Much ado about nothing? Discrepancy between the available data on the antiviral effect of hydroxychloroquine in March 2020 and its inclusion in COVID-19 clinical trials and outpatient prescriptions.

OBJECTIVES: Many of the 2020 COVID-19 clinical trials included an (hydroxy)chloroquine ((H)CQ) arm. We aimed to juxtapose the state of science before April 2020 regarding the benefits of (H)CQ for viral infections with the number and size of the clinical trials studying (H)CQ and the volume of (H)CQ dispensed in France. STUDY DESIGN: We identified and analysed published scientific material regarding the antiviral activity of (H)CQ and publicly available data regarding clinical trials and drug dispensation in France. METHODS: We conducted a review of scientific publications available before April 2020 and a systematic analysis of COVID-19 clinical trials featuring (H)CQ registered on clinicaltrials.gov. RESULTS: Before April 2020, 894 scientific publications mentioning (H)CQ for viruses other than coronaviruses were available, including 35 in vitro studies (reporting an inconstant inhibition of viral replication), 11 preclinical studies (reporting no or disputable positive effects), and 32 clinical trials (reporting no or disputable positive effects). Moreover, 67 publications on (H)CQ and coronavirus infections were available, including 12 in vitro studies (reporting an inconstant inhibition of viral replication), two preclinical studies (reporting contradictory results), and no clinical trials. Meanwhile, 253 therapeutic clinical trials featuring an HCQ arm were registered in 2020, intending to enrol 246,623 patients. CONCLUSIONS: The number and size of (H)CQ clinical trials for COVID-19 launched in 2020 were not supported by the literature published before April 2020.

Changing profile of encephalitis: Results of a 4-year study in France.

CONTEXT: In 2007, we performed a nationwide prospective study to assess the epidemiology of encephalitis in France. We aimed to evaluate epidemiological changes 10years later. METHODS: We performed a 4-year prospective cohort study in France (ENCEIF) from 2016 to 2019. Medical history, comorbidities, as well as clinical, biological, imaging, and demographic data were collected. For the comparison analysis, we selected similar data from adult patients enrolled in the 2007 study. We used Stata statistical software, version 15 (Stata Corp). Indicative variable distributions were compared using Pearson's Chi2 test, and means were compared using Student's t-test for continuous variables. RESULTS: We analyzed 494 cases from 62 hospitals. A causative agent was identified in 65.7% of cases. Viruses represented 81.8% of causative agents, Herpesviridae being the most frequent (63.6%). Arboviruses accounted for 10.8%. Bacteria and parasites were responsible for respectively 14.8% and 1.2% of documented cases. Zoonotic infections represented 21% of cases. When comparing ENCEIF with the 2007 cohort (222 adults patients from 59 hospitals), a higher proportion of etiologies were obtained in 2016-2019 (66% vs. 53%). Between 2007 and 2016-2019, the proportions of Herpes simplex virus and Listeria encephalitis cases remained similar, but the proportion of tuberculosis cases decreased (P=0.0001), while tick-borne encephalitis virus (P=0.01) and VZV cases (P=0.03) increased. In the 2016-2019 study, 32 causative agents were identified, whereas only 17 were identified in the 2007 study. CONCLUSION: Our results emphasize the need to regularly perform such studies to monitor the evolution of infectious encephalitis and to adapt guidelines.

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).

COVID-19 vaccines: Frequently asked questions and updated answers.

At the end of December 2019, China notified the World Health Organization about a viral pneumonia epidemic soon to be named COVID-19, of which the infectious agent, SARS-CoV-2, was rapidly identified. Less than one year later, published phase 3 clinical trials underlined the effectiveness of vaccines utilizing hitherto unusual technology consisting in injection of the messenger RNA (m-RNA) of a viral protein. In the meantime, numerous clinical trials had failed to identify a maximally effective antiviral treatment, and mass vaccination came to be considered as the strategy most likely to put an end to the pandemic. The objective of this text is to address and hopefully answer the questions being put forward by healthcare professionals on the different anti-SARS-CoV-2 vaccines as regards their development, their modes of action, their effectiveness, their limits, and their utilization in different situations; we are proposing a report on both today's state of knowledge, and the 14 February 2021 recommendations of the French health authorities.

COVID-19 in clinical practice: A narrative synthesis.

The coronavirus disease 2019 (COVID-19) was first reported in the city of Wuhan, China. The disease rapidly spread to the rest of China, to Southern-East Asia, then to Europe, America, and on to the rest of the world. COVID-19 is associated with a betacoronavirus named SARS-CoV-2. The virus penetrates the organism through the respiratory tract, conveyed by contaminated droplets. The main cell receptor targeted is the surface-bound ACE-2. As of the 26th July 2020, 15,200,000 COVID-19 cases and 650,000 deaths were reported worldwide. The mortality rate is estimated between 1.3 and 18.3%. The reproductive rate without any public health intervention is estimated around 4-5.1 in France. Most hospitalized patients for COVID-19 present respiratory symptoms, which in some cases is associated with fever. Up to 86% of admissions to ICU are related to acute respiratory failure. To date, no anti-viral therapy has proven its efficacy considering randomized trials. Only immunomodulatory treatments such as corticosteroids have shown to cause significant improvement in patient outcome.

Immune profile at HIV infection diagnosis: Evolution in the French Alps area over the last 20 years.

OBJECTIVES: Health of HIV-infected people relies on early antiretroviral therapy, i.e. early diagnosis. We aimed to determine whether the characteristics at HIV diagnosis in two French medical centres changed over the last 20 years. PATIENTS AND METHODS: All individuals diagnosed with HIV infection in Grenoble University Hospital (N=814) and Annecy Hospital (N=246) between 1997 and 2015 were included. We collected age, country of birth, mode of transmission, CD4T cell count, CD4/CD8 ratio, and HIV viral load. RESULTS: Among the 1060 patients (mean age 37.4±11 years, 70.2% of men), 42.5% were men having sex with men (MSM); 65.2% were born in France, and 24.4% were born in Africa. Mean CD4T cell count at diagnosis was 396±288/mm3 and was stable over the study period when considering all patients; when considering the MSM group, a significant increase over time was observed, with a mean increase of 7.3 CD4/mm3 per year (P<0.001). A higher CD4 count at diagnosis was observed after 2005 (400±289 vs 468±271/mm3, P=0.005). The proportion of MSM patients with a CD4 count<200/mm3 at diagnosis was lower after 2005 (14.7% after 2005 and 25.6% before, P=0.028) This was not observed in heterosexual patients (born in Africa or not). CONCLUSION: In the MSM population, CD4 count at diagnosis is higher after 2005, suggesting that screening campaigns have become more efficient. This was not observed in other populations, who should be better targeted in future strategies.

Satisfaction with sexual life in people living with HIV/AIDS: the persistent weight of the fear of transmission.

Sexual life is an important dimension of quality of life, which may be affected by the fear of transmission in people living with HIV/AIDS (PLWHA), despite the fact that antiretroviral therapy prevents person-to-person transmission. We, therefore, aimed to explore the sexual life satisfaction of PLWHA and its correlation with their fear of HIV transmission and self-esteem. Consecutive adult PLWHA from seven HIV care facilities in the Rhone-Alpes region, France, were asked to complete a self-administered, anonymous questionnaire concerning sociological and medical data, satisfaction with sexual life (18 questions), and self-esteem (Rosenberg score). Overall, 690 PLWHA answered the questionnaire (mean age 49.2 ± 11 years); 74.9% were men, of which 75.1% had sex with men. Overall, 68.0% of respondents feared transmitting HIV (a lot/a bit). A lower satisfaction with sexual life was significantly associated with being female, not having a stable sexual partner, being unemployed, having a low income, experiencing a fear of HIV transmission, having lower self-esteem, and not reporting an excellent/very good health status. These results strongly suggest that the information concerning the antiretroviral-induced suppression of infectivity should be widely diffused, as this may enhance the quality of sexual life in PLWHA.

Hepatitis B vaccination status in an at-risk adult population: long-term immunity but insufficient coverage.

In France, hepatitis B (HB) vaccine has been offered to all infants since 1994, and was proposed to all children aged 11 years from 1994 to 1998. Nevertheless, HB vaccine hesitancy may result in low vaccination coverage in present-day at-risk adults. We aimed to determine HB vaccination coverage in adults attending a free testing center for sexually transmitted infections (STI). As part of routine care, three classes of data were anonymously collected from attendees over a 3-month period: results of HB serologic tests; date and number of past anti-hepatitis B virus (HBV) immunization(s) (if any) according to health records; and the risk of STI and blood-transmitted infections (BTI). The study included 735 participants (age 27.9 ± 9.2; 59.9% men). According to available health records (341 participants), 56.6% had received at least three and 67.2% at least one vaccine injection(s); 57.7% had received their last injection between 1994 and 1998, reflecting the strong vaccine policy during these years. Serologic testing (in 705 participants) showed evidence of a past or active HBV infection for 33 participants; of the remaining patients, 55.3% had anti-HBs antibody titers ≥10 IU/L. This rate was not higher in participants considered at risk for STI/BTI. Of the participants who received their last vaccine injection more than 15 years previously, 90.5% had anti-HBs antibody concentrations ≥10 and 60.3% ≥100 IU/mL. HB vaccination coverage is low in this population. Most of the vaccinated participants were immunized between 1994 and 1998, suggesting a failure of catch-up immunization of adolescents and at-risk adults. Long-term seroprotection persisted among vaccinated participants.

Assessment of linezolid prescriptions in three French hospitals.

The use of linezolid to treat gram-positive cocci infections is increasing in France. Linezolid is approved in pneumonia and complicated skin and soft tissue infections. Overuse and misuse of linezolid can favor the emergence and spreading of linezolid-resistant strains. We aimed to assess the appropriateness of linezolid use in French hospitals. This is a multicenter, retrospective study conducted in three tertiary care hospitals. Appropriateness of linezolid indications and adequacy (composite score concerning dosage, route of administration and blood monitoring) were assessed. Over a three-month period, all prescriptions of linezolid were extracted and analyzed by two independent infectious disease experts. Among the 81 initial prescriptions that were evaluated, indication was appropriate in 48% of cases. Among those, 51% complied with international guidelines. Fifty-seven percent of the prescriptions were adequate regarding dosage, route of administration and blood monitoring. Overall, 23% of prescriptions combined both appropriateness and adequacy. The most frequent reasons for inappropriateness were the possibility of choosing narrower-spectrum antibiotics and the empirical use of linezolid in severe sepsis or septic shock. Initial treatment was the most frequently appropriate in bone and joint infection cases (p = 0.001). Our study shows that even if modalities of use were mostly correct, appropriateness of linezolid indications is low. Educational programs are mandatory to improve practices, as well as clinical studies to better assess the efficacy and safety of linezolid in clinical situations other than pneumonia or complicated skin and soft tissue infections.

Elaboration of a clinical and paraclinical score to estimate the probability of herpes simplex virus encephalitis in patients with febrile, acute neurologic impairment.

Herpes simplex virus (HSV) encephalitis is associated with a high risk of mortality and sequelae, and early diagnosis and treatment in the emergency department are necessary. However, most patients present with non-specific febrile, acute neurologic impairment; this may lead clinicians to overlook the diagnosis of HSV encephalitis. We aimed to identify which data collected in the first hours in a medical setting were associated with the diagnosis of HSV encephalitis. We conducted a multicenter retrospective case-control study in four French public hospitals from 2007 to 2013. The cases were the adult patients who received a confirmed diagnosis of HSV encephalitis. The controls were all the patients who attended the emergency department of Grenoble hospital with a febrile acute neurologic impairment, without HSV detection by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF), in 2012 and 2013. A multivariable logistic model was elaborated to estimate factors significantly associated with HSV encephalitis. Finally, an HSV probability score was derived from the logistic model. We identified 36 cases and 103 controls. Factors independently associated with HSV encephalitis were the absence of past neurological history (odds ratio [OR] 6.25 [95 % confidence interval (CI): 2.22-16.7]), the occurrence of seizure (OR 8.09 [95 % CI: 2.73-23.94]), a systolic blood pressure ≥140 mmHg (OR 5.11 [95 % CI: 1.77-14.77]), and a C-reactive protein <10 mg/L (OR 9.27 [95 % CI: 2.98-28.88]). An HSV probability score was calculated summing the value attributed to each independent factor. HSV encephalitis diagnosis may benefit from the use of this score based upon some easily accessible data. However, diagnostic evocation and probabilistic treatment must remain the rule.

Success and failure of artesunate treatment in five transplant recipients with disease caused by drug-resistant cytomegalovirus.

Cytomegalovirus (CMV) strains resistant to ganciclovir, cidofovir and/or foscarnet were genotypically and phenotypically characterised in two haematopoietic stem cell transplant recipients and three solid-organ transplant recipients with CMV disease. The anti-malaria drug artesunate led to a favourable virological and clinical response in three cases with mild CMV diseases (fever and neutropaenia) but was ineffective in two fatal CMV diseases with lung involvement in spite of a decrease in the CMV DNA load in blood and bronchoalveolar fluid.

Pneumocystis jirovecii (Pj) quantitative PCR to differentiate Pj pneumonia from Pj colonization in immunocompromised patients.

Conventional polymerase chain reaction (PCR) in respiratory samples does not differentiate between Pneumocystis pneumonia (PCP) and Pneumocystis jirovecii (Pj) colonization. We used Pj real-time quantitative PCR (qPCR) with the objective to discriminate PCP from Pj colonization in immunocompromised patients. All positive Pj qPCR [targeting the major surface glycoprotein (MSG) gene] obtained in respiratory samples from immunocompromised patients presenting pneumonia at the Grenoble University Hospital, France, were collected between August 2009 and April 2011. Diagnoses were retrospectively determined by a multidisciplinary group of experts blinded to the Pj qPCR results. Thirty-one bronchoalveolar lavages and four broncho aspirations positive for the Pj qPCR were obtained from 35 immunocompromised patients. Diagnoses of definite, probable, and possible PCP, and pneumonia from another etiology were retrospectively made for 7, 4, 5, and 19 patients, respectively. Copy numbers were significantly higher in the "definite group" (median 465,000 copies/ml) than in the "probable group" (median 38,600 copies/ml), the "possible group" (median 1,032 copies/ml), and the "other diagnosis group" (median 390 copies/ml). With the value of 3,160 copies/ml, the sensitivity and specificity of qPCR for the diagnosis of PCP were 100 % and 70 %, respectively. With the value of 31,600 copies/ml, the sensitivity and specificity were 80 % and 100 %, respectively. The positive predictive value was 100 % for results with more than 31,600 copies/ml and the negative predictive value was 100 % for results with fewer than 3,160 copies/ml. qPCR targeting the MSG gene can be helpful to discriminate PCP from Pj colonization in immunocompromised patients, using two cut-off values, with a gray zone between them.

Outcome of central venous catheter-related bacteraemia according to compliance with guidelines: experience with 91 episodes.

BACKGROUND: Infection is a major complication associated with the use of central venous catheters. Guidelines for medical management of catheter-related bacteraemia have been published, but no study has assessed the appropriateness of physician practices. AIM: To assess medical practices in cases of central venous catheter-related bacteraemia (CRB) in a university hospital. METHODS: Cases were recorded over a period of 12 months and their management was evaluated. All cases of positive blood cultures based on central venous catheter sampling were analysed, and episodes of CRB were determined in this group of patients. Medical management and patient outcome were analysed independently by two physicians. FINDINGS: In all, 187 cases of positive blood culture were recorded and 91 cases of CRB were analysed. Systemic antimicrobial therapy was optimal in 56% of the episodes. In 51 episodes, catheter salvage was attempted, for 29 with an indication in agreement with the guidelines but without antibiotic-lock therapy in 20 episodes. The overall medical management was appropriate in 41.8% of the episodes. The overall cure rate was 72.5%. CRB-related death occurred in 5.5% of the episodes. Cure was associated with guideline compliance (P = 0.03) and with adaptation of systemic antimicrobial therapy (P < 0.01). Conservative treatment success was associated with compliance with the guidelines for the indication (P = 0.01). CONCLUSION: Medical management of CRB did not closely adhere to international guidelines. CRB outcome was associated with the appropriateness of this management, particularly when conservative treatment was attempted.

Phototoxicity and photocarcinogenesis associated with voriconazole.

The antifungal voriconazole was given its marketing authorization in 2002. Several kinds of adverse effects have been reported, including acute and chronic cutaneous adverse effects, mainly due to a phototoxicity mechanism. More recently, some authors have reported that voriconazole was involved in the occurrence of multiple and often-aggressive cutaneous squamous cell carcinomas if the treatment was maintained for a long time. According to safety data in studies assessing voriconazole effectiveness, 8% of outpatients may experience phototoxic events. An overview of the different types of phototoxicity and of the concerned population was given by the 61 published case reports of photo-induced voriconazole-related skin adverse events (including 18 cases of squamous cell carcinomas). The most likely mechanisms may be phototoxicity directly related to either voriconazole or to its N-oxide main metabolite, and an interaction with retinoid metabolism; moreover, immunodeficiency may enhance the risk of skin cancer. Several issues remain to be investigated, and studies are needed concerning the phototoxicity and photocarcinogenesis of voriconazole and the prognosis of chronic non-malignant skin lesions. Voriconazole prescription must be associated with strict photoprotection; in case of a phototoxic adverse event, another azole may be recommended.