Risk factors for nosocomial COVID-19 in a French university hospital.

OBJECTIVES: Prevention strategies implemented by hospitals to reduce nosocomial transmission of SARS-CoV-2 sometimes failed. Our aim was to determine the risk factors for nosocomial COVID-19. PATIENTS AND METHODS: A case-control study was conducted (September 1, 2020-January 31, 2021) with adult patients hospitalized in medical or surgical units. Infants or patients hospitalized in ICU were excluded. Cases were patients with nosocomial COVID-19 (clinical symptoms and RT-PCR + for SARS-CoV-2 or RT-PCR + for SARS-CoV-2 with Ct ≤ 28 more than 5 days after admission); controls were patients without infection (RT-PCR- for SARS-CoV-2 > 5 days after admission). They were matched according to length of stay before diagnosis and period of admission. Analyses were performed with a conditional logistic regression. RESULTS: A total of 281 cases and 441 controls were included. In the bivariate analysis, cases were older (OR per 10 years: 1.22; 95%CI [1.10;1.36]), had more often shared a room (OR: 1.74; 95%CI [1.25;2.43]) or a risk factor for severe COVID-19 (OR: 1.94; 95%CI [1.09;3.45]), were more often hospitalized in medical units [OR: 1.59; 95%CI [1.12;2.25]), had higher exposure to contagious health care workers (HCW; OR per 1person-day: 1.12; 95%CI [1.08;1.17]) and patients (OR per 1 person-day: 1.11; 95%CI [1.08;1.14]) than controls. In an adjusted model, risk factors for nosocomial COVID-19 were exposure to contagious HCW (aOR per 1person-day: 1.08; 95%CI [1.03;1.14]) and to contagious patients (aOR per 1person-day: 1.10; 95%CI [1.07;1.13]). CONCLUSIONS: Exposure to contagious professionals and patients are the main risk factors for nosocomial COVID-19.

Effect of point-of-care influenza tests on antibiotic prescriptions by emergency physicians in a French hospital.

BACKGROUND: Influenza is a public health issue worldwide. Although antibiotics should not be used to treat viral infections, they are often prescribed to patients with influenza-like illness (ILI). Such misuse promotes antibiotic resistance. The role of rapid point-of-care tests (POCTs) in preventing antibiotic misuse in adults with ILI symptoms remains relatively unexplored. AIM: To evaluate whether POCT implemented in 2018-2019 to detect influenza viruses led to a decrease in antibiotic prescriptions compared with laboratory-based influenza tests. METHODS: Adult patients with ILI in one emergency department (ED) were retrospectively enrolled over three epidemic seasons (from 2016-2017 to 2018-2019). The primary outcome was the rate of antibiotic prescriptions, which was compared between the three seasons in bivariate and multivariate analyses. Prescriptions for ancillary laboratory tests, chest X-rays and oseltamivir were also compared, along with hospitalizations and length of stay (LOS) at the ED. FINDINGS: Overall, 1849 patients were included. Median age was over 70 years throughout all three seasons. The number of antibiotic prescriptions was significantly different between the three periods in bivariate analysis (48.3% in 2016/2017, 44% in 2017/2018 and 31.1% in 2018/2019; P<0,0001) and in multivariate analysis (adjusted odds ratio (aOR) = 0.48, 95% confidence interval (CI) = 0.30-0.76 for 2018/2019 and aOR = 0.99, 95%CI = 0.67-1.46 for 2017/2018, compared with 2016/2017). There were significantly fewer prescriptions of ancillary laboratory tests, X-rays, hospitalizations and more oseltamivir prescriptions in 2018/2019, compared with the previous seasons. LOS was significantly lower in 2018/2019 only for influenza-positive patients. CONCLUSIONS: ED influenza POCT decreased antibiotic use and led to less ancillary testing, X-rays and hospitalizations among patients with ILI. However, medico-economic studies are necessary before formulating definite recommendations.

SARS-CoV-2 nosocomial infection acquired in a French university hospital during the 1st wave of the Covid-19 pandemic, a prospective study.

BACKGROUND: In healthcare facilities, nosocomial transmissions of respiratory viruses are a major issue. SARS-CoV-2 is not exempt from nosocomial transmission. Our goals were to describe COVID-19 nosocomial cases during the first pandemic wave among patients in a French university hospital and compliance with hygiene measures. METHODS: We conducted a prospective observational study in Grenoble Alpes University Hospital from 01/03/2020 to 11/05/2020. We included all hospitalised patients with a documented SARS-CoV-2 diagnosis. Nosocomial case was defined by a delay of 5 days between hospitalisation and first symptoms. Hygiene measures were evaluated between 11/05/2020 and 22/05/2020. Lockdown measures were effective in France on 17/03/2020 and ended on 11/05/2020. Systematic wearing of mask was mandatory for all healthcare workers (HCW) and visits were prohibited in our institution from 13/03/2021 and for the duration of the lockdown period. RESULTS: Among 259 patients included, 14 (5.4%) were considered as nosocomial COVID-19. Median time before symptom onset was 25 days (interquartile range: 12-42). Eleven patients (79%) had risk factors for severe COVID-19. Five died (36%) including 4 deaths attributable to COVID-19. Two clusters were identified. The first cluster had 5 cases including 3 nosocomial acquisitions and no tested HCWs were positive. The second cluster had 3 cases including 2 nosocomial cases and 4 HCWs were positive. Surgical mask wearing and hand hygiene compliance were adequate for 95% and 61% of HCWs, respectively. CONCLUSIONS: The number of nosocomial COVID-19 cases in our hospital was low. Compliance regarding mask wearing, hand hygiene and lockdown measures drastically reduced transmission of the virus. Monitoring of nosocomial COVID-19 cases during the first wave enabled us to determine to what extent the hygiene measures taken were effective and patients protected. Trial registration Study ethics approval was obtained retrospectively on 30 September 2020 (CECIC Rhône-Alpes-Auvergne, Clermont-Ferrand, IRB 5891).

Hepatitis C subtype distribution in chronically infected patients with mild liver fibrosis in France: the GEMHEP study.

Treatment options for Hepatitis C infection have greatly improved with direct-acting antiviral (DAA) combinations achieving high cure rates. Nevertheless, the cost of this treatment is still high and access to treatment in many countries has been preferentially reserved for patients with more severe fibrosis (F3 and F4). In this French nationwide study, we investigated the epidemiological characteristics and genotype distribution of hepatitis C virus (HCV) in treatment-naive patients with METAVIR fibrosis stages between F0 and F2 in order to identify patient profiles that became eligible for unrestricted treatment in a second period. Between 2015 and 2016 we collected data from nine French university hospitals on a total of 584 HCV positive patients with absent, mild or moderate liver fibrosis. The most represented genotypes were genotype 1b (159/584; 27.2%), followed by genotype 1a (150/584; 25.7%); genotype 3 (87/584: 14.9%); genotype 4 (80/584; 13.7%). Among genotype 4: 4a was predominantly encountered with 22 patients (27.5% of genotype 4). Genotypes 1b and 1a are currently the most frequent virus types present in treatment-naive patients with mild fibrosis in France. They can be readily cured using the available DAA. Nevertheless, non-a/non-d genotype 4 is also frequent in this population and clinical data on the efficacy of DAA on these subtypes is missing. The GEMHEP is the French group for study and evaluation of viral hepatitis on a national scale. Data collection on epidemiological and molecular aspects of viral hepatitis is performed on a regular basis in all main French teaching hospitals and serves as a basis for surveillance of these infections. Analysis and trends are regularly published on behalf of the GEMHEP group. Data collection was performed retrospectively over the 2015-2016 period, covering nine main university hospitals in France. A total of 584 hepatitis C positive patients were included in this study. Genotyping of the circulating viruses showed a high prevalence of genotypes 1b and 1a in our population. The epidemiology of hepatitis C is slowly changing in France, particularly as a consequence of the rise of 'non-a non-d' genotype 4 viruses mainly originating from African populations. More data concerning treatment efficacy of these genotypes is needed in order to guide clinical care.

Using high-throughput sequencing for investigating intra-host hepatitis C evolution over long retrospective periods.

Collections of biological samples held by hospitals represent invaluable resources for conducting retrospective evolutionary studies of chronic infections. Using high-throughput sequencing, those collections permit analysis of within-host genetic diversity over long follow-up periods, and allow a better understanding of resistance to treatment regimes during disease evolution. Here, we studied the evolution of hepatitis C virus (HCV) populations in two patients with an absence of response to dual therapies. We implemented amplicon sequencing to survey genomic variation at the Core and NS5B regions of HCV over a period of 13 years from blood samples obtained at multiple time points. We observed mixed infection by multiple HCV genotypes in both patients. Genetic heterogeneity and sample composition analysis provided information about the changes in viral population over the course of clinical treatment, with NS5B experiencing an increase in diversity after treatment initiation. Secondary infections were estimated to predate treatment year, and our results pointed towards diversifying selection occurring post-treatment, acting on standing genomic variation and maintaining high genetic heterogeneity during infection. For these two patients infected with multiple HCV genotypes, the maintenance of viral diversity was explained with the hypothesis of soft selective sweep started at the same time as antiviral treatment was initiated.

First next-generation sequencing full-genome characterization of a hepatitis C virus genotype 7 divergent subtype.

We report the near-full-length genome sequence of a hepatitis C virus (HCV) isolate from a man originating from Democratic Republic of Congo, the genotype of which could not be determined by the routinely used sequencing technique. The near-complete genome sequence of this variant BAK1 was obtained by the association of two next-generation sequencing technologies. Evolutionary analysis indicates that this isolate, BAK1, could be the first reported strain belonging to a new HCV-7b subtype. This new subtype has been incorrectly identified as genotype 2 by the Versant HCV Genotype 2.0 assay (LiPA). The requirement of three independent isolates has been filled, and a new subtype can be assigned. More examples of HCV-7 are required to better understand its origin, its pathogenicity and its relationship with genotype 2.

Amplification and pyrosequencing of near-full-length hepatitis C virus for typing and monitoring antiviral resistant strains.

Directly acting antiviral drugs have contributed considerable progress to hepatitis C virus (HCV) treatment, but they show variable activity depending on virus genotypes and subtypes. Therefore, accurate genotyping including recombinant form detection is still of major importance, as is the detection of resistance-associated mutations in case of therapeutic failure. To meet these goals, an approach to amplify the HCV near-complete genome with a single long-range PCR and sequence it with Roche GS Junior was developed. After optimization, the overall amplification success rate was 73% for usual genotypes (i.e. HCV 1a, 1b, 3a and 4a, 16/22) and 45% for recombinant forms RF_2k/1b (5/11). After pyrosequencing and subsequent de novo assembly, a near-full-length genomic consensus sequence was obtained for 19 of 21 samples. The genotype and subtype were confirmed by phylogenetic analysis for every sample, including the suspected recombinant forms. Resistance-associated mutations were detected in seven of 13 samples at baseline, in the NS3 (n = 3) or NS5A (n = 4) region. Of these samples, the treatment of one patient included daclatasvir, and that patient experienced a relapse. Virus sequences from pre- and posttreatment samples of four patients who experienced relapse after sofosbuvir-based therapy were compared: the selected variants seem too far from the NS5B catalytic site to be held responsible. Although tested on a limited set of samples and with technical improvements still necessary, this assay has proven to be successful for both genotyping and resistance-associated variant detection on several HCV types.

Identification of a duplicated V3 domain in NS5A associated with cirrhosis and hepatocellular carcinoma in HCV-1b patients.

BACKGROUND: The NS5A protein of the hepatitis C virus has been shown to be involved in the development of hepatocellular carcinoma. OBJECTIVES: In a French multicenter study, we investigated the clinical and epidemiological features of a new HCV genotype 1b strain bearing a wide insertion into the V3 domain. STUDY DESIGN: We studied NS5A gene sequences in 821 French patients infected with genotype 1b HCV. RESULTS: We identified an uncharacterized V3 insertion without ORF disruption in 3.05% of the HCV sequences. The insertion comprised 31 amino-acids for the majority of patients; 3 patients had 27 amino-acids insertions and 1 had a 12 amino-acids insertion. Sequence identity between the 31 amino-acids insertions and the V3 domain ranged from 48 to 96% with E-values above 4e(-5), thus illustrating sequence homology and a partial gene duplication event that to our knowledge has never been reported in HCV. Moreover we showed the presence of the duplication at the time of infection and its persistence at least during 12 years in the entire quasispecies. No association was found with extrahepatic diseases. Conversely, patients with cirrhosis were two times more likely to have HCV with this genetic characteristic (p=0.04). Moreover, its prevalence increased with liver disease severity (from 3.0% in patients without cirrhosis to 9.4% in patients with both cirrhosis and HCC, p for trend=0.045). CONCLUSIONS: We identified a duplicated V3 domain in the HCV-1b NS5A protein for the first time. The duplication may be associated with unfavorable evolution of liver disease including a possible involvement in liver carcinogenesis.

Recent evidence of underestimated circulation of hepatitis C virus intergenotypic recombinant strain RF2k/1b in the Rhône-Alpes region, France, January to August 2014: implications for antiviral treatment.

Since the beginning of 2014, hepatitis C virus (HCV) recombinant forms RF2k/1b have been detected in the Rhône-Alpes French region in 10 patients originating from the Caucasus area. Circulation of this particular HCV strain is very likely to be underestimated. It is also prone to be misgenotyped when using genotyping methods based on the 5' region of the viral genome, which may lead to suboptimal treatment.

Association between hepatitis E and neurological disorders: two case studies and literature review.

Hepatitis E (HEV) is an emerging disease in our developed countries, but is not routinely tested for in case of liver cytolysis. However, a growing number of extra-hepatic manifestations of HEV infection associated with acute hepatitis are reported. In this article, we discuss two cases of HEV with neurological symptoms, one with encephalitis, and the other with Parsonage Turner syndrome. All these disorders appeared concomitantly with liver cytolysis and disappeared quickly, following the viral kinetics. Only twenty cases of neurological manifestation of HEV have been described before. The use of HEV serology in patients with concurrent liver cytolysis and neurological symptoms has to be improved.