungal treatment.

The risk and clinical outcome of candidemia depending on underlying malignancy.

PURPOSE: To assess the risk factors and outcomes associated with fungemia caused by the six most commonly occurring Candida species in patients with and without malignancies. METHODS: Analysis of the episodes of fungemia due to common Candida species in adults, based on an active hospital-based surveillance program (Paris area, France, 2002 to 2014). RESULTS: Of the 3417 patients (3666 isolates), 1164 (34.1%) had a solid tumor (45.7% digestive tract) and 586 (17.1%) a hematological malignancy (41.8% lymphoma, 33.5% acute leukemia). The hematology patients were significantly younger, more often pre-exposed to antifungals, more often infected by C. tropicalis, C. krusei, or C. kefyr, and more often treated in the first instance with an echinocandin. Compared with inpatients who were not in ICU at the time of fungemia, those in ICU were less frequently infected by C. parapsilosis (p < 0.02), had more recent surgery (p < 0.03), and died more frequently before day 8 and day 30 (p < 0.0001). An increase in crude mortality over time in ICU was observed only in oncology patients (p < 0.04). For all patients, lack of prescription of antifungals despite knowledge of positive blood culture increased the risk of death. The odds of being infected by a given Candida species compared with C. albicans were uneven regarding age, gender, type of malignancy, hospitalization in ICU, central venous catheter, HIV status, intravenous drug addiction, and previous exposure to antifungal drugs. Compared with C. albicans, C. glabrata (OR = 0.69 [0.54-0.89]) and C. parapsilosis (OR = 0.49 [0.35-0.67]) were associated with a decreased risk of death by day 8 and day 30. CONCLUSION: The clinical context of underlying malignancy and hospitalization in ICU may be relevant to the initial management of candidemia.

Absence of Fungal Spore Internalization by Bronchial Epithelium in Mouse Models Evidenced by a New Bioimaging Approach and Transmission Electronic Microscopy.

Clinical data and experimental studies suggest that bronchial epithelium could serve as a portal of entry for invasive fungal infections. We therefore analyzed the interactions between molds and the bronchial/bronchiolar epithelium at the early steps after inhalation. We developed invasive aspergillosis (Aspergillus fumigatus) and mucormycosis (Lichtheimia corymbifera) murine models that mimic the main clinical risk factors for these infections. Histopathology studies were completed with a specific computer-assisted morphometric method to quantify bronchial and alveolar spores and with transmission electron microscopy. Morphometric analysis revealed a higher number of bronchial/bronchiolar spores for A. fumigatus than L. corymbifera. The bronchial/bronchiolar spores decreased between 1 and 18 hours after inoculation for both fungi, except in corticosteroid-treated mice infected with A. fumigatus, suggesting an effect of cortisone on bronchial spore clearance. No increase in the number of spores of any species was observed over time at the basal pole of the epithelium, suggesting the lack of transepithelial crossing. Transmission electron microscopy did not show spore internalization by bronchial epithelial cells. Instead, spores were phagocytized by mononuclear cells on the apical pole of epithelial cells. Early epithelial internalization of fungal spores in vivo cannot explain the bronchial/bronchiolar epithelium invasion observed in some invasive mold infections. The bioimaging approach provides a useful means to accurately enumerate and localize the fungal spores in the pulmonary tissues.

Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002-2010).

PURPOSE: To analyze trends in incidence and mortality of candidemia in intensive care units (ICUs) vs. non-ICU hospitalized patients and to determine risk factors for infection by specific species and for death. METHODS: Active hospital-based surveillance program of incident episodes of candidemia due to common species in 24 tertiary care hospitals in the Paris area, France between October 2002 and September 2010. RESULTS: Among 2,507 adult cases included, 2,571 Candida isolates were collected and species were C. albicans (56 %), C. glabrata (18.6 %), C. parapsilosis (11.5 %), C. tropicalis (9.3 %), C. krusei (2.9 %), and C. kefyr (1.8 %). Candidemia occurred in ICU in 1,206 patients (48.1 %). When comparing ICU vs. non-ICU patients, the former had significantly more frequent surgery during the past 30 days, were more often preexposed to fluconazole and treated with echinocandin, and were less frequently infected with C. parapsilosis. Risk factors and age remained unchanged during the study period. A significant increased incidence in the overall population and ICU was found. The odds of being infected with a given species in ICU was influenced by risk factors and preexposure to fluconazole and caspofungin. Echinocandins initial therapy increased over time in ICU (4.6 % first year of study, to 48.5 % last year of study, p < 0.0001). ICU patients had a higher day-30 death rate than non-ICU patients (odds ratio [OR] 2.12; 95 % confidence interval [CI] 1.66-2.72; p < 0.0001). The day-30 and early (

Increase in dengue fever imported from Côte d’Ivoire and West Africa to France.

Dengue is usually not considered a significant health problem in Africa because severe forms of dengue illness are rarely reported. In the absence of local surveillance data, the investigation of dengue cases imported to France contributed to document the circulation of dengue virus in this area. From 1 July 2006 to 31 December 2008, a total of 148 dengue cases imported to metropolitan France were reported through the mandatory notification system. Arthralgia and signs of severity (haemorrhage, thrombocytopenia) were less frequent in patients returning from West African countries. DENV-3 was isolated in two patients from Côte d’Ivoire in 2008. The number and proportion of patients returning from Côte d’Ivoire to France increased significantly in 2008 compared with the previous 18-month period. In parallel, the marginal increase in air travel does not explain the high increase observed in imported dengue cases to France. Our data illustrate increased dengue circulation and the emergence of DENV-3 in this area, with public health implications for epidemiological surveillance and case management locally.