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Background Older adults are recommended to receive influenza vaccination annually, and many use statins. Statins have immunomodulatory properties that might modify influenza vaccine effectiveness (VE) and alter influenza infection risk. Methods Using the test-negative design and linked laboratory and health administrative databases in Ontario, Canada, we estimated VE against laboratory-confirmed influenza among community-dwelling statin users and nonusers aged ≥66 years during the 2010–2011 to 2018–2019 influenza seasons. We also estimated the odds ratio for influenza infection comparing statin users and nonusers by vaccination status. Results Among persons tested for influenza across the 9 seasons, 54 243 had continuous statin exposure before testing and 48 469 were deemed unexposed. The VE against laboratory-confirmed influenza was similar between statin users and nonusers (17% [95% confidence interval, 13%–20%] and 17% [13%–21%] respectively; test for interaction, P =.87). In both vaccinated and unvaccinated persons, statin users had higher odds of laboratory-confirmed influenza than nonusers (odds ratios for vaccinated and unvaccinated persons 1.15 [95% confidence interval, 1.10–1.21] and 1.15 [1.10–1.20], respectively). These findings were consistent by mean daily dose and statin type. VE did not differ between users and nonusers of other cardiovascular drugs, except for β-blockers. We did not observe that vaccinated and unvaccinated users of these drugs had increased odds of influenza, except for unvaccinated β-blocker users. Conclusions Influenza VE did not differ between statin users and nonusers. Statin use was associated with increased odds of laboratory-confirmed influenza in vaccinated and unvaccinated persons, but these associations might be affected by residual confounding. [ABSTRACT FROM AUTHOR]

Background Respiratory syncytial virus (RSV) contributes significantly to morbidity in children, placing substantial burdens on health systems, thus RSV vaccine development and program implementation are a public health priority. More data on burden are needed by policymakers to identify priority populations and formulate prevention strategies as vaccines are developed and licensed. Methods Using health administrative data, we calculated incidence rates of RSV hospitalization in a population-based birth cohort of all children born over a six-year period (May 2009 to June 2015) in Ontario, Canada. Children were followed until their first RSV hospitalization, death, 5th birthday, or the end of the study period (June 2016). RSV hospitalizations were identified using a validated algorithm based on International Classification of Diseases, 10th Revision, and/or laboratory-confirmed outcomes. We calculated hospitalization rates by various characteristics of interest, including calendar month, age groups, sex, comorbidities, and gestational age. Results The overall RSV hospitalization rate for children <5 years was 4.2 per 1000 person-years (PY) with a wide range across age groups (from 29.6 to 0.52 per 1000 PY in children aged 1 month and 36–59 months, respectively). Rates were higher in children born at a younger gestational age (23.2 per 1000 PY for those born at <28 weeks versus 3.9 per 1000 PY born at ≥37 weeks); this increased risk persisted as age increased. While the majority of children in our study had no comorbidities, rates were higher in children with comorbidities. For all age groups, rates were highest between December and March. Conclusions Our results confirm the high burden of RSV hospitalization and highlight young infants are at additional risk, namely premature infants. These results can inform prevention efforts. [ABSTRACT FROM AUTHOR]

Background Older adults are at increased risk of mortality from influenza infections. We estimated influenza vaccine effectiveness (VE) against mortality following laboratory-confirmed influenza. Methods Using a test-negative design study and linked laboratory and health administrative databases in Ontario, Canada, we estimated VE against all-cause mortality following laboratory-confirmed influenza for community-dwelling adults aged >65 years during the 2010–2011 to 2015–2016 influenza seasons. Results Among 54 116 older adults tested for influenza across the 6 seasons, 6837 died within 30 days of specimen collection. Thirteen percent (925 individuals) tested positive for influenza, and 50.6% were considered vaccinated for that season. Only 23.2% of influenza test-positive cases had influenza recorded as their underlying cause of death. Before and after multivariable adjustment, we estimated VE against all-cause mortality following laboratory-confirmed influenza to be 20% (95% confidence interval [CI], 8%–30%) and 20% (95% CI, 7%–30%), respectively. This estimate increased to 34% after correcting for influenza vaccination exposure misclassification. We observed significant VE against deaths following influenza confirmation during 2014–2015 (VE = 26% [95% CI, 5%–42%]). We also observed significant VE against deaths following confirmation of influenza A/H1N1 and A/H3N2, and against deaths with COPD as the underlying cause. Conclusions These results support the importance of influenza vaccination in older adults, who account for most influenza-associated deaths annually. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Most infants hospitalized with respiratory syncytial virus (RSV) do not meet common "high-risk" criteria and are otherwise healthy. The objective of this study was to quantify the risks and relative importance of socioeconomic factors for severe, early-life RSV-related illness. We hypothesized several of these factors, particularly those indicating severe social vulnerability, would have statistically significant associations with increased RSV hospitalization rates and may offer impactful targets for population-based RSV prevention strategies, such as prophylaxis programs. METHODS: We used linked health, laboratory, and sociodemographic administrative data for all children born in Ontario (2012-2018) to identify all RSV-related hospitalizations occurring before the third birthday or end of follow-up (March 31, 2019). We estimated rate ratios and population attributable fractions using a fully adjusted model. RESULTS: A total of 11 782 RSV-related hospitalizations were identified among 789 484 children. Multiple socioeconomic factors were independently associated with increased RSV-related admissions, including young maternal age, maternal criminal involvement, and maternal history of serious mental health and/or addiction concerns. For example, an estimated 4.1% (95% confidence interval: 2.2 to 5.9) of RSV-related admissions could be prevented by eliminating the increased admissions risks among children whose mothers used welfarebased drug insurance. Notably, 41.6% (95% confidence interval: 39.6 to 43.5) of admissions may be prevented by targeting older siblings (eg, through vaccination). CONCLUSIONS: Many social factors were independently associated with early-life RSV-related hospitalization. Existing RSV prophylaxis and emerging vaccination programs should consider the importance of both clinical and social risk factors when determining eligibility and promoting compliance. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) infection is a major cause of hospitalization in young children in Canada, despite routine immunoprophylaxis in those with medical risk factors. We aimed to determine if cold temperatures are associated with RSV hospitalization.Methods: We conducted a population-based nested case-control study of children in Ontario, Canada, using health administrative data. We compared children hospitalized for RSV between September 1, 2011 and August 31, 2012 to age and sex matched controls. We used multivariable logistic regression to identify associations between minimum daily temperature and RSV hospitalizations with adjustment for sociodemographic and environmental factors.Results: We identified 1670 children with RSV hospitalizations during the study period and 6680 matched controls. Warmer temperatures (OR = 0.94, 95%CI: 0.93, 0.95) were associated with lower odds of RSV hospitalization. Southern ecozone (OR = 1.6, 95%CI: 1.2, 2.1), increased ozone concentration (OR = 1.03, 95%CI: 1.01, 1.06) and living in a lower income neighbourhood (OR = 1.3, 95%CI: 1.1, 1.5) significantly increased the odds of RSV hospitalization, as did living in a household with a larger number of siblings in a sub-cohort of children (OR = 1.34, 95%CI: 1.26, 1.41).Conclusions: In Ontario, the likelihood of having an RSV hospitalization is associated with colder temperature exposures and socioeconomic factors. [ABSTRACT FROM AUTHOR]

Background: Annual influenza immunization is recommended for people with chronic obstructive pulmonary disease (COPD) by all major COPD clinical practice guidelines. We sought to determine the seasonal influenza vaccine effectiveness (VE) against laboratory-confirmed influenza-associated hospitalizations among older adults with COPD.Methods: We conducted a test-negative study of influenza VE in community-dwelling older adults with COPD in Ontario, Canada using health administrative data and respiratory specimens collected from patients tested for influenza during the 2010-11 to 2015-16 influenza seasons. Influenza vaccination was ascertained from physician and pharmacist billing claims. Multivariable logistic regression was used to estimate the adjusted odds ratio of influenza vaccination in people with, compared to those without, laboratory-confirmed influenza.Results: Receipt of seasonal influenza vaccine was associated with an adjusted 22% (95% confidence interval [CI], 15%-27%) reduction in laboratory-confirmed influenza-associated hospitalization. Adjustment for potential misclassification of vaccination status increased this to 43% (95% CI, 35%-52%). Vaccine effectiveness was not found to vary by patient- or influenza-related variables.Conclusions: During the studied influenza seasons, influenza vaccination was at least modestly effective in reducing laboratory-confirmed influenza-associated hospitalizations in people with COPD. The imperfect effectiveness emphasizes the need for better influenza vaccines and other preventive strategies. [ABSTRACT FROM AUTHOR]

Background: Vitamin D is a pleiotropic hormone important for the recovery of organ systems after critical illness. Recent observational studies have suggested that three out of every four children are vitamin D deficient following cardiac surgery, with inadequate preoperative intake and surgical losses playing important contributory roles. Observed associations between postoperative levels, cardiovascular dysfunction and clinical course suggest that perioperative optimization of vitamin D status could improve outcome. With this two-arm, parallel, double blind, randomized controlled trial (RCT), we aim to compare immediate postoperative vitamin D status in children requiring cardiopulmonary bypass for congenital heart disease who receive preoperative daily high dose vitamin D supplementation (high-dose arm) with those who receive usual intake (low-dose arm).Methods/design: Eligibility requirements include age (>36 weeks, <18 years) and a congenital heart defect requiring cardiopulmonary bypass surgical correction. Enrollment of 62 participants will take place at a single Canadian tertiary care center over a period of 2 years. Children randomized to the high-dose group will receive age-based dosing that was informed by the Institute of Medicine (IOM) daily tolerable upper intake level (<1 year old = 1,600 IU/day, >1 year old = 2,400 IU/day). Children in the low-dose arm will receive usual care based on IOM recommendations (<1 year old = 400 IU, >1 year old = 600 IU). The primary outcome measure is immediate postoperative vitamin D status, using blood 25(OH)D.Discussion: Maintaining adequate postoperative vitamin D levels following surgery could represent an effective therapy to speed recovery following CHD surgery. The proposed research project will determine whether preoperative supplementation with a dosing regimen based on the IOM recommended daily upper tolerable intake will prevent postoperative vitamin-D deficiency in the majority of children. The results will then be used to inform the design of a large international RCT exploring whether preoperative optimization of vitamin D status might improve short and long-term outcomes in this vulnerable population.Trial Registration: Clinicaltrials.gov Identifier--NCT01838447 Date of registration: 11 April 2013. [ABSTRACT FROM AUTHOR]

Background: Randomized trials conducted in low- and middle-income settings demonstrated efficacy of influenza vaccination during pregnancy against influenza infection among infants <6 months of age. However, vaccine effectiveness (VE) estimates from settings with different population characteristics and influenza seasonality remain limited., Methods: We conducted a test-negative study in Ontario, Canada. All influenza virus tests among infants <6 months from 2010 to 2019 were identified and linked with health databases to ascertain information on maternal-infant dyads. VE was estimated from the odds ratio for influenza vaccination during pregnancy among cases versus controls, computed using logistic regression with adjustment for potential confounders., Results: Among 23 806 infants tested for influenza, 1783 (7.5%) were positive and 1708 (7.2%) were born to mothers vaccinated against influenza during pregnancy. VE against laboratory-confirmed infant influenza infection was 64% (95% confidence interval [CI], 50%-74%). VE was similar by trimester of vaccination (first/second, 66% [95% CI, 40%-80%]; third, 63% [95% CI, 46%-74%]), infant age at testing (0 to <2 months, 63% [95% CI, 46%-75%]; 2 to <6 months, 64% [95% CI, 36%-79%]), and gestational age at birth (≥37 weeks, 64% [95% CI, 50%-75%]; < 37 weeks, 61% [95% CI, 4%-86%]). VE against influenza hospitalization was 67% (95% CI, 50%-78%)., Conclusions: Influenza vaccination during pregnancy offers effective protection to infants <6 months, for whom vaccines are not currently available., Competing Interests: Potential conflicts of interest . During the conduct of this work, D. B. F. worked for the University of Ottawa and had academic appointments at the Children's Hospital of Eastern Ontario Research Institute and ICES; she is currently employed by Pfizer. K. W. is a cofounder and Chief Scientific Officer of CANImmunize, Inc; he served on the Independent Data Monitoring Committee for Medicago; and is a member of the Moderna Global Advisory Core Consultancy Group. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

BackgroundWaning immunity from seasonal influenza vaccination can cause suboptimal protection during peak influenza activity. However, vaccine effectiveness studies assessing waning immunity using vaccinated and unvaccinated individuals are subject to biases.AimWe examined the association between time since vaccination and laboratory-confirmed influenza to assess the change in influenza vaccine protection over time.MethodsUsing linked laboratory and health administrative databases in Ontario, Canada, we identified community-dwelling individuals aged ≥ 6 months who received an influenza vaccine before being tested for influenza by RT-PCR during the 2010/11 to 2018/19 influenza seasons. We estimated the adjusted odds ratio (aOR) for laboratory-confirmed influenza by time since vaccination (categorised into intervals) and for every 28 days.ResultsThere were 53,065 individuals who were vaccinated before testing for influenza, with 10,264 (19%) influenza-positive cases. The odds of influenza increased from 1.05 (95% CI: 0.91-1.22) at 42-69 days after vaccination and peaked at 1.27 (95% CI: 1.04-1.55) at 126-153 days when compared with the reference interval (14-41 days). This corresponded to 1.09-times increased odds of influenza every 28 days (aOR = 1.09; 95% CI: 1.04-1.15). Individuals aged 18-64 years showed the greatest decline in protection against influenza A(H1N1) (aOR per 28 days  = 1.26; 95% CI: 0.97-1.64), whereas for individuals aged ≥ 65 years, it was against influenza A(H3N2) (aOR per 28 days  = 1.20; 95% CI: 1.08-1.33). We did not observe evidence of waning vaccine protection for individuals aged < 18 years.ConclusionsInfluenza vaccine protection wanes during an influenza season. Understanding the optimal timing of vaccination could ensure robust protection during seasonal influenza activity.

Background: Respiratory syncytial virus (RSV) infection poses a substantial clinical burden among infants and young children. We sought to determine the health care costs of hospitalizations attributable to RSV in Ontario, Canada, from the health care payer perspective., Methods: For this population-based matched cohort study, we identified children younger than 24 months who were or were not hospitalized with RSV infections in 2006-2016. We performed a cost-of-illness analysis using linked administrative health data, with subjects stratified by gestational age and congenital heart disease, and propensity score-matched on established risk factors. The primary outcome was attributable health care costs per patient, reflecting the difference in direct medical costs between the groups, calculated to 12 months postdischarge in 2020 Canadian dollars., Results: We identified 14 608 RSV-infected children, matched to 72 040 controls. The adjusted attributable cost of hospitalized RSV was $134 931 900 over 10 years, or $9240 per patient (95% confidence interval [CI] $8790-$9690). Health care costs escalated 3 days before hospitalization, and persisted up to 12 months after discharge. Increased costs were associated with major comorbidities, but not extreme premature birth. The highest mean attributable cost per patient was in the presence of hemodynamically significant heart disease ($60 110, 95% CI $26 700-$93 060). Infants born at 36-43 weeks' gestation constituted the greatest overall cost burden at $117 886 720., Interpretation: Although the greatest direct medical costs per patient hospitalized with RSV infection are among children with cardiac disease, the greatest overall cost burden is from children born at or near term, who are not targeted by current prophylaxis strategies. The substantial attributable health care costs of RSV can inform cost-effectiveness analyses of novel RSV vaccines and prioritization of health care resources., Competing Interests: Competing interests: Krista Lanctot reports grants from AbbVie Canada and stock from Highmark Interactive, outside the submitted work. J. Dayre McNally reports funding from the Canadian Institutes of Health Research, outside the submitted work. No other competing interests were declared., (© 2021 CMA Joule Inc. or its licensors.)

IntroductionAnnual influenza vaccination is recommended for older adults, but evidence regarding the impact of repeated vaccination has been inconclusive.AimWe investigated vaccine effectiveness (VE) against laboratory-confirmed influenza and the impact of repeated vaccination over 10 previous seasons on current season VE among older adults.MethodsWe conducted an observational test-negative study in community-dwelling adults aged > 65 years in Ontario, Canada for the 2010/11 to 2015/16 seasons by linking laboratory and health administrative data. We estimated VE using multivariable logistic regression. We assessed the impact of repeated vaccination by stratifying by previous vaccination history.ResultsWe included 58,304 testing episodes for respiratory viruses, with 11,496 (20%) testing positive for influenza and 31,004 (53%) vaccinated. Adjusted VE against laboratory-confirmed influenza for the six seasons combined was 21% (95% confidence interval (CI): 18 to 24%). Patients who were vaccinated in the current season, but had received no vaccinations in the previous 10 seasons, had higher current season VE (34%; 95%CI: 9 to 52%) than patients who had received 1-3 (26%; 95%CI: 13 to 37%), 4-6 (24%; 95%CI: 15 to 33%), 7-8 (13%; 95%CI: 2 to 22%), or 9-10 (7%; 95%CI: -4 to 16%) vaccinations (trend test p = 0.001). All estimates were higher after correcting for misclassification of current season vaccination status. For patients who were not vaccinated in the current season, residual protection rose significantly with increasing numbers of vaccinations received previously.ConclusionsAlthough VE appeared to decrease with increasing numbers of previous vaccinations, current season vaccination likely provides some protection against influenza regardless of the number of vaccinations received over the previous 10 influenza seasons.

Background: Linking data on laboratory specimens collected during clinical practice with health administrative data permits highly powered vaccine effectiveness (VE) studies to be conducted at relatively low cost, but bias from using convenience samples is a concern. We evaluated the validity of using such data for estimating VE., Methods: We created the Flu and Other Respiratory Viruses Research (FOREVER) Cohort by linking individual-level data on respiratory virus laboratory tests, hospitalizations, emergency department visits, and physician services. For community-dwelling adults aged > 65 years, we assessed the presence and magnitude of information and selection biases, generated VE estimates under various conditions, and compared our VE estimates with those from other studies., Results: We included 65,648 unique testing episodes obtained from 54,434 individuals during the 2010-11 to 2015-16 influenza seasons. To examine information bias, we found the proportion testing positive for influenza for patients with unknown interval from illness onset to specimen collection was more similar to patients for whom illness onset date was ≤ 7 days before specimen collection than to patients for whom illness onset was > 7 days before specimen collection. To assess the presence of selection bias, we found the likelihood of influenza testing was comparable between vaccinated and unvaccinated individuals, although the adjusted odds ratios were significantly greater than 1 for some healthcare settings and during some influenza seasons. Over 6 seasons, VE estimates ranged between 36% (95%CI, 27-44%) in 2010-11 and 5% (95%CI, -2, 11%) in 2014-15. VE estimates were similar under a range of conditions, but were consistently higher when accounting for misclassification of vaccination status through a quantitative sensitivity analysis. VE estimates from the FOREVER Cohort were comparable to those from other studies., Conclusions: Routinely collected laboratory and health administrative data contained in the FOREVER Cohort can be used to estimate influenza VE in community-dwelling older adults., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Respiratory illnesses are a major contributor to pediatric hospitalizations, with influenza and respiratory syncytial virus (RSV) causing substantial morbidity and cost each season. We compared the characteristics and outcomes of children 0-59 months of age who were hospitalized with laboratory-confirmed influenza or RSV between 2009 and 2014 in Ontario, Canada., Methods: We included hospitalized children who were tested for influenza A, influenza B and RSV and were positive for a single virus. We characterized individuals by their demographics and healthcare utilization patterns and compared their hospital outcomes, in-hospital cost and postdischarge healthcare use by virus type and by presence of underlying comorbidities., Results: We identified and analyzed 7659 hospitalizations during which a specimen tested positive for influenza or RSV. Children with RSV were the youngest whereas children with influenza B were the oldest [median ages 6 months (interquartile range: 2-17 months) and 25 months (interquartile range: 10-45 months), respectively]. Complex chronic conditions were more prevalent among children with all influenza (sub)types than RSV (31%-34% versus 20%). In-hospital outcomes were similar by virus type, but in children with comorbidities, postdischarge outcomes varied. We observed no differences in in-hospital cost between viruses or by presence of comorbidities [overall median cost: $4150 Canadian dollars (interquartile range: $3710-$4948)]., Conclusions: Influenza and RSV account for large numbers of pediatric hospitalizations. RSV and influenza were similar in terms of severity and cost in hospitalized children. Influenza vaccination should be promoted in pregnant women and young children, and a vaccine against RSV would mitigate the high burden of RSV.

Introduction: Pediatric shock is associated with significant morbidity and limited evidence suggests treatment with corticosteroids. The objective of this study was to describe practice patterns and outcomes associated with corticosteroid use in children with shock., Methods: We conducted a retrospective, cohort study in four pediatric intensive care units (PICU) in Canada. Patients aged newborn to 17 years admitted to PICU with shock between January 2010 and June 2011 were eligible., Results: 364 patients were included. The frequency of hydrocortisone administration was 22.3% overall (95% CI: 18.0, 26.5) and 59.4% in patients who received at least 60 cc/kg of fluid and were on two or more vasoactive agents. Patients administered hydrocortisone had higher PRISM scores (19, IQR 11-24 versus 9, IQR 5-16; P < 0.0001), higher inotrope scores (15, IQR 10-25 versus 7.5, IQR 3.3-10.6, P < 0.0001) and were more likely to have received 60 cc/kg of fluid resuscitation (59.3% versus 33.6%, OR 2.88, 95% CI: 2.09, 3.96). In an adjusted analysis, patients who received hydrocortisone spent more time on vasoactive infusions (64 versus 34  hours, hazard ratio 0.72, 95% CI: 0.62, 0.84) and had a higher incidence of positive cultures between day 4 and day 28 post admission (24.7% versus 14.5%, OR 1.79, 95% CI: 1.58, 2.04)., Conclusion: Hydrocortisone administration was associated with longer time on vasopressors and increased incidence of positive cultures even after correcting for illness severity. Caution should be exercised in administering hydrocortisone for shock until there is clear evidence for benefit in this patient population.