Contribution of voriconazole N-oxide plasma concentration measurements to voriconazole therapeutic drug monitoring in patients with invasive fungal infection.

BACKGROUND: Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient's drug metabolism capacity. OBJECTIVES: Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. PATIENTS AND METHODS: Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. RESULTS: Based on 225 measurements, the median and interquartile range were 2.4 µg/ml (1.2; 4.2), 2.1 µg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2 µg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2 µg/ml and above 5.5 µg/ml, respectively, at the next visit. CONCLUSIONS: Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision-making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results.

Effectiveness of mRNA-BNT162b2, mRNA-1273, and ChAdOx1 nCoV-19 vaccines against COVID-19 in healthcare workers: an observational study using surveillance data.

OBJECTIVES: Healthcare workers (HCWs) at increased risk of coronavirus disease 2019 (COVID-19) were among the primary targets for vaccine campaigns. We aimed to estimate the protective efficacy of the first three COVID-19 vaccines available in Western Europe. METHODS: We merged two prospective databases that systematically recorded, in our institution: (a) HCWs positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by RT-PCR on nasopharyngeal samples, and (b) HCWs who received at least one dose of COVID-19 vaccine. We excluded HCWs with SARS-CoV-2 infection during the 6 months prior to the study. HCWs were categorized as non-vaccinated if they received no vaccine and until the first injection +13 days, partially vaccinated from the first injection +14 days to the second injection +13 days, and fully vaccinated thereafter. RESULTS: Of the 8165 HCWs employed in our institution, 360 (4.4%) tested positive for SARS-CoV-2 by RT-PCR during the study period (4th January to 17th May 2021). Incidence was 9.1% (8.2-10.0) in non-vaccinated HCWs, 1.2% (0.7-1.9) after one dose of ChAdOx1 nCoV-19, 1.4% (0.6-2.3) and 0.5% (0.1-1.0) after one and two doses of mRNA BNT162b2, 0.7% (0.1-1.9) and 0% after one and two doses of mRNA-1273 (p < 0.0001). Vaccine effectiveness (Cox model) was estimated at, respectively, 86.2% (76.5-91.0), 38.2% (6.3-59.2), and 49.2% (19.1-68.1) 14 days after the first dose for ChAdOx1 nCoV-19, mRNA-1273, and mRNA-BNT162b2, and 100% (ND) and 94.6% (61.0-99.2) 14 days after the second dose for mRNA-1273 and mRNA-BNT162b2. CONCLUSIONS: In this real-world study, the observed effectiveness of COVID-19 vaccines in HCWs was in line with the efficacy reported in pivotal randomized trials.

COVID-19 vaccine hesitancy among healthcare workers.

OBJECTIVE: To characterize healthcare workers' (HCWs) intention to receive the COVID-19 vaccine by the beginning of the vaccine campaign in France. METHODS: Data were collected on a self-administered questionnaire through the website of a tertiary care center (February 9-18, 2021). RESULTS: Among 1,965 respondents, 1,436 (73.1%), 453 (23.1%), and 76 (3.9%) declared themselves in favor, hesitant, or against the COVID-19 vaccine: <60% of auxiliary nurses and technicians intended to be vaccinated, as compared to 60-79% of nurses and support staff, and>80% of medical staff. On multivariate analysis, age, occupation, flu vaccine history, and controversy over the AstraZeneca vaccine tolerability were independently associated with COVID-19 vaccine intention. CONCLUSIONS: Patterns of vaccine hesitancy related to the COVID-19 and influenza vaccines are similar among HCWs. Media communication on vaccine side effects have a dramatic effect on vaccine hesitancy. Efforts are requested to inform HCWs about the risk/benefit balance of COVID-19 vaccines.

Prevalence and characteristics of persistent symptoms after non-severe COVID-19: a prospective cohort study.

We performed a prospective cohort study of 311 outpatients with non-severe COVID-19 (187 women, median age 39 years). Of the 214 (68.8%) who completed the 6-week follow-up questionnaire, 115 (53.7%) had recovered. Others mostly reported dyspnea (n = 86, 40.2%), weight loss (n = 83, 38.8%), sleep disorders (n = 68, 31.8%), and anxiety (n = 56, 26.2%). Of those who developed ageusia and anosmia, these symptoms were still present at week 6 in, respectively, 11/111 (9.9%) and 19/114 (16.7%). Chest CT scan and lung function tests found no explanation in the most disabled patients (n = 23). This study confirms the high prevalence of persistent symptoms after non-severe COVID-19.

Implementation of a Self-Triage Web Application for Suspected COVID-19 and Its Impact on Emergency Call Centers: Observational Study.

BACKGROUND: We developed a self-triage web application for COVID-19 symptoms, which was launched in France in March 2020, when French health authorities recommended all patients with suspected COVID-19 call an emergency phone number. OBJECTIVE: Our objective was to determine if a self-triage tool could reduce the burden on emergency call centers and help predict increasing burden on hospitals. METHODS: Users were asked questions about their underlying conditions, sociodemographic status, postal code, and main COVID-19 symptoms. Participants were advised to call an emergency call center if they reported dyspnea or complete loss of appetite for over 24 hours. Data on COVID-19-related calls were collected from 6 emergency call centers and data on COVID-19 hospitalizations were collected from Santé Publique France and the French Ministry of Health. We examined the change in the number of emergency calls before and after the launch of the web application. RESULTS: From March 17 to April 2, 2020, 735,419 questionnaires were registered in the study area. Of these, 121,370 (16.5%) led to a recommendation to call an emergency center. The peak number of overall questionnaires and of questionnaires leading to a recommendation to call an emergency center were observed on March 22, 2020. In the 17 days preceding the launch of the web application, emergency call centers in the study area registered 66,925 COVID-19-related calls and local hospitals admitted 639 patients for COVID-19; the ratio of emergency calls to hospitalizations for COVID-19 was 104.7 to 1. In the 17 days following the launch of the web application, there were 82,347 emergency calls and 6009 new hospitalizations for COVID-19, a ratio of 13.7 calls to 1 hospitalization (chi-square test: P<.001). CONCLUSIONS: The self-triage web application launch was followed by a nearly 10-fold increase in COVID-19-related hospitalizations with only a 23% increase in emergency calls. The peak of questionnaire completions preceded the peak of COVID-19-related hospitalizations by 5 days. Although the design of this study does not allow us to conclude that the self-triage tool alone contributed to the alleviation of calls to the emergency call centers, it does suggest that it played a role, and may be used for predicting increasing burden on hospitals. TRIAL REGISTRATION: ClinicalTrials.gov NCT04331171; https://clinicaltrials.gov/ct2/show/NCT04331171.

Non-influenza respiratory viruses in adult patients admitted with influenza-like illness: a 3-year prospective multicenter study.

PURPOSE: To describe the burden, and characteristics, of influenza-like illness (ILI) associated with non-influenza respiratory viruses (NIRV). METHODS: We performed a prospective, multicenter, observational study of adults admitted with ILI during three influenza seasons (2012-2015). Patients were screened for picornavirus, respiratory syncytial virus (RSV), coronavirus, human metapneumovirus, adenovirus, bocavirus, parainfluenza virus, and influenza, by PCR on nasopharyngeal samples. We excluded patients coinfected with NIRV and influenza. RESULTS: Among 1421 patients enrolled, influenza virus was detected in 535 (38%), and NIRV in 215 (15%), mostly picornavirus (n = 61), RSV (n = 53), coronavirus 229E (n = 48), and human metapneumovirus (n = 40). In-hospital mortality was 5% (NIRV), 4% (influenza), and 5% (no respiratory virus). As compared to influenza, NIRV were associated with age (median, 73 years vs. 68, P = 0.026), chronic respiratory diseases (53% vs. 45%, P = 0.034), cancer (14% vs. 9%, P = 0.029), and immunosuppressive drugs (21% vs. 14%, P = 0.028), and inversely associated with diabetes (18% vs. 25%, P = 0.038). On multivariable analysis, only chronic respiratory diseases (OR 1.5 [1.1-2.0], P = 0.008), and diabetes (OR 0.5 [0.4-0.8], P = 0.01) were associated with NIRV detection. CONCLUSIONS: NIRV are common in adults admitted with ILI during influenza seasons. Outcomes are similar in patients with NIRV, influenza, or no respiratory virus.

COVID-19 in Patient with Sarcoidosis Receiving Long-Term Hydroxychloroquine Treatment, France, 2020.

Because of in vitro studies, hydroxychloroquine has been evaluated as a preexposure or postexposure prophylaxis for coronavirus disease (COVID-19) and as a possible COVID-19 curative treatment. We report a case of COVID-19 in a patient with sarcoidosis who was receiving long-term hydroxychloroquine treatment and contracted COVID-19 despite adequate plasma concentrations.

Epidemiological Observations on the Association Between Anosmia and COVID-19 Infection: Analysis of Data From a Self-Assessment Web Application.

BACKGROUND: We developed a self-assessment and participatory surveillance web application for coronavirus disease (COVID-19), which was launched in France in March 2020. OBJECTIVE: Our objective was to determine if self-reported symptoms could help monitor the dynamics of the COVID-19 outbreak in France. METHODS: Users were asked questions about underlying conditions, sociodemographic status, zip code, and COVID-19 symptoms. Depending on the symptoms reported and the presence of coexisting disorders, users were told to either stay at home, contact a general practitioner (GP), or call an emergency phone number. Data regarding COVID-19-related hospitalizations were retrieved from the Ministry of Health. RESULTS: As of March 29, 2020, the application was opened 4,126,789 times; 3,799,535 electronic questionnaires were filled out; and 2,477,174 users had at least one symptom. In total, 34.8% (n=1,322,361) reported no symptoms. The remaining users were directed to self-monitoring (n=858,878, 22.6%), GP visit or teleconsultation (n=1,033,922, 27.2%), or an emergency phone call (n=584,374, 15.4%). Emergency warning signs were reported by 39.1% of participants with anosmia, a loss of the sense of smell (n=127,586) versus 22.7% of participants without anosmia (n=1,597,289). Anosmia and fever and/or cough were correlated with hospitalizations for COVID-19 (Spearman correlation coefficients=0.87 and 0.82, respectively; P<.001 for both). CONCLUSIONS: This study suggests that anosmia may be strongly associated with COVID-19 and its severity. Despite a lack of medical assessment and virological confirmation, self-checking application data could be a relevant tool to monitor outbreak trends. TRIAL REGISTRATION: ClinicalTrials.gov NCT04331171; https://clinicaltrials.gov/ct2/show/NCT04331171.