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Background: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems., Methods: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation., Results: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir ( n = 634) or standard of care ( n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care ( p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups., Interpretation: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration : ClinicalTrials.gov, no. NCT04330690., Competing Interests: Competing interests: Alexandra Binnie reports receiving research grants from the Canadian Institutes of Health Research (CIHR) and the Physicians Services Incorporated Foundation. Sergio Borgia reports receiving honoraria from Gilead Sciences and GSK. Yiorgos Alexandros Cavayas reports receiving a grant from CIHR. Matthew Cheng reports receiving grants from the McGill Interdisciplinary Initiative in Infection and Immunity and from CIHR, during the conduct of the study (payments made to the institution). Dr. Cheng also reports receiving personal fees from AstraZeneca, outside the submitted work; and from Nplex Biosciences and GEn1E lifesciences (in the form of stock options for being a member of the scientific advisory board) outside the submitted work. Dr. Cheng co-founded Kanvas Biosicences and owns equity in the company, and reports 3 patents pending. John Conly reports receiving grants from CIHR, Pfizer, the World Health Organization (WHO), Sunnybrook Research Institute, University of Calgary, and the Calgary Health Foundation. Dr. Conly also reports receiving support to attend the Think Tank Meeting 2019. Dr. Conly is a member and Chair of the WHO Infection Prevention and Control Research and Development Expert Group for COVID-19, a member of the WHO Health Emergencies Programme (WHE) Ad-hoc COVID-19 IPC Guidance Development Group, and a member of the Cochrane Acute Respiratory Infections Group. Madeleine Durand reports receiving grants from CIHR and the Fonds Recherche du Québec–Santé (FRQS). Rob Fowler reports receiving a grant from CIHR for the CATCO trial and is the H. Barrie Fairley Professor of Critical Care at the University Health Network. Michael Fralick reports receiving multiple grants from CIHR and support from grants from the Canadian military for clinical trials to identify treatments for COVID-19 (payments made to institution). Dr. Fralick is a paid consultant for a start-up company called Proof DiagnosticsDx, which has created a point-of-care testing device using CRISPR for COVID-19. Holly Hoang reports receiving payment from CATCO Sunnybrook to fund research assistant (payment made to institution) and a research grant from Covenant Health Research Centre. Marina Klein reports receiving grants from Gilead, ViiV Healthcare, Merck and AbbVie for investigator-initiated studies, and consulting fees from Gilead, ViiV Healthcare, Merck and AbbVie, all outside the submitted work. Todd Lee reports receiving operating grants from CIHR and McGill Interdisciplinary Initiative in Infection and Immunity (MI4), and research salary support from FRQS. Alexandra Lostun reports receiving per-case funding to cover the costs of enrolling patients (paid to institution, North York General Hospital). François Carrier reports receiving grants from the Instituts de recherche en santé du Canada and the Canadian Donation and Transplantation Research Program, and a grant and salary support from FRQS. Marlee McGuinty reports receiving speaking fees from Merck. Srinivas Murthy reports receiving a grant from CIHR, during the conduct of the study, and is the Health Research Foundation and Innovative Medicines Canada Chair in Pandemic Preparedness Research. Conar O’Neil reports receiving conference sponsorship from Gilead Sciences, and is a member of a Gilead Sciences advisory board. Jesse Papenburg reports receiving a grant from CIHR, during the conduct of the study, as well as research grants and contracts from AbbVie and research contracts (site investigator for clinical trial) from MedImmune, Merck and Sanofi Pasteur. Dr. Papenburg has received consulting fees from Merck for an ad hoc advisory board meeting, and honoraria for presentations from Seegene, AbbVie and AstraZeneca. Dr. Papenburg is also a voting member of the National Advisory Committee on Immunization. Ken Kuljit S. Parhar reports receiving a CIHR project grant, Alberta Innovates grant and Alberta Health Innovation Implementation and Spread grant (all paid to institution). Seema Nair Parvathy reports receiving funding from St. Joseph’s Health Care Foundation and London Health Sciences Foundation. Moira Rushton-Marovac reports receiving advisory board honoraria from Gilead. Marina Salvadori reports being an employee of the Public Health Agency of Canada. Makeda Semret reports receiving support from the McGill MI4 for the clinical research platform through which CATCO was supported at the McGill University Health Centre. Ameeta Singh reports receiving consulting fees from Gilead for membership of an advisory board. Ranjani Somayaji reports receiving contract research funding from Sunnybrook Research Institute, University of Calgary and Calgary Health Foundation, and clinical research funding from CIHR and the Cystic Fibrosis Foundation. Dr. Somayaji also reports participation on an oncovir data monitoring safety board. Darrell Tan reports receiving grants from AbbVie (in-kind drug only) and Gilead (in-kind drug and grants to institution), and a contract between GSK and the institution for clinical trials. Alain Tremblay reports receiving contract research funding from the Sunnybrook Research Institute, and grants for COVID-19 clinical trials from the University of Calgary and Calgary Health Foundation. Alexis Turgeon reports receiving a grant from CIHR. Jason Weatherald reports receiving grants (paid to institution) and consulting fees (paid to Dr. Weatherald) from Janssen and Actelion, as well as honoraria and travel support from Janssen. Dr. Weatherald has served on advisory boards for Janssen and Acceleron (paid) and on a Data Safety Monitoring Board for Université Laval (unpaid). Dr. Weatherald also reports membership of the Medical Advisory Committee of the Pulmonary Hypertension Association of Canada, and is a shareholder of Precision Lung Consultants and Diagnostics. Cedric Yansouni reports receiving grants from FRQS and consulting fees from Medicago Inc. Dr. Yansouni also reports participation in a Medicago Inc. Independent Data Monitoring Committee and held the role of scientific advisor for the COVID-19 Immunity Task Force. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Objectives: Antivirals are recommended for children hospitalized with influenza but are underutilized. We describe antiviral prescribing during influenza admissions in Canadian pediatric centers and identify factors associated with antiviral use., Methods: We performed active surveillance for laboratory-confirmed influenza hospitalizations among children ≤16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from 2010-2011 to 2018-2019. Logistic regression analyses were used to identify factors associated with antiviral use., Results: Among 7545 patients, 57.4% were male; median age was 3 years (interquartile range: 1.1-6.3). Overall, 41.3% received antiviral agents; 72.8% received antibiotics. Antiviral use varied across sites (range, 10.2% to 81.1%) and influenza season (range, 19.9% to 59.6%) and was more frequent in children with ≥1 chronic health condition (52.7% vs 36.7%; P < .001). On multivariable analysis, factors associated with antiviral use included older age (adjusted odds ratio [aOR] 1.04 [95% confidence interval (CI), 1.02-1.05]), more recent season (highest aOR 9.18 [95% CI, 6.70-12.57] for 2018-2019), admission during peak influenza period (aOR 1.37 [95% CI, 1.19-1.58]), availability of local treatment guideline (aOR 1.54 [95% CI, 1.17-2.02]), timing of laboratory confirmation (highest aOR 2.67 [95% CI, 1.97-3.61] for result available before admission), presence of chronic health conditions (highest aOR 4.81 [95% CI, 3.61-6.40] for cancer), radiographically confirmed pneumonia (aOR 1.39 [95% CI, 1.20-1.60]), antibiotic treatment (aOR 1.51 [95% CI, 1.30-1.76]), respiratory support (1.57 [95% CI, 1.19-2.08]), and ICU admission (aOR 3.62 [95% CI, 2.88-4.56])., Conclusions: Influenza antiviral agents were underused in Canadian pediatric hospitals, including among children with high-risk chronic health conditions. Prescribing varied considerably across sites, increased over time, and was associated with patient and hospital-level characteristics. Multifaceted hospital-based interventions are warranted to strengthen adherence to influenza treatment guidelines and antimicrobial stewardship practices., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: In 2015, the Quebec Ministry of Health limited palivizumab prophylaxis for respiratory syncytial virus (RSV) in premature infants to those born at <33 weeks gestational age (wGA), unless other indications were present. We compared RSV-related costs for 2 seasons before the change (2013-2014, 2014-2015) and 2 seasons after (2015-2016, 2016-2017) in premature infants 33-35 wGA., Methods: Using payer and societal perspectives, costs associated with hospitalizations for RSV and lower respiratory tract infection (LRTI) in infants born at 33-35 wGA were estimated. Inputs were from a 2013-2017 retrospective cohort study in 25 Quebec hospitals of RSV/LRTI hospitalizations among infants <6 months old at the start of, or born during, the RSV season. Resource utilization data (hospital stay, procedures, visits, transportation, out-of-pocket expenses and work productivity) were collected from charts and parent interviews allowing estimation of direct and indirect costs. Costs, including palivizumab administration, were derived from provincial sources and adjusted to 2018 Canadian dollars. Costs were modeled for preterm infants hospitalized for RSV/LRTI pre- and postrevision of guidelines and with matched term infants hospitalized for RSV/LRTI during 2015-2017 (comparator)., Results: Average total direct and indirect costs for 33-35 wGA infants were higher postrevision of guidelines ($29,208/patient, 2015-2017; n = 130) compared with prerevision ($16,976/patient, 2013-2015; n = 105). Total costs were higher in preterm infants compared with term infants (n = 234) postrevision of guidelines ($29,208/patient vs. $10,291/patient)., Conclusions: Immunoprophylaxis for RSV in infants born at 33-35 wGA held a cost advantage for hospitalizations due to RSV/LRTI.

Background: Aboriginal infants are at risk for serious respiratory infection., Objective: To determine the hazard rate (HR) for respiratory-related illness (RIH) and respiratory syncytial virus (RSV) specific infection hospitalization (RSVH) in Aboriginal versus non-Aboriginal children receiving palivizumab and the effect of adherence on hospitalization., Methods: Palivizumab recipients in the Canadian registry from 2005 to 2014 were included. Adherence was determined by the number of palivizumab doses received during the RSV season and interdose time interval. Adherence proportions between groups were compared by χ test. Cox proportional hazard analysis determined the effect of Aboriginal status and adherence on the risk of RIH and RSVH., Results: Aboriginal infants comprised 3.6% (701/19,235) of the registry. HR was 1.6 [95% confidence interval (CI): 1.3-2.0, P < 0.001] and 1.2 (95% CI: 0.7-2.2, P = 0.383) for RIH and RSVH. Aboriginal infants were 62.8% and 63.3% adherent with all recommended injections and within stipulated time intervals, respectively, whereas 81.9% (χ = 162.45, df = 1, P < 0.001) and 72.4% (χ = 27.35, df = 1, P = 0.002) of non-Aboriginal infants were correspondingly adherent. Only 39.9% of Aboriginals were perfectly adherent (adherent to total number and injection intervals), compared with 61.7% of non-Aboriginals (χ = 133.89, df = 1, P < 0.001). Even after adjustment for known risk factors, being Aboriginal and nonadherent was associated with higher RIH hazard (HR = 1.4, 95% CI: 1.1-1.8; HR = 1.3, 95% CI: 1.1-1.4, P = 0.004), respectively. Aboriginals nonadherent with interdose intervals had a 2.2-fold increased HR for RSVH (HR = 2.2, 95% CI: 1.2-4.2, P = 0.015)., Conclusions: Prophylaxed Aboriginal infants have a significantly increased RIH and RSVH hazard than non-Aboriginal infants. Improving adherence especially interdose frequency may further reduce hospitalizations in this vulnerable population.

Neuraminidase inhibitor (NI) dispensing has emerged as a possible automated data source for influenza surveillance. We aimed to evaluate its timeliness, correlation, and predictive accuracy in relation to influenza activity in Quebec, Canada, 2010-2013. Our secondary objective was to use the same metrics to compare NI dispensing to visits for influenza-like illness (ILI) in emergency departments (EDs). Provincial weekly counts of positive influenza laboratory tests were used as a reference measure for the level of influenza circulation. We applied ARIMA models to account for serial correlation. We computed cross-correlations to measure the strengths of association and lead-lag relationships between NI dispensing, ILI ED visits, and our reference indicator. Finally, using an ARIMA model, we evaluated the ability of NI dispensing and ILI ED visits to predict laboratory-confirmed influenza. NI dispensing was significantly correlated (R = 0·68) with influenza activity with no lag. The maximal correlation of ILI ED visits was not as strong (R = 0·50). Both NI dispensing and ILI ED visits were significant predictors of laboratory-confirmed influenza in a multivariable model; predictive potential was greatest when NI counts were lagged to precede laboratory surveillance by 2 weeks. We conclude that NI dispensing data provides timely and valuable information for influenza surveillance.

Background: A point-of-care rapid test (POCRT) may help early and targeted use of antiviral drugs for the management of influenza A infection., Objective: (i) To determine whether antiviral treatment based on a POCRT for influenza A is cost-effective and, (ii) to determine the thresholds of key test parameters (sensitivity, specificity and cost) at which a POCRT based-strategy appears to be cost effective., Methods: An hybrid « susceptible, infected, recovered (SIR) » compartmental transmission and Markov decision analytic model was used to simulate the cost-effectiveness of antiviral treatment based on a POCRT for influenza A in the social perspective. Data input parameters used were retrieved from peer-review published studies and government databases. The outcome considered was the incremental cost per life-year saved for one seasonal influenza season., Results: In the base-case analysis, the antiviral treatment based on POCRT saves 2 lives/100,000 person-years and costs $7600 less than the empirical antiviral treatment based on clinical judgment alone, which demonstrates that the POCRT-based strategy is dominant. In one and two way-sensitivity analyses, results were sensitive to the POCRT accuracy and cost, to the vaccination coverage as well as to the prevalence of influenza A. In probabilistic sensitivity analyses, the POCRT strategy is cost-effective in 66% of cases, for a commonly accepted threshold of $50,000 per life-year saved., Conclusion: The influenza antiviral treatment based on POCRT could be cost-effective in specific conditions of performance, price and disease prevalence., (© 2015 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

A small proportion (1%-1.5%) of 2009 pandemic influenza A/H1N1 virus strains (A[H1N1]pdm09) are oseltamivir resistant, almost exclusively because of a H275Y mutation in the neuraminidase protein. However, many individuals infected with resistant strains had not received antivirals. Whether drug-resistant viruses are initially present as minor variants in untreated individuals before they emerge as the dominant strain in a virus population is of great importance for predicting the speed at which resistance will arise. To address this issue, we used ultra-deep sequencing of viral populations from serial nasopharyngeal specimens from an immunocompromised child and from 2 individuals in a household outbreak. We observed that the Y275 mutation was present as a minor variant in infected hosts before the onset of therapy. We also found evidence for the transmission of this drug-resistant variant with drug-susceptible viruses. These observations provide important information on the relative fitness of the Y275 mutation in the absence of oseltamivir treatment.