Clinical Presentations and Outcomes of Children in Canada With Recurrent Invasive Pneumococcal Disease From the IMPACT Surveillance Network.

BACKGROUND: Invasive pneumococcal disease due to Streptococcus pneumoniae can cause mortality and severe morbidity due to sepsis, meningitis and pneumonia, particularly in young children and the elderly. Recurrent invasive pneumococcal disease is rare yet serious sequelae of invasive pneumococcal disease that is associated with the immunocompromised and leads to a high mortality rate. METHOD: This retrospective study reviewed recurrent invasive pneumococcal disease cases from the Canadian Immunization Monitoring Program, ACTive (IMPACT) between 1991 and 2019, an active network for surveillance of vaccine-preventable diseases and adverse events following immunization for children ages 0-16 years. Data were collected from 12 pediatric tertiary care hospitals across all 3 eras of public pneumococcal conjugate vaccine implementation in Canada. RESULTS: The survival rate within our cohort of 180 recurrent invasive pneumococcal disease cases was 98.3%. A decrease of 26.4% in recurrent invasive pneumococcal disease due to vaccine serotypes was observed with pneumococcal vaccine introduction. There was also a 69.0% increase in the rate of vaccination in children with preexisting medical conditions compared with their healthy peers. CONCLUSION: The decrease in recurrent invasive pneumococcal disease due to vaccine-covered serotypes has been offset by an increase of non-vaccine serotypes in this sample of Canadian children.

Endothelial activation is associated with intestinal epithelial injury, systemic inflammation and treatment regimen in children living with vertically acquired HIV-1 infection.

BACKGROUND: Premature development of cardiovascular disease in children living with HIV-1 (CLWH) may be associated with compromised gut barrier function, microbial translocation, immune activation, systemic inflammation and endothelial activation. Biomarkers of these pathways may provide insights into pathogenesis of atherosclerotic disease in CLWH. METHODS: This was a cross-sectional study of CLWH enrolled in the multicentre Early Pediatric Initiation-Canadian Child Cure Cohort (EPIC4 ) who were on antiretroviral therapy (ART) with undetectable viral load. Plasma biomarkers of intestinal epithelial injury [intestinal fatty acid binding protein-1 (IFABP)], systemic inflammation [tumour necrosis factor (TNF) and interleukin-6 (IL-6)] and endothelial activation [angiopoietin-2 (Ang2), soluble vascular endothelial growth factor-1 (sVEGFR1) and soluble endoglin (sEng)] were quantified by enzyme-linked immunosorbent assay. Correlation and factor analysis of biomarkers were used to examine associations between innate immune pathways. RESULTS: Among 90 CLWH, 16% of Ang2, 15% of sVEGFR1 and 23% of sEng levels were elevated relative to healthy historic controls. Pairwise rank correlations between the three markers of endothelial activation were statistically significant (ρ = 0.69, ρ = 0.61 and ρ = 0.65, P < 0.001 for all correlations). An endothelial activation index, derived by factor analysis of the three endothelial biomarkers, was correlated with TNF (ρ = 0.47, P < 0.001), IL-6 (ρ = 0.60, P < 0.001) and intestinal fatty acid binding protein-1 (ρ = 0.67, P < 0.001). Current or past treatment with ritonavir-boosted lopinavir (LPV/r) was associated with endothelial activation (odds ratio = 5.0, 95% CI: 1.7-17, P = 0.0020). CONCLUSIONS: Endothelial activation is prevalent in CLWH despite viral suppression with combination ART and is associated with intestinal epithelial injury, systemic inflammation and treatment with LPV/r.

Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.

OBJECTIVE: Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. DESIGN: The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. SETTING: Paediatric HIV clinics. POPULATION: Live-born infants born in Canada to WLWH between 2007 and 2017. METHODS: Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. MAIN OUTCOME MEASURES: Congenital anomalies. RESULTS: Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). CONCLUSION: Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. TWEETABLE ABSTRACT: Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.

Summary of the NACI Seasonal Influenza Vaccine Statement for 2018-2019.

BACKGROUND: There are many different influenza vaccines authorized for use in Canada and new evidence on influenza and vaccines is emerging all the time. The National Advisory Committee on Immunization (NACI) provides recommendations annually regarding seasonal influenza vaccines to the Public Health Agency of Canada (PHAC). OBJECTIVE: To summarize the NACI recommendations regarding the use of seasonal influenza vaccines for the 2018-2019 influenza season in light of two NACI reviews conducted on 1) the risk of serious influenza-related complications in children and adults with neurologic and neurodevelopment conditions and 2) the efficacy/effectiveness of high-dose and adjuvanted inactivated influenza vaccines in persons 65 years of age and older. METHODS: For both topics, NACI's Influenza Working Group developed a predefined search strategy to identify all eligible studies, assessed their quality, summarized and analyzed the findings, proposed recommendations and identified the Grade of evidence that supported them. In light of the evidence, the recommendations were then considered and approved by NACI. RESULTS: NACI concludes there is fair evidence to recommend that children and adults with neurologic and neurodevelopment conditions are groups for whom influenza immunization is particularly recommended (Evidence Grade B recommendation). On choosing influenza vaccines for persons 65 years of age and older, at a programmatic level, NACI recommends that any of the four influenza vaccines available for use should be used. There is insufficient evidence to make a comparative recommendation on the use of these vaccines at a programmatic level (Grade I). At an individual level, NACI recommends that high-dose trivalent inactivated influenza vaccine (TIV) should be offered over standard-dose TIV to persons 65 years of age and older (Grade A). There is insufficient evidence to make comparative recommendations on the use of MF59-adjuvanted TIV and quadrivalent inactivated influenza vaccine over standard-dose TIV (Grade I). CONCLUSION: NACI continues to recommend annual influenza vaccination for all individuals aged six months and older, with particular focus on people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk, people who provide essential community services and people in direct contact during culling operations with poultry infected with avian influenza.

Summary of the NACI Statement on Seasonal Influenza Vaccine for 2017-2018.

BACKGROUND: Influenza is a respiratory infection caused primarily by influenza A and B viruses. Vaccination is the most effective way to prevent influenza and its complications. The National Advisory Committee on Immunization (NACI) provides recommendations regarding seasonal influenza vaccines annually to the Public Health Agency of Canada (PHAC). OBJECTIVE: To summarize the NACI recommendations regarding the use of seasonal influenza vaccines for the 2017-2018 influenza season. METHODS: Annual influenza vaccine recommendations are developed by NACI's Influenza Working Group for consideration and approval by NACI, based on NACI's evidence-based process for developing recommendations. The recommendations include a consideration of the burden of influenza illness and the target populations for vaccination; efficacy and effectiveness, immunogenicity and safety of influenza vaccines; vaccine schedules; and other aspects of influenza immunization. These recommendations are published annually on the Agency's website in the NACI Advisory Committee Statement: Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine (the Statement). RESULTS: The annual statement has been updated for the 2017-2018 influenza season to incorporate recommendations for the use of live attenuated influenza vaccine (LAIV) that were contained in two addenda published after the 2016-2017 statement. These recommendations were 1) that egg-allergic individuals may be vaccinated against influenza using the low ovalbumin-containing LAIV licensed for use in Canada and 2) to continue to recommend the use of LAIV in children and adolescents 2-17 years of age, but to remove the preferential recommendation for its use. CONCLUSION: NACI continues to recommend annual influenza vaccination for all individuals aged six months and older, with particular focus on people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk, and others as indicated.

The Canadian Immunization Monitoring Program, ACTive (IMPACT): Active surveillance for vaccine adverse events and vaccine-preventable diseases.

For almost 25 years the Canadian Immunization Monitoring Program, ACTive (IMPACT) has been conducting active surveillance for severe adverse events following immunization (AEFIs) and vaccine-preventable diseases in children. The network, which consists of volunteer paediatric infectious diseases investigators at 12 tertiary care paediatric hospitals, is an important component of Canada's AEFI monitoring. The network employs nurses at each of the sites to search for and report possible AEFIs to local, provincial and national public health authorities. The active nature of the surveillance ensures a high level of vigilance for severe AEFIs in children.

Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients.

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients < or =2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 x body surface area x creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 +/- 11.9 microg * h/mL; liver 61.7 +/- 29.5 microg * h/mL; heart 58.0 +/- 21.8 microg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults.

Case report and literature review of late-onset group B streptococcal disease manifesting as necrotizing fasciitis in preterm infants: is this a new syndrome?

We describe a 5-month-old preterm female infant who presented with necrotizing fasciitis involving the face and neck caused by group B streptococcus (GBS). Because of the extent and anatomic location of the necrosis, surgical debridement was delayed for 16 days, but the infant survived. Review of the literature demonstrated that 3 of the 10 previously reported cases of necrotizing fasciitis caused by GBS involved preterm infants and that 2 of these cases also involved the head and neck.

Reduced susceptibility to penicillin among pneumococci causing invasive infection in children - Canada, 1991 to 1998.

OBJECTIVE: To determine, over time, the rate and serotypes of pneumococci with reduced penicillin susceptibility obtained from children with invasive infection. DESIGN: Active, hospital-based, multicentre surveillance spanning from 1991 to 1998. SETTING: Eleven Canadian tertiary care paediatric facilities located from coast to coast. POPULATION STUDIED: 1847 children with invasive pneumococcal infection whose isolates (from a normally sterile site) were available for serotyping and standardized testing for penicillin susceptibility at the National Centre for Streptococcus. MAIN RESULTS: The prevalence of reduced penicillin susceptibility increased from 2.5% of 197 cases in 1991 to 13.0% of 276 cases in 1998. In the latter year, 8.7% of isolates had intermediate level resistance, and 4.3% had high level resistance. Since they were first detected in 1992, strains with high level resistance have been encountered only sporadically at most centres, but by 1998, all centres but two had encountered examples. Of 40 isolates with high level resistance and 101 isolates with intermediate level resistance, serotypes matched those included in new seven-valent conjugate vaccines for children in 97.5% and 79.2% of cases, respectively. CONCLUSIONS: Pneumococci with reduced susceptibility to penicillin are increasing in frequency across Canada among children with invasive infection. The Immunization Monitoring Program, Active data indicate that new conjugate vaccines could help to curb infections due to pneumococci with reduced susceptibility to penicillin but are unlikely to control completely the problem of antibiotic resistance.

The Immunization Monitoring Program Active (IMPACT) prospective five year study of Canadian children hospitalized for chickenpox or an associated complication.

BACKGROUND: Varicella vaccine was approved for use in Canada in 1998. A major goal of universal varicella vaccine programs is to reduce severe infection and associated complications. Baseline data are essential against which to judge the effectiveness of routine childhood immunization. OBJECTIVE: To describe morbidity and mortality among children hospitalized for chickenpox. Methods. From January 1, 1991, to March 31, 1996, chickenpox admissions to 11 pediatric referral centers were actively identified. Patient and illness characteristics were compared for 3 subgroups defined by prior health: healthy; unhealthy but immunocompetent; immunocompromised. RESULTS: Of 861 cases 488 (56.7%) were healthy, 75(8.7%) were unhealthy and 298 (34.6%) were immunocompromised. The immunocompromised children differed from healthy/unhealthy cases in mean age (6.4 vs. 4.0/4.6 years, respectively, P < 0.0001); median interval from rash onset to admission (2 vs. 5/5 days, P < 0.0001); complication rate (20% vs. 90%/79%; P = 0.001); and rate of acyclovir therapy (98% vs. 24%/39%; P = 0.001). Unhealthy vs. healthy cases had a higher frequency (P < 0.01) of intensive care (13.3% vs. 4.7%), ventilation (9.3% vs. 2.0%) and death (4% vs. 0.2%). CONCLUSION: These data provide a baseline for morbidity/mortality resulting from chickenpox before varicella vaccine use in Canada.

Population-based surveillance of Hib invasive infections in children in British Columbia Alberta and Ontario - 1995 to 1997.

OBJECTIVE: To assess vaccine effectiveness through enhanced disease surveillance following the change in childhood immunization programs in 1995, when all provinces and territories chose to use polyribosyl ribitol phosphate-tetanus protein (PRP-T) Haemophilus influenzae type b (Hib) conjugate vaccine, generally in combination with diphtheria-pertussis-tetanus inactivated polio vaccine (DPT-IPV) (as PENTA vaccine) because the protective efficacy of this regimen had not been directly measured. DESIGN: Prospective, active, laboratory-based Hib case surveillance was implemented in British Columbia and Alberta, and enhanced, stimulated laboratory surveillance in Ontario during 1995 to 1997, centred on invasive infections in children. Case details and immunization histories were uniformly collected and centrally collated. MAIN RESULTS: Thirty-eight Hib cases were detected, but only 12 cases arose among PENTA-eligible children, an attack rate of 0.85 cases/100,000 child-years of observation. Annual case totals declined from 20 in 1995 to seven in 1997, when only one to three cases were encountered in each province and the incidence rate in children under age five years was 0.6/100,000. Only four cases occurred after primary immunization with PENTA, a failure rate of 0.28 cases/100,000 child-years of observation. Three cases among PENTA-eligible children reflected parental refusal of infant vaccinations, accounting for 25% of cases in eligible children. CONCLUSIONS: PRP-T conjugate vaccine was highly effective when given in combination with DPT-IPV vaccine. Provincial programs that used this regimen resulted in the near elimination of invasive Hib disease in children, but unimmunized children remain at risk.

Epidemiological features of pertussis in hospitalized patients in Canada, 1991-1997: report of the Immunization Monitoring Program--Active (IMPACT).

To assess the morbidity associated with the continued high levels of pertussis, we studied all children <2 years of age who were admitted to the 11 Immunization Monitoring Program--Active (IMPACT) centers, which constitute 85% of Canada's tertiary care pediatric beds. In the 7 years preceding implementation of acellular pertussis vaccine, a total of 1,082 pertussis cases were reported, of which 49.1% were culture-confirmed. The median age of the patients was 12.4 weeks; 78.9% of cases were in children <6 months of age. Complications of pertussis were common: pneumonia was reported in 9.4% of cases, new seizures in 2.3%, and encephalopathy in 0.5%. There were 10 deaths (0.9%), all in children < or =6 months of age. Duration of hospitalization was longer (9.3 days vs. 4.9 days; P = .001) and intensive care was required more frequently (19.2% vs. 4.9%; P = .001) in infants under <6 months of age than in those > or =6 months. Pertussis continues to cause significant morbidity and occasional mortality in Canada, particularly in young infants.